Trial Outcomes & Findings for Safety and Efficacy Study of ULTRASE® MT20 in Participants With Cystic Fibrosis (CF) and Exocrine Pancreatic Insufficiency (PI) (NCT NCT00408317)

Last Updated: 2017-03-16

Results Overview

Percent (%) CFA was calculated as (\[fat intake - fat excretion\]/fat intake)\*100, determined by the stools collected during the 72-hour period which could extend to 96 hours during both intervention periods. Mean CFA percent was calculated for 72-hour/96-hour period during Day 3 to Day 7 in the first and second intervention periods.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

36 participants

Primary outcome timeframe

Day 3 to Day 7 in first intervention period and second intervention period

Results posted on

2017-03-16

Participant Flow

Participants with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI) were recruited from centers with CF specialists.

Out of 36 participants who entered the screening period (11 days), and treated with Ultrase® MT20, 31 were randomized to first intervention period.

Participant milestones

Participant milestones
Measure	Ultrase® MT20 First, Then Placebo Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in the first intervention period followed by placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in the second intervention period. Break period of 3 to 6 days and fixed dose second stabilization period of 4 days was maintained after first intervention period.	Placebo First, Then Ultrase®MT20 Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in the first intervention period followed by Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in the second intervention period. Break period of 3 to 6 days and fixed dose second stabilization period of 4 days was maintained after first intervention period.
First Intervention Period STARTED	14	17
First Intervention Period COMPLETED	14	16
First Intervention Period NOT COMPLETED	0	1
Second Intervention Period STARTED	14	16
Second Intervention Period COMPLETED	12	14
Second Intervention Period NOT COMPLETED	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Ultrase® MT20 First, Then Placebo Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in the first intervention period followed by placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in the second intervention period. Break period of 3 to 6 days and fixed dose second stabilization period of 4 days was maintained after first intervention period.	Placebo First, Then Ultrase®MT20 Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in the first intervention period followed by Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in the second intervention period. Break period of 3 to 6 days and fixed dose second stabilization period of 4 days was maintained after first intervention period.
First Intervention Period Adverse Event	0	1
Second Intervention Period Adverse Event	2	0
Second Intervention Period Protocol Violation	0	1
Second Intervention Period Withdrawal of consent	0	1

Baseline Characteristics

Safety and Efficacy Study of ULTRASE® MT20 in Participants With Cystic Fibrosis (CF) and Exocrine Pancreatic Insufficiency (PI)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Entire Study Population n=31 Participants Includes all participants who received Ultrase® MT20 first and placebo first.
Age, Continuous	19.6 years STANDARD_DEVIATION 6.6 • n=99 Participants
Sex: Female, Male Female	11 Participants n=99 Participants
Sex: Female, Male Male	20 Participants n=99 Participants

PRIMARY outcome

Timeframe: Day 3 to Day 7 in first intervention period and second intervention period

Population: Intent-to-Treat (ITT) population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.

Outcome measures

Outcome measures
Measure	Ultrase® MT20 n=25 Participants Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo n=27 Participants Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Percent Coefficient of Fat Absorption (CFA)	88.55 Percent CFA Standard Deviation 4.94	55.61 Percent CFA Standard Deviation 25.10

SECONDARY outcome

Timeframe: Day 3 to Day 7 in first intervention period and second intervention period

Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.

Percent (%) CNA was calculated as \[(nitrogen intake-nitrogen excretion)/nitrogen intake\]\*100, determined by the stools collected during the 72-hour period which could extend to 96 hours during both intervention periods. Nitrogen intake was calculated as protein intake/6.25. Mean percent CNA was calculated for 72-hour/96-hour period during Day 3 to Day 7 in the first and second intervention periods.

Outcome measures

Outcome measures
Measure	Ultrase® MT20 n=25 Participants Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo n=27 Participants Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Percent Coefficient of Nitrogen Absorption (CNA)	84.05 Percent CNA Standard Deviation 7.24	58.78 Percent CNA Standard Deviation 20.57

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 3 on first intervention period and second intervention period

Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.

Number of bowel movements of each participant was calculated from frequency of stools by the participant per day. Mean daily number of bowel movements on Day 3 for the first treatment period and second treatment period was summarized.

Outcome measures

Outcome measures
Measure	Ultrase® MT20 n=29 Participants Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo n=30 Participants Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Number of Bowel Movements	1.5 bowel movements Standard Deviation 1.0	3.1 bowel movements Standard Deviation 1.8

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 4 on first intervention period and second intervention period

Population: ITT population included all randomized participants. Here, 'N' (number of participants analyzed) signifies those participants who were evaluated for this outcome measure.

Stool consistency was categorized as hard, formed/normal, soft or watery stool. Percentage of stools of a specific consistency of each participant was calculated as the number of stools with a specific consistency relative to the total number of stools during the collection period. Mean percentage of stool with specific consistency on Day 4 for the first treatment period and second treatment period period for total participants was summarized.

Outcome measures

Outcome measures
Measure	Ultrase® MT20 n=28 Participants Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion, for 6 to 7 days in either first intervention period or second intervention period.	Placebo n=28 Participants Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Percentage of Stool Categorized by Consistency Hard Stools	11.31 percentage of stools Standard Deviation 27.98	3.57 percentage of stools Standard Deviation 18.90
Percentage of Stool Categorized by Consistency Formed/Normal Stools	76.19 percentage of stools Standard Deviation 39.13	25.71 percentage of stools Standard Deviation 43.84
Percentage of Stool Categorized by Consistency Soft Stools	12.50 percentage of stools Standard Deviation 29.27	66.73 percentage of stools Standard Deviation 45.08
Percentage of Stool Categorized by Consistency Watery Stools	0 percentage of stools Standard Deviation 0	3.99 percentage of stools Standard Deviation 13.65

Adverse Events

Ultrase® MT20

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 27 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Ultrase® MT20 n=30 participants at risk Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion,for 6 to 7 days in either first intervention period or second intervention period.	Placebo n=31 participants at risk Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
General disorders General physical health deterioration	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
General disorders Pyrexia	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Investigations Breath sounds abnormal	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Investigations Pulmonary function test decreased	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Respiratory, thoracic and mediastinal disorders Productive cough	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Respiratory, thoracic and mediastinal disorders Rales	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.

Other adverse events

Additional Information

Robert Winkler, MD, VP, Clinical Development and Operations

Aptalis Pharma US, Inc.

Phone: 1-800-472-2634

Results disclosure agreements

Principal investigator is a sponsor employee Restrictions may vary in accordance with each agreement that is negotiated with individual investigators. Sponsor will allow publication after multi-center publication has been published or after an agreed period of time if no such multi-center publication is submitted for publication. Sponsor can ask that Sponsor's confidential information be removed from any publication and defer publication for period of time to allow Sponsor to obtain patent or other intellectual property right protection.
Publication restrictions are in place

Restriction type: OTHER

Measure	Ultrase® MT20 n=30 participants at risk Ultrase® MT 20 capsules containing enteric-coated minitablets orally daily at a dose stabilized during the first stabilization period (4 days), as per investigator's discretion,for 6 to 7 days in either first intervention period or second intervention period.	Placebo n=31 participants at risk Placebo matched to Ultrase® MT 20 capsules orally daily for 6 to 7 days in either first intervention period or second intervention period.
Gastrointestinal disorders Abdominal pain	6.7% 2/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	38.7% 12/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Gastrointestinal disorders Abdominal pain upper	13.3% 4/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	19.4% 6/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Gastrointestinal disorders Constipation	6.7% 2/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	6.5% 2/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Gastrointestinal disorders Flatulence	3.3% 1/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	16.1% 5/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Investigations Alaninie aminotransferase increased	3.3% 1/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	6.5% 2/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Investigations Fecal fat increased	13.3% 4/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	29.0% 9/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Investigations Weight decreased	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	9.7% 3/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Gastrointestinal disorders Abdominal tenderness	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	6.5% 2/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Gastrointestinal disorders Diarrhoea	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	9.7% 3/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Gastrointestinal disorders Nausea	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	16.1% 5/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Gastrointestinal disorders Vomiting	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	9.7% 3/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Investigations Blood glucose increased	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	6.5% 2/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Investigations Laboratory test abnormal	10.0% 3/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	22.6% 7/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Nervous system disorders Headache	6.7% 2/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	6.7% 2/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Respiratory, thoracic and mediastinal disorders Rales	6.7% 2/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	3.2% 1/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	3.3% 1/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	9.7% 3/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	6.5% 2/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.
Vascular disorders Epistaxis	6.7% 2/30 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.	0.00% 0/31 • Day 1 of first stabilization period up to Day 7 of second intervention period Adverse event (AE) was defined as any untoward medical occurrence regardless of causal relationship to study medication. Serious adverse event (SAE) was any event that resulted in death, life threatening, required or prolonged in-patient hospitalization, significant disability/incapacity,or was a congenital anomaly/birth defect.