Trial Outcomes & Findings for A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma (NCT NCT01689519)

Last Updated: 2022-05-02

Results Overview

Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

495 participants

Primary outcome timeframe

Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Results posted on

2022-05-02

Participant Flow

Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.

Participant milestones

Participant milestones
Measure	Cobimetinib + Vemurafenib Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Placebo + Vemurafenib Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Intent to Treat STARTED	247	248
Intent to Treat COMPLETED	0	0
Intent to Treat NOT COMPLETED	247	248
Safety Population STARTED	248	245
Safety Population COMPLETED	0	0
Safety Population NOT COMPLETED	248	245

Reasons for withdrawal

Reasons for withdrawal
Measure	Cobimetinib + Vemurafenib Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Placebo + Vemurafenib Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Intent to Treat Death	157	167
Intent to Treat Lost to Follow-up	4	8
Intent to Treat Other	2	4
Intent to Treat Physician Decision	4	1
Intent to Treat Study terminated by Spon6sor	59	48
Intent to Treat Withdrawal by Subject	21	20
Safety Population Death	158	165
Safety Population Lost to Follow-up	4	8
Safety Population Other	2	4
Safety Population Physician Decision	4	1
Safety Population Study Terminated By Sponsor	60	47
Safety Population Withdrawal by Subject	20	20

Baseline Characteristics

A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma

Baseline characteristics by cohort

PRIMARY outcome

Timeframe: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.

Outcome measures

Outcome measures
Measure	Cobimetinib + Vemurafenib n=247 Participants Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Placebo + Vemurafenib n=248 Participants Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Progression-free Survival Primary Analysis: 9 May 2014	9.90 Months Interval 9.0 to NA = not estimable, could not be calculated due to too few events.	6.20 Months Interval 5.55 to 7.39
Progression-free Survival Post hoc Efficacy Analysis: 16 January 2015	12.30 Months Interval 9.5 to 13.4	7.20 Months Interval 5.6 to 7.5
Progression-free Survival Extended 5-Year Analysis: 21 July 2019	12.60 Months Interval 9.5 to 14.8	7.20 Months Interval 5.6 to 7.5

SECONDARY outcome

Timeframe: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.

Overall survival was defined as the time from randomization until the date of death from any cause.

Outcome measures

Outcome measures
Measure	Cobimetinib + Vemurafenib n=247 Participants Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Placebo + Vemurafenib n=248 Participants Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Overall Survival Post hoc Analysis 16 January 2015	NA Months Interval 20.7 to NA = not estimable, could not be calculated due to too few events.	17.00 Months Interval 15.0 to NA = not estimable, could not be calculated due to too few events.
Overall Survival Primary Analysis 9 May 2014	NA Months NA = not estimable, could not be calculated due to too few events.	NA Months NA = not estimable, could not be calculated due to too few events.
Overall Survival Final Analysis 28 August 2015	22.30 Months Interval 20.3 to NA = not estimable, could not be calculated due to too few events.	17.40 Months Interval 15.0 to 19.8
Overall Survival Extended 5-year Analysis 21 July 2019	22.50 Months Interval 20.3 to 28.8	17.40 Months Interval 15.0 to 19.8

SECONDARY outcome

Timeframe: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.

An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Cobimetinib + Vemurafenib n=247 Participants Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Placebo + Vemurafenib n=248 Participants Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Percentage of Participants With an Objective Response Primary Analysis: 9 May 2014	67.60 Percentage of participants Interval 61.39 to 73.41	44.80 Percentage of participants Interval 38.46 to 51.18
Percentage of Participants With an Objective Response Post hoc Efficacy Analysis: 16 January 2015	69.60 Percentage of participants Interval 63.5 to 75.3	50.00 Percentage of participants Interval 43.6 to 56.4
Percentage of Participants With an Objective Response Extended 5-Year Analysis: 21 July 2019	69.60 Percentage of participants Interval 63.49 to 75.31	49.60 Percentage of participants Interval 43.21 to 55.99

SECONDARY outcome

Timeframe: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Population: Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received. Only participants with an objective response were included in the analysis.

Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Outcome measures

Outcome measures
Measure	Cobimetinib + Vemurafenib n=247 Participants Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Placebo + Vemurafenib n=248 Participants Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Duration of Response Primary Analysis: 9 May 2014	NA Months Interval 9.3 to NA = not estimable, could not be calculated due to too few events.	7.29 Months Interval 5.78 to NA = not estimable, could not be calculated due to too few events.
Duration of Response Extended 5-Year Analysis: 21 July 2019	14.65 Months Interval 12.9 to 19.3	9.23 Months Interval 7.5 to 12.9

Adverse Events

Placebo + Vemurafenib

Serious events: 71 serious events

Other events: 236 other events

Deaths: 164 deaths

Cobimetinib + Vemurafenib

Serious events: 105 serious events

Other events: 239 other events

Deaths: 160 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

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 only after the first publication or presentation that involves the Overall Study. The 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	Cobimetinib + Vemurafenib n=247 Participants Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Placebo + Vemurafenib n=248 Participants Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Total n=495 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	183 Participants n=5 Participants	179 Participants n=7 Participants	362 Participants n=5 Participants
Age, Categorical >=65 years	64 Participants n=5 Participants	69 Participants n=7 Participants	133 Participants n=5 Participants
Age, Continuous	54.9 Years STANDARD_DEVIATION 14.0 • n=5 Participants	55.3 Years STANDARD_DEVIATION 13.8 • n=7 Participants	55.1 Years STANDARD_DEVIATION 13.9 • n=5 Participants
Sex: Female, Male Female	101 Participants n=5 Participants	108 Participants n=7 Participants	209 Participants n=5 Participants
Sex: Female, Male Male	146 Participants n=5 Participants	140 Participants n=7 Participants	286 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Count of Participants n=5 Participants	0 Count of Participants n=7 Participants	1 Count of Participants n=5 Participants
Race/Ethnicity, Customized More than one race	1 Count of Participants n=5 Participants	1 Count of Participants n=7 Participants	2 Count of Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islande	0 Count of Participants n=5 Participants	1 Count of Participants n=7 Participants	1 Count of Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 Count of Participants n=5 Participants	0 Count of Participants n=7 Participants	0 Count of Participants n=5 Participants
Race/Ethnicity, Customized White	227 Count of Participants n=5 Participants	235 Count of Participants n=7 Participants	462 Count of Participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	16 Count of Participants n=5 Participants	9 Count of Participants n=7 Participants	25 Count of Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Count of Participants n=5 Participants	2 Count of Participants n=7 Participants	4 Count of Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	14 Count of Participants n=5 Participants	12 Count of Participants n=7 Participants	26 Count of Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	213 Count of Participants n=5 Participants	223 Count of Participants n=7 Participants	436 Count of Participants n=5 Participants
Race/Ethnicity, Customized Not Stated	16 Count of Participants n=5 Participants	10 Count of Participants n=7 Participants	26 Count of Participants n=5 Participants
Race/Ethnicity, Customized Unknown	4 Count of Participants n=5 Participants	3 Count of Participants n=7 Participants	7 Count of Participants n=5 Participants

Serious adverse events
Measure	Placebo + Vemurafenib n=245 participants at risk Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Cobimetinib + Vemurafenib n=248 participants at risk Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Blood and lymphatic system disorders ANAEMIA	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders ACUTE CORONARY SYNDROME	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders ATRIAL FIBRILLATION	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	1.6% 4/248 • Number of events 8 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders CARDIAC ARREST	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders CARDIAC FAILURE	0.82% 2/245 • Number of events 2 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders CARDIAC TAMPONADE	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders MYOCARDIAL INFARCTION	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.81% 2/248 • Number of events 2 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders PERICARDIAL EFFUSION	1.6% 4/245 • Number of events 4 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders SUPRAVENTRICULAR TACHYCARDIA	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Cardiac disorders TACHYCARDIA	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Endocrine disorders HYPERTHYROIDISM	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders CHORIORETINOPATHY	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	1.2% 3/248 • Number of events 5 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders IRIDOCYCLITIS	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders RETINAL DETACHMENT	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders RETINAL HAEMORRHAGE	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders SEROUS RETINAL DETACHMENT	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.81% 2/248 • Number of events 2 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders UVEITIS	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders ABDOMINAL PAIN	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders APHTHOUS ULCER	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders COLITIS	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders CONSTIPATION	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders DIARRHOEA	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	1.2% 3/248 • Number of events 3 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders DYSPHAGIA	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders GASTRIC ANTRAL VASCULAR ECTASIA	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders GASTROINTESTINAL HAEMORRHAGE	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders GASTROINTESTINAL PAIN	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders GASTROOESOPHAGEAL REFLUX DISEASE	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders INGUINAL HERNIA	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders INTESTINAL OBSTRUCTION	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders INTESTINAL PERFORATION	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders MELAENA	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders OBSTRUCTION GASTRIC	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders PANCREATITIS	0.82% 2/245 • Number of events 2 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders PERIODONTAL DISEASE	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders RECTAL POLYP	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.00% 0/248 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders SMALL INTESTINAL OBSTRUCTION	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	1.2% 3/248 • Number of events 3 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders VOMITING	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.81% 2/248 • Number of events 2 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders ASTHENIA	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders CHEST PAIN	0.00% 0/245 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders DEATH	0.41% 1/245 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	0.40% 1/248 • Number of events 1 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.

Other adverse events
Measure	Placebo + Vemurafenib n=245 participants at risk Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Cobimetinib + Vemurafenib n=248 participants at risk Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Blood and lymphatic system disorders ANAEMIA	8.6% 21/245 • Number of events 26 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	20.6% 51/248 • Number of events 76 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders CHORIORETINOPATHY	1.6% 4/245 • Number of events 9 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	12.1% 30/248 • Number of events 36 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Eye disorders VISION BLURRED	3.3% 8/245 • Number of events 9 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	12.9% 32/248 • Number of events 37 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders ABDOMINAL PAIN	8.2% 20/245 • Number of events 23 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	12.1% 30/248 • Number of events 37 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders ABDOMINAL PAIN UPPER	7.3% 18/245 • Number of events 21 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	6.0% 15/248 • Number of events 17 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders CONSTIPATION	11.8% 29/245 • Number of events 31 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	10.9% 27/248 • Number of events 37 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders DIARRHOEA	34.3% 84/245 • Number of events 162 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	60.9% 151/248 • Number of events 311 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders DYSPEPSIA	5.3% 13/245 • Number of events 15 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	7.7% 19/248 • Number of events 22 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders NAUSEA	27.3% 67/245 • Number of events 83 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	43.5% 108/248 • Number of events 184 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders STOMATITIS	1.2% 3/245 • Number of events 3 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	6.9% 17/248 • Number of events 27 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Gastrointestinal disorders VOMITING	13.5% 33/245 • Number of events 42 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	27.8% 69/248 • Number of events 108 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders ASTHENIA	17.6% 43/245 • Number of events 50 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	20.6% 51/248 • Number of events 96 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders CHILLS	5.7% 14/245 • Number of events 17 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	10.1% 25/248 • Number of events 28 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders FATIGUE	33.9% 83/245 • Number of events 99 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	37.5% 93/248 • Number of events 137 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders OEDEMA PERIPHERAL	11.4% 28/245 • Number of events 32 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	15.3% 38/248 • Number of events 49 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
General disorders PYREXIA	24.5% 60/245 • Number of events 77 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	31.0% 77/248 • Number of events 130 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Infections and infestations CONJUNCTIVITIS	3.3% 8/245 • Number of events 10 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	7.3% 18/248 • Number of events 19 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Infections and infestations FOLLICULITIS	4.9% 12/245 • Number of events 15 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	7.7% 19/248 • Number of events 22 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Infections and infestations NASOPHARYNGITIS	7.3% 18/245 • Number of events 21 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	9.3% 23/248 • Number of events 29 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	4.5% 11/245 • Number of events 15 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	5.6% 14/248 • Number of events 18 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Infections and infestations URINARY TRACT INFECTION	4.5% 11/245 • Number of events 13 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	6.9% 17/248 • Number of events 25 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Injury, poisoning and procedural complications SUNBURN	18.4% 45/245 • Number of events 68 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	14.9% 37/248 • Number of events 60 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations ALANINE AMINOTRANSFERASE INCREASED	18.0% 44/245 • Number of events 48 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	26.2% 65/248 • Number of events 94 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations ASPARTATE AMINOTRANSFERASE INCREASED	11.8% 29/245 • Number of events 30 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	25.8% 64/248 • Number of events 87 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations BLOOD ALKALINE PHOSPHATASE INCREASED	10.6% 26/245 • Number of events 30 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	18.5% 46/248 • Number of events 67 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations BLOOD BILIRUBIN INCREASED	6.9% 17/245 • Number of events 22 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	8.1% 20/248 • Number of events 29 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations BLOOD CHOLESTEROL INCREASED	4.1% 10/245 • Number of events 10 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	6.5% 16/248 • Number of events 19 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations BLOOD CREATINE PHOSPHOKINASE INCREASED	4.1% 10/245 • Number of events 13 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	36.3% 90/248 • Number of events 171 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations BLOOD CREATININE INCREASED	8.2% 20/245 • Number of events 25 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	18.1% 45/248 • Number of events 59 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations BLOOD LACTATE DEHYDROGENASE INCREASED	3.3% 8/245 • Number of events 8 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	6.0% 15/248 • Number of events 30 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations EJECTION FRACTION DECREASED	4.9% 12/245 • Number of events 13 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	12.5% 31/248 • Number of events 46 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations ELECTROCARDIOGRAM QT PROLONGED	5.3% 13/245 • Number of events 19 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	4.8% 12/248 • Number of events 15 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations GAMMA-GLUTAMYLTRANSFERASE INCREASED	18.4% 45/245 • Number of events 61 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	23.0% 57/248 • Number of events 82 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Investigations WEIGHT DECREASED	5.7% 14/245 • Number of events 17 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	7.3% 18/248 • Number of events 20 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Metabolism and nutrition disorders DECREASED APPETITE	20.4% 50/245 • Number of events 55 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	22.2% 55/248 • Number of events 75 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Metabolism and nutrition disorders HYPONATRAEMIA	1.2% 3/245 • Number of events 3 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	5.2% 13/248 • Number of events 19 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Musculoskeletal and connective tissue disorders ARTHRALGIA	42.9% 105/245 • Number of events 179 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	38.7% 96/248 • Number of events 172 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Musculoskeletal and connective tissue disorders BACK PAIN	6.1% 15/245 • Number of events 15 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	8.5% 21/248 • Number of events 30 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Musculoskeletal and connective tissue disorders MUSCULOSKELETAL PAIN	6.5% 16/245 • Number of events 19 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	6.9% 17/248 • Number of events 18 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Musculoskeletal and connective tissue disorders MYALGIA	13.5% 33/245 • Number of events 37 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.	16.5% 41/248 • Number of events 53 • Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months). 1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.