Trial Outcomes & Findings for Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects (NCT NCT00631371)

Last Updated: 2016-04-27

Results Overview

PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by independent imaging reviewers using Response Evaluation Criteria in Solid Tumors (RECIST) criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the lowest blood counts); measurable increase in non-target lesion; appearance of new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

791 participants

Primary outcome timeframe

Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Results posted on

2016-04-27

Participant Flow

Approximately 800 participants enrolled in this study at 200 sites.

Participants were randomized in a 1:1 ratio, stratified by prior nephrectomy status (yes/no) and Memorial Sloan Kettering Cancer Center (MSKCC) risk factors (good/intermediate/poor), and received either the combination treatment of Temisirolimus + Bevacizumab (Temsr+Bev) or Interferon-alfa + Bevacizumab (IFN+Bev).

Participant milestones

Participant milestones
Measure	Bevacizumab+Temsirolimus Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Overall Study STARTED	400	391
Overall Study Treated	393	391
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	400	391

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab+Temsirolimus Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Overall Study Lost to Follow-up	24	19
Overall Study Other reason	5	12
Overall Study subject request	38	45
Overall Study Discontinuation of study by Sponsor	70	76
Overall Study Death	263	239

Baseline Characteristics

Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab+Temsirolimus n=400 Participants Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa n=391 Participants Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Total n=791 Participants Total of all reporting groups
Age, Continuous	58.6 years STANDARD_DEVIATION 10.1 • n=99 Participants	58.2 years STANDARD_DEVIATION 10.4 • n=107 Participants	58.4 years STANDARD_DEVIATION 10.2 • n=206 Participants
Sex: Female, Male Female	114 Participants n=99 Participants	121 Participants n=107 Participants	235 Participants n=206 Participants
Sex: Female, Male Male	286 Participants n=99 Participants	270 Participants n=107 Participants	556 Participants n=206 Participants

PRIMARY outcome

Timeframe: Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Population: Intent-to-treat (ITT) population included all participants who were randomized to the study.

Outcome measures

Outcome measures
Measure	Bevacizumab+Temsirolimus n=400 Participants Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa n=391 Participants Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Progression-Free Survival (PFS): Independent-Assessment	9.1 months Interval 8.1 to 10.2	9.3 months Interval 9.0 to 11.2

SECONDARY outcome

Timeframe: Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Population: ITT population included all participants who were randomized to the study.

PFS was defined as the interval from the date of randomization until the earlier date of progression or death. Progression was assessed by investigator imaging reviewers using RECIST criteria which is 20% increase in sum of longest diameter of target lesions from nadir (the lowest blood counts); measurable increase in non-target lesion; appearance of new lesions.

Outcome measures

Outcome measures
Measure	Bevacizumab+Temsirolimus n=400 Participants Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa n=391 Participants Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Progression-Free Survival (PFS): Investigator-Assessment	9.1 months Interval 8.1 to 10.5	10.8 months Interval 9.1 to 11.2

SECONDARY outcome

Timeframe: Baseline until disease progression, initiation of new anticancer treatment, or death, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Population: ITT population included all participants who were randomized to the study.

Percentage of participants with OR based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST. Confirmed response were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30% decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent.

Outcome measures

Outcome measures
Measure	Bevacizumab+Temsirolimus n=400 Participants Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa n=391 Participants Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Percentage of Participants With Objective Response (Complete Response/Partial Response): Independent-Assessment	27.0 percentage of participants Interval 22.7 to 31.6	27.4 percentage of participants Interval 23.0 to 32.1

SECONDARY outcome

Timeframe: Baseline until death due to any cause, assessed every 8 weeks (up to cut-off date: 19 April 2012)

Population: ITT population included all participants who were randomized to the study.

OS was defined as the time from randomization to death due to any cause, censored at the last date known alive. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).

Outcome measures

Outcome measures
Measure	Bevacizumab+Temsirolimus n=400 Participants Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa n=391 Participants Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Overall Survival (OS)	25.8 months Interval 21.1 to 30.7	25.5 months Interval 22.4 to 30.8

Adverse Events

Bevacizumab+Temsirolimus

Serious events: 184 serious events

Other events: 383 other events

Deaths: 0 deaths

Bevacizumab+ Interferon-Alfa

Serious events: 158 serious events

Other events: 378 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Bevacizumab+Temsirolimus n=393 participants at risk Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa n=391 participants at risk Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Blood and lymphatic system disorders Anaemia	2.5% 10/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.1% 12/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Disseminated intravascular coagulation	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Neutropenia	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Acute coronary syndrome	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Acute myocardial infarction	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Angina pectoris	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Atrial fibrillation	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac failure	0.76% 3/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiac valve disease	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Cardiopulmonary failure	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Coronary artery disease	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Coronary ostial stenosis	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Cardiac disorders Left ventricular dysfunction	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Ear and labyrinth disorders Vertigo	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Retinopathy	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.51% 2/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Eye disorders Vitreous floaters	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	2.0% 8/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.5% 6/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Anal fissure	0.51% 2/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Anal fistula	0.51% 2/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.51% 2/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Anal haemorrhage	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Ascites	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Colitis	0.51% 2/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	1.8% 7/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	1.3% 5/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastric fistula	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastric ulcer haemorrhage	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastritis	0.51% 2/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrointestinal perforation	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Haemorrhoids	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Ileal perforation	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Ileus	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Ileus paralytic	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Intestinal haemorrhage	0.00% 0/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Intestinal obstruction	0.51% 2/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.00% 0/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Intestinal perforation	0.25% 1/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Large intestine perforation	0.51% 2/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	0.26% 1/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Other adverse events
Measure	Bevacizumab+Temsirolimus n=393 participants at risk Bevacizumab 10 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with temsirolimus 25 mg intravenous infusion over at least 30 minutes once a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.	Bevacizumab+ Interferon-Alfa n=391 participants at risk Bevacizumab 10 mg/kg intravenous infusion over 90 minutes, 60 minutes or 30 minutes depending on the participant's tolerability every other week along with interferon-alfa (IFN) 9 million units (MU) subcutaneous injection every 3 times a week. Treatment was continued until disease progression, unacceptable toxicities, withdrawal of consent, or death.
Blood and lymphatic system disorders Anaemia	20.4% 80/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	16.9% 66/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Leukopenia	4.3% 17/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.2% 40/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Lymphopenia	6.1% 24/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	9.7% 38/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Neutropenia	4.6% 18/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	16.9% 66/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Blood and lymphatic system disorders Thrombocytopenia	12.7% 50/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.2% 40/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	12.2% 48/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.7% 42/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain upper	7.9% 31/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.4% 21/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	10.9% 43/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.3% 48/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	32.1% 126/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	22.0% 86/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gingival bleeding	1.3% 5/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.4% 21/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Haemorrhoids	7.1% 28/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.3% 13/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	17.6% 69/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	19.9% 78/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Stomatitis	26.0% 102/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.0% 39/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Toothache	9.4% 37/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.6% 14/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Vomiting	13.5% 53/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	13.6% 53/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Asthenia	24.2% 95/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	28.9% 113/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Chills	3.8% 15/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	11.3% 44/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Fatigue	23.4% 92/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	31.2% 122/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Influenza like illness	3.6% 14/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.3% 48/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Mucosal inflammation	26.7% 105/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.2% 40/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	17.0% 67/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	8.2% 32/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
General disorders Pyrexia	20.1% 79/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	39.4% 154/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Upper respiratory tract infection	5.1% 20/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.8% 15/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Infections and infestations Urinary tract infection	5.9% 23/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.4% 21/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Alanine aminotransferase increased	9.7% 38/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	9.0% 35/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Aspartate aminotransferase increased	8.4% 33/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.5% 41/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Blood creatinine increased	10.2% 40/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	6.4% 25/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Investigations Weight decreased	22.9% 90/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	23.8% 93/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Decreased appetite	26.2% 103/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	32.5% 127/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypercholesterolaemia	32.1% 126/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	10.0% 39/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperglycaemia	21.9% 86/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.9% 19/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyperkalaemia	7.4% 29/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	9.5% 37/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypertriglyceridaemia	29.0% 114/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	21.0% 82/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypocalcaemia	6.1% 24/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	3.3% 13/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypomagnesaemia	5.1% 20/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.1% 16/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hyponatraemia	5.9% 23/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.4% 21/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypophosphataemia	10.2% 40/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	4.6% 18/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Arthralgia	13.2% 52/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	12.5% 49/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Back pain	12.0% 47/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	13.6% 53/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Musculoskeletal and connective tissue disorders Bone pain	4.6% 18/393 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.	5.6% 22/391 • Adverse events were collected and reported from the signing of the informed consent until end of treatment but no later than 30 days after the last dose of study medication. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.