Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) in Patients With Non-Squamous Non-Small Cell Lung Cancer With Asymptomatic Untreated Brain Metastasis (NCT NCT00800202)

Last Updated: 2014-11-19

Results Overview

Tumor progression was defined according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 as increase by at least 20% in the sum of the longest diameters of each target lesion, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. PFS (investigator assessed) was defined as the time between the first dose of study treatment and the first event of progression or death by any cause. Participants without an event were censored the last time they were known to be progression free. PFS was analyzed using the Kaplan-Meier method in each treatment arm.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

91 participants

Primary outcome timeframe

6 months

Results posted on

2014-11-19

Participant Flow

Participant milestones

Participant milestones
Measure	Bevacizumab+Paclitaxel+Carboplatin Participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (iv) every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 milligrams per square meter (mg/m\^2) iv every 3 weeks for 6 cycles and carboplatin Area Under Curve (AUC) 6.0 milligrams per milliliter per minute (mg/mL/min) iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib150 milligrams per day (mg/day) administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Overall Study STARTED	67	24
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	67	24

Reasons for withdrawal

Reasons for withdrawal
Measure	Bevacizumab+Paclitaxel+Carboplatin Participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (iv) every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 milligrams per square meter (mg/m\^2) iv every 3 weeks for 6 cycles and carboplatin Area Under Curve (AUC) 6.0 milligrams per milliliter per minute (mg/mL/min) iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib150 milligrams per day (mg/day) administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Overall Study Adverse Event	7	6
Overall Study Death	1	0
Overall Study Other	5	0
Overall Study Disease Progression	54	18

Baseline Characteristics

A Study of Avastin (Bevacizumab) in Patients With Non-Squamous Non-Small Cell Lung Cancer With Asymptomatic Untreated Brain Metastasis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.	Total n=91 Participants Total of all reporting groups
Age, Continuous	60.37 years STANDARD_DEVIATION 8.31 • n=5 Participants	54.17 years STANDARD_DEVIATION 9.73 • n=7 Participants	58.74 years STANDARD_DEVIATION 9.07 • n=5 Participants
Sex: Female, Male Female	21 Participants n=5 Participants	13 Participants n=7 Participants	34 Participants n=5 Participants
Sex: Female, Male Male	46 Participants n=5 Participants	11 Participants n=7 Participants	57 Participants n=5 Participants

PRIMARY outcome

Timeframe: 6 months

Population: ITT Population

Outcome measures

Outcome measures
Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Percentage of Participants Achieving Progression-Free Survival (PFS) Without Disease Progression or Death at 6 Months	56.5 percentage of participants Interval 43.8 to 67.4	57.2 percentage of participants Interval 37.0 to 76.3

PRIMARY outcome

Timeframe: Screening, Day 1 of Cycles 3 and 5 and every 2 cycles until end of treatment visit or disease progression or death up to 18 months after enrollment of last participant

Population: ITT Population

Tumor progression was defined according to the RECIST criteria as increase by at least 20% in the sum of the longest diameters of each target lesion, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. PFS (investigator assessed) was defined as the time between the first dose of study treatment and the first event of progression or death by any cause. Participants without an event were censored the last time they were known to be progression free. PFS was analyzed using the Kaplan-Meier method in each treatment arm.

Outcome measures

Outcome measures
Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Percentage of Participants With Disease Progression or Death	89.6 percentage of participants	91.7 percentage of participants

PRIMARY outcome

Timeframe: Screening, Day 1 of Cycles 3 and 5 and every 2 cycles until end of treatment visit or disease progression or death up to 18 months after enrollment of last participant

Population: ITT Population; only participants with progression or death were included in the analysis.

Tumor progression was defined as increase by at least 20% in the sum of the longest diameters of each target lesion, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. Time to event was determined as the number of months between the first dose of study treatment and the first event of progression or death by any cause. PFS was analyzed using the Kaplan-Meier method in each treatment arm.

Outcome measures

Outcome measures
Measure	Bevacizumab+Paclitaxel+Carboplatin n=60 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=22 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Time to Disease Progression or Death	6.7 months Interval 5.7 to 7.1	6.3 months Interval 3.0 to 8.4

SECONDARY outcome

Timeframe: Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 3 weeks up to 18 months or until death

Population: ITT Population

Outcome measures

Outcome measures
Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Percentage of Participants Who Died	83.6 percentage of participants	91.7 percentage of participants

SECONDARY outcome

Timeframe: Months 12 and 18

Population: ITT Population

Outcome measures

Outcome measures
Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Probability of Being Alive at 12 and 18 Months 12 Months	64.2 percent Interval 51.5 to 74.4	50.0 percent Interval 30.5 to 69.5
Probability of Being Alive at 12 and 18 Months 18 Months	43.3 percent Interval 31.3 to 54.7	41.7 percent Interval 23.1 to 61.5

SECONDARY outcome

Timeframe: Day 1 of Cycles 1, 2, 3, 4, 5, 6 and every 3 weeks up to 18 months or until death

Population: ITT Population; only participants with an event of death were included in the analysis.

Time to death was determined as the number of months between the first dose of study treatment and the event of death by any cause. Overall survival was analyzed using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Bevacizumab+Paclitaxel+Carboplatin n=56 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=22 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Time to Death	16.0 months Interval 12.0 to 21.0	12.0 months Interval 8.9 to 20.2

SECONDARY outcome

Timeframe: Screening, Day 1 of Cycles 3 and 5 and every 2 cycles until end of treatment visit or disease progression or death up to 18 months after enrollment of last participant

Population: ITT Population

Overall response defined as best response according to RECIST recorded from date of randomization until disease progression or recurrence. Complete Response (CR): disappearance of all target lesions; Partial response (PR): reduction by at least 30 percent (%) of sum of the longest diameters of each target lesion, taking initial sum of longest diameters as a reference. Participants with a missing response were considered non-responders. 95% CI for one sample binomial using Pearson-Clopper method.

Outcome measures

Outcome measures
Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 Participants Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Percentage of Participants Achieving a Best Overall Response of Complete Response or Partial Response as Assessed by the Investigator Using RECIST	62.7 percentage of participants Interval 50.0 to 74.2	12.5 percentage of participants Interval 2.7 to 32.4

Adverse Events

Bevacizumab+Paclitaxel+Carboplatin

Serious events: 27 serious events

Other events: 67 other events

Deaths: 0 deaths

Bevacizumab+Erlotinib

Serious events: 7 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann- LaRoche

Phone: 1-800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The study being conducted under this agreement is part of the overall study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the study, but after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 participants at risk Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 participants at risk Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
Blood and lymphatic system disorders Neutropenia	23.9% 16/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Febrile neutropenia	4.5% 3/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Anaemia	3.0% 2/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Febrile bone marrow aplasia	3.0% 2/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Bicytopenia	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Thrombocytopenia	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
General disorders General physical health deterioration	3.0% 2/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
General disorders Hyperthermia	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
General disorders Injection site extravasation	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Cerebral haemorrhage	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Convulsion	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Epilepsy	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Somnolence	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Hypertensive encephalopathy	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Ischaemic stroke	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	3.0% 2/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Respiratory, thoracic and mediastinal disorders Lung disorder	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Infections and infestations Cellulitis	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Infections and infestations Urosepsis	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Infections and infestations Staphylococcal sepsis	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Renal and urinary disorders Glomerulonephropathy	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Renal and urinary disorders Urinary retention	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Renal and urinary disorders Haematuria	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Renal and urinary disorders Proteinuria	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Cardiac disorders Arrhythmia	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Diarrhoea	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Abdominal pain	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Oesophageal ulcer	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.
Hepatobiliary disorders Portal vein thrombosis	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Metabolism and nutrition disorders Hyperkalaemia	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Psychiatric disorders Anxiety	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Vascular disorders Peripheral artery thrombosis	1.5% 1/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Vascular disorders Hypertension	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	8.3% 2/24 • Adverse events were recorded from the date of randomization until end of study or death.
Injury, poisoning and procedural complications Post procedural haematoma	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	4.2% 1/24 • Adverse events were recorded from the date of randomization until end of study or death.

Measure	Bevacizumab+Paclitaxel+Carboplatin n=67 participants at risk Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with paclitaxel 200 mg/m\^2 iv every 3 weeks for 6 cycles and carboplatin: AUC 6.0 mg/mL/min iv every 3 weeks for 6 cycles. Bevacizumab was used in addition to standard first line chemotherapy.	Bevacizumab+Erlotinib n=24 participants at risk Participants received bevacizumab 15 mg/kg iv every 3 weeks until progression or unacceptable toxicity along with erlotinib 150 mg/day administered as tablets orally until progression or unacceptable toxicity. Bevacizumab was used as second-line treatment in addition to erlotinib.
General disorders Asthenia	71.6% 48/67 • Adverse events were recorded from the date of randomization until end of study or death.	62.5% 15/24 • Adverse events were recorded from the date of randomization until end of study or death.
General disorders Mucosal inflammation	13.4% 9/67 • Adverse events were recorded from the date of randomization until end of study or death.	20.8% 5/24 • Adverse events were recorded from the date of randomization until end of study or death.
General disorders Pyrexia	13.4% 9/67 • Adverse events were recorded from the date of randomization until end of study or death.	12.5% 3/24 • Adverse events were recorded from the date of randomization until end of study or death.
General disorders Xerosis	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	41.7% 10/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Neutropenia	49.3% 33/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Anaemia	34.3% 23/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Thrombocytopenia	34.3% 23/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Blood and lymphatic system disorders Lymphopenia	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	12.5% 3/24 • Adverse events were recorded from the date of randomization until end of study or death.
Psychiatric disorders Insomnia	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	12.5% 3/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Nausea	41.8% 28/67 • Adverse events were recorded from the date of randomization until end of study or death.	25.0% 6/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Constipation	26.9% 18/67 • Adverse events were recorded from the date of randomization until end of study or death.	20.8% 5/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Diarrhoea	26.9% 18/67 • Adverse events were recorded from the date of randomization until end of study or death.	62.5% 15/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Vomiting	25.4% 17/67 • Adverse events were recorded from the date of randomization until end of study or death.	25.0% 6/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Abdominal pain	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	12.5% 3/24 • Adverse events were recorded from the date of randomization until end of study or death.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	12.5% 3/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Paraesthesia	28.4% 19/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Neuropathy peripheral	23.9% 16/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Headache	16.4% 11/67 • Adverse events were recorded from the date of randomization until end of study or death.	33.3% 8/24 • Adverse events were recorded from the date of randomization until end of study or death.
Nervous system disorders Dizziness	10.4% 7/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Respiratory, thoracic and mediastinal disorders Epistaxis	44.8% 30/67 • Adverse events were recorded from the date of randomization until end of study or death.	41.7% 10/24 • Adverse events were recorded from the date of randomization until end of study or death.
Respiratory, thoracic and mediastinal disorders Cough	14.9% 10/67 • Adverse events were recorded from the date of randomization until end of study or death.	25.0% 6/24 • Adverse events were recorded from the date of randomization until end of study or death.
Respiratory, thoracic and mediastinal disorders Dysphonia	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	20.8% 5/24 • Adverse events were recorded from the date of randomization until end of study or death.
Vascular disorders Hypertension	52.2% 35/67 • Adverse events were recorded from the date of randomization until end of study or death.	33.3% 8/24 • Adverse events were recorded from the date of randomization until end of study or death.
Skin and subcutaneous tissue disorders Alopecia	43.3% 29/67 • Adverse events were recorded from the date of randomization until end of study or death.	20.8% 5/24 • Adverse events were recorded from the date of randomization until end of study or death.
Skin and subcutaneous tissue disorders Rash	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	16.7% 4/24 • Adverse events were recorded from the date of randomization until end of study or death.
Skin and subcutaneous tissue disorders Dermatitis acneiform	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	12.5% 3/24 • Adverse events were recorded from the date of randomization until end of study or death.
Metabolism and nutrition disorders Decreased appetite	37.3% 25/67 • Adverse events were recorded from the date of randomization until end of study or death.	29.2% 7/24 • Adverse events were recorded from the date of randomization until end of study or death.
Renal and urinary disorders Proteinuria	20.9% 14/67 • Adverse events were recorded from the date of randomization until end of study or death.	33.3% 8/24 • Adverse events were recorded from the date of randomization until end of study or death.
Infections and infestations Rhinitis	13.4% 9/67 • Adverse events were recorded from the date of randomization until end of study or death.	0.00% 0/24 • Adverse events were recorded from the date of randomization until end of study or death.
Infections and infestations Folliculitis	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	45.8% 11/24 • Adverse events were recorded from the date of randomization until end of study or death.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	13.4% 9/67 • Adverse events were recorded from the date of randomization until end of study or death.	12.5% 3/24 • Adverse events were recorded from the date of randomization until end of study or death.
Investigations Weight decreased	11.9% 8/67 • Adverse events were recorded from the date of randomization until end of study or death.	16.7% 4/24 • Adverse events were recorded from the date of randomization until end of study or death.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/67 • Adverse events were recorded from the date of randomization until end of study or death.	16.7% 4/24 • Adverse events were recorded from the date of randomization until end of study or death.