Trial Outcomes & Findings for CSP #562 - The VA Keratinocyte Carcinoma Chemoprevention Trial (NCT NCT00847912)

Last Updated: 2021-06-11

Results Overview

Diagnosis of the first Primary Basil Cell Carcinoma (BCC) or primary Squamous Cell Carcinoma (SCC) on the face or ears that was removed surgically.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

954 participants

Primary outcome timeframe

From randomization to last visit prior to end of study date (6/30/2013), assessed up to four years

Results posted on

2021-06-11

Participant Flow

Participant milestones

Participant milestones
Measure	Arm 1: 5-fluorouracil Group assigned to blinded 5-FU (5-fluorouracil) cream applied to face and ears twice daily for maximum of 56 doses 5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.	Arm 2: Placebo, Vehicle Control Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses Placebo, vehicle control: Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but vehicle control cream will be stopped.
Overall Study STARTED	477	477
Overall Study COMPLETED	468	464
Overall Study NOT COMPLETED	9	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm 1: 5-fluorouracil Group assigned to blinded 5-FU (5-fluorouracil) cream applied to face and ears twice daily for maximum of 56 doses 5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.	Arm 2: Placebo, Vehicle Control Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses Placebo, vehicle control: Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but vehicle control cream will be stopped.
Overall Study Protocol Violation	6	7
Overall Study Withdrawal by Subject	3	6

Baseline Characteristics

CSP #562 - The VA Keratinocyte Carcinoma Chemoprevention Trial

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm 1: 5-fluorouracil n=468 Participants Group assigned to blinded 5-FU (5-fluorouracil) cream applied to face and ears twice daily for maximum of 56 doses 5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.	Arm 2: Placebo, Vehicle Control n=464 Participants Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses Placebo, vehicle control: Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but vehicle control cream will be stopped.	Total n=932 Participants Total of all reporting groups
Age, Continuous	70.7 years STANDARD_DEVIATION 9.2 • n=99 Participants	71.5 years STANDARD_DEVIATION 9.4 • n=107 Participants	71.1 years STANDARD_DEVIATION 9.3 • n=206 Participants
Sex: Female, Male Female	11 Participants n=99 Participants	5 Participants n=107 Participants	16 Participants n=206 Participants
Sex: Female, Male Male	457 Participants n=99 Participants	459 Participants n=107 Participants	916 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=99 Participants	5 Participants n=107 Participants	9 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	464 Participants n=99 Participants	459 Participants n=107 Participants	923 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) White	455 Participants n=99 Participants	457 Participants n=107 Participants	912 Participants n=206 Participants
Race (NIH/OMB) More than one race	10 Participants n=99 Participants	4 Participants n=107 Participants	14 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=99 Participants	2 Participants n=107 Participants	4 Participants n=206 Participants
Region of Enrollment United States	468 participants n=99 Participants	464 participants n=107 Participants	932 participants n=206 Participants

PRIMARY outcome

Timeframe: From randomization to last visit prior to end of study date (6/30/2013), assessed up to four years

Diagnosis of the first Primary Basil Cell Carcinoma (BCC) or primary Squamous Cell Carcinoma (SCC) on the face or ears that was removed surgically.

Outcome measures

Outcome measures
Measure	Arm 1: 5-fluorouracil n=468 Participants Group assigned to blinded 5-fluorouracil (5-FU) cream applied to face and ears twice daily for maximum of 56 doses 5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.	Arm 2: Placebo, Vehicle Control n=464 Participants Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses Placebo, vehicle control: Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but vehicle control cream will be stopped.
The Time to Diagnosis of the First Keratinocyte Carcinoma (KC) on the Face or Ears for Which Surgery is Performed	3.37 years Interval 3.21 to Upper 95% confidence interval could not be estimated due to an insufficient number of participants with events	3.52 years Interval 3.08 to 3.7

PRIMARY outcome

Timeframe: date of randomization to last visit before end of study follow up (6/30/2013), assessed up to four years

Outcome measures

Outcome measures
Measure	Arm 1: 5-fluorouracil n=468 Participants Group assigned to blinded 5-fluorouracil (5-FU) cream applied to face and ears twice daily for maximum of 56 doses 5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.	Arm 2: Placebo, Vehicle Control n=464 Participants Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses Placebo, vehicle control: Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but vehicle control cream will be stopped.
Hazard Ratio for Surgically Treated KC	182 participants	177 participants

Adverse Events

Arm 1: 5-fluorouracil

Serious events: 190 serious events

Other events: 451 other events

Deaths: 0 deaths

Arm 2: Placebo

Serious events: 190 serious events

Other events: 227 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Martin Weinstock MD, PhD

Providence VA mendical Center

Phone: 401-457-3333

Email: [email protected]; [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Arm 1: 5-fluorouracil n=468 participants at risk Group assigned to blinded 5-FU (5-fluorouracil) cream applied to face and ears twice daily for maximum of 56 doses 5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.	Arm 2: Placebo n=464 participants at risk Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses Placebo, vehicle control: Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but vehicle control cream will be stopped.
Blood and lymphatic system disorders Anaemia	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Blood and lymphatic system disorders Leukocytosis	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Blood and lymphatic system disorders Retroperitoneal lymphadenopathy	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Acute coronary syndrome	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.86% 4/464 • Number of events 4 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Acute myocardial infarction	0.64% 3/468 • Number of events 3 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	1.1% 5/464 • Number of events 5 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Angina pectoris	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Angina unstable	1.1% 5/468 • Number of events 5 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Aortic valve disease	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Aortic valve incompetence	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Aortic valve stenosis	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Arrhythmia	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Arteriosclerosis coronary artery	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Atrial fibrillation	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	2.8% 13/464 • Number of events 16 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Atrial flutter	0.64% 3/468 • Number of events 3 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Atrial tachycardia	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Atrial thrombosis	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Atrioventricular block	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Atrioventricular block first degree	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Bradycardia	0.43% 2/468 • Number of events 3 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.65% 3/464 • Number of events 4 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Cardiac arrest	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Cardiac disorder	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Cardiac failure	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Cardiac failure congestive	1.5% 7/468 • Number of events 11 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	1.5% 7/464 • Number of events 8 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Cardiomyopathy	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Cardio-respiratory arrest	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Coronary artery disease	1.1% 5/468 • Number of events 6 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	3.0% 14/464 • Number of events 17 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Coronary artery stenosis	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Left ventricular dysfunction	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Mitral valve incompetence	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Myocardial infarction	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	1.5% 7/464 • Number of events 7 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Myocardial ischaemia	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Palpitations	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Pericarditis	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Sick sinus syndrome	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Supraventricular tachycardia	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.65% 3/464 • Number of events 4 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Tachycardia	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Ventricular tachycardia	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 3 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Congenital, familial and genetic disorders Haemorrhagic arteriovenous malformation	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Congenital, familial and genetic disorders Heart disease congenital	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.

Other adverse events
Measure	Arm 1: 5-fluorouracil n=468 participants at risk Group assigned to blinded 5-FU (5-fluorouracil) cream applied to face and ears twice daily for maximum of 56 doses 5-fluorouracil: Apply thin layer of topical 5-FU 5% cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily 5-FU, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping 5-FU, if and only if the participant has not received at least the minimum 2 week (28 dose) course, 5-FU treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but 5-FU will be stopped.	Arm 2: Placebo n=464 participants at risk Group assigned to blinded placebo, vehicle control cream applied to face and ears twice daily for maximum of 56 doses Placebo, vehicle control: Apply thin layer of vehicle control cream twice daily to face and ears for 4 weeks. Treatment to be initiated immediately after randomization. If unable to tolerate the twice daily vehicle control cream, they will discontinue the treatment and initiate "cool-down" treatment with triamcinolone 0.1% cream twice daily until the symptoms resolve. At 3 weeks after stopping vehicle control cream, if and only if the participant has not received at least the minimum 2 week (28 dose) course, vehicle control cream treatment will be resumed on a once-daily basis to complete the 56 dose course. If this is not tolerated, the "cool-down" routine will be followed, but vehicle control cream will be stopped.
Blood and lymphatic system disorders Anaemia	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Blood and lymphatic system disorders Lymphadenopathy	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Bradycardia	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Cardiac disorders Coronary artery disease	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Ear and labyrinth disorders Ear congestion	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Ear and labyrinth disorders Ear pain	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Ear and labyrinth disorders Vertigo	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Endocrine disorders Adrenal mass	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Eye haemorrhage	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Eye irritation	0.64% 3/468 • Number of events 3 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Eye pain	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Eye pruritus	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Eye swelling	0.85% 4/468 • Number of events 4 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Eyelid ptosis	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Iris cyst	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Photophobia	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Eye disorders Visual acuity reduced	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Abdominal discomfort	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Abdominal pain	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Abdominal pain upper	0.43% 2/468 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Cheilitis	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Constipation	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Diarrhoea	0.64% 3/468 • Number of events 4 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Diverticulum	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Dyspepsia	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Gastritis	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Gingival pain	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Nausea	1.1% 5/468 • Number of events 5 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Oral discomfort	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Stomatitis	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Tooth loss	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.43% 2/464 • Number of events 2 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
Gastrointestinal disorders Vomiting	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.65% 3/464 • Number of events 3 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
General disorders Chest discomfort	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
General disorders Device occlusion	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
General disorders Fatigue	0.64% 3/468 • Number of events 3 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
General disorders Feeling of body temperature change	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
General disorders Hernia	0.21% 1/468 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.00% 0/464 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.
General disorders Impaired healing	0.00% 0/468 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.	0.22% 1/464 • Number of events 1 • Active monitoring of Adverse Events and Serious Adverse Events began when the participant signed the Consent Form. Adverse Event data collection ended when the participant ended study participation, and Serious Adverse Event data collection continued until 30 days after study participation ended, assessed up to four years. Adverse events collected were those related to the study intervention. Data on adverse events were collected spontaneously through patient reports, actively elicited at each clinic visit through open ended questionings and examination, and gathered at the time of telephone contact during the therapy period. All serious adverse events were collected, including those considered related and unrelated to the study interventions.Subjects were monitored for SAE at each study visit and telephone call.