Trial Outcomes & Findings for A Study of Sapanisertib, Combination of Sapanisertib With MLN1117, Paclitaxel and Combination of Sapanisertib With Paclitaxel in Women With Endometrial Cancer (NCT NCT02725268)

Last Updated: 2021-11-24

Results Overview

PFS is defined as the time in months from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST v1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

241 participants

Primary outcome timeframe

Up to approximately 30 months

Results posted on

2021-11-24

Participant Flow

Participants took part in the study at 60 investigative sites in Australia, Belgium, Germany, Italy, Netherlands, Norway, Spain, United Kingdom, Canada and the United States from 01 April 2016 to 30 October 2020.

The female participants with a diagnosis of endometrial carcinoma were enrolled and randomized into 1:1:1:1 ratio to receive single agent paclitaxel, paclitaxel in combination with sapanisertib, single agent sapanisertib or sapanisertib in combination with MLN1117.

Participant milestones

Participant milestones
Measure	Paclitaxel 80 mg/m^2 Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Overall Study STARTED	90	90	41	20
Overall Study Started	90	90	41	20
Overall Study Completed	18	20	3	2
Overall Study COMPLETED	18	20	3	2
Overall Study NOT COMPLETED	72	70	38	18

Reasons for withdrawal

Reasons for withdrawal
Measure	Paclitaxel 80 mg/m^2 Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Overall Study Death	58	59	30	16
Overall Study Lost to Follow-up	4	3	0	1
Overall Study Site Terminated by Sponsor	0	1	0	0
Overall Study Withdrawal by Subject	8	6	8	1
Overall Study Reason not Specified	2	1	0	0

Baseline Characteristics

Number analyzed is number of participants with data available for height at Baseline.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Paclitaxel 80 mg/m^2 n=90 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=90 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).	Total n=241 Participants Total of all reporting groups
Age, Continuous	63.7 years STANDARD_DEVIATION 7.14 • n=90 Participants	64.4 years STANDARD_DEVIATION 7.63 • n=90 Participants	64.0 years STANDARD_DEVIATION 6.99 • n=41 Participants	62.0 years STANDARD_DEVIATION 10.20 • n=20 Participants	63.9 years STANDARD_DEVIATION 7.57 • n=241 Participants
Sex: Female, Male Female	90 Participants n=90 Participants	90 Participants n=90 Participants	41 Participants n=41 Participants	20 Participants n=20 Participants	241 Participants n=241 Participants
Sex: Female, Male Male	0 Participants n=90 Participants	0 Participants n=90 Participants	0 Participants n=41 Participants	0 Participants n=20 Participants	0 Participants n=241 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=90 Participants	5 Participants n=90 Participants	3 Participants n=41 Participants	4 Participants n=20 Participants	15 Participants n=241 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	84 Participants n=90 Participants	80 Participants n=90 Participants	37 Participants n=41 Participants	15 Participants n=20 Participants	216 Participants n=241 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=90 Participants	5 Participants n=90 Participants	1 Participants n=41 Participants	1 Participants n=20 Participants	10 Participants n=241 Participants
Race/Ethnicity, Customized White	77 Participants n=90 Participants	78 Participants n=90 Participants	37 Participants n=41 Participants	18 Participants n=20 Participants	210 Participants n=241 Participants
Race/Ethnicity, Customized Black or African American	3 Participants n=90 Participants	4 Participants n=90 Participants	0 Participants n=41 Participants	1 Participants n=20 Participants	8 Participants n=241 Participants
Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander	1 Participants n=90 Participants	0 Participants n=90 Participants	1 Participants n=41 Participants	0 Participants n=20 Participants	2 Participants n=241 Participants
Race/Ethnicity, Customized Asian	6 Participants n=90 Participants	3 Participants n=90 Participants	1 Participants n=41 Participants	1 Participants n=20 Participants	11 Participants n=241 Participants
Race/Ethnicity, Customized Other	0 Participants n=90 Participants	2 Participants n=90 Participants	2 Participants n=41 Participants	0 Participants n=20 Participants	4 Participants n=241 Participants
Race/Ethnicity, Customized Not Reported	3 Participants n=90 Participants	3 Participants n=90 Participants	0 Participants n=41 Participants	0 Participants n=20 Participants	6 Participants n=241 Participants
Region of Enrollment Australia	5 Participants n=90 Participants	6 Participants n=90 Participants	3 Participants n=41 Participants	2 Participants n=20 Participants	16 Participants n=241 Participants
Region of Enrollment Belgium	5 Participants n=90 Participants	10 Participants n=90 Participants	2 Participants n=41 Participants	3 Participants n=20 Participants	20 Participants n=241 Participants
Region of Enrollment Germany	6 Participants n=90 Participants	4 Participants n=90 Participants	1 Participants n=41 Participants	0 Participants n=20 Participants	11 Participants n=241 Participants
Region of Enrollment Italy	14 Participants n=90 Participants	22 Participants n=90 Participants	9 Participants n=41 Participants	4 Participants n=20 Participants	49 Participants n=241 Participants
Region of Enrollment Netherlands	2 Participants n=90 Participants	3 Participants n=90 Participants	0 Participants n=41 Participants	0 Participants n=20 Participants	5 Participants n=241 Participants
Region of Enrollment Norway	3 Participants n=90 Participants	1 Participants n=90 Participants	1 Participants n=41 Participants	0 Participants n=20 Participants	5 Participants n=241 Participants
Region of Enrollment Spain	10 Participants n=90 Participants	7 Participants n=90 Participants	5 Participants n=41 Participants	6 Participants n=20 Participants	28 Participants n=241 Participants
Region of Enrollment United Kingdom	9 Participants n=90 Participants	4 Participants n=90 Participants	6 Participants n=41 Participants	2 Participants n=20 Participants	21 Participants n=241 Participants
Region of Enrollment Canada	15 Participants n=90 Participants	10 Participants n=90 Participants	2 Participants n=41 Participants	0 Participants n=20 Participants	27 Participants n=241 Participants
Region of Enrollment United States	21 Participants n=90 Participants	23 Participants n=90 Participants	12 Participants n=41 Participants	3 Participants n=20 Participants	59 Participants n=241 Participants
Height	160.60 cm STANDARD_DEVIATION 6.335 • n=87 Participants • Number analyzed is number of participants with data available for height at Baseline.	160.23 cm STANDARD_DEVIATION 5.798 • n=82 Participants • Number analyzed is number of participants with data available for height at Baseline.	159.01 cm STANDARD_DEVIATION 6.471 • n=41 Participants • Number analyzed is number of participants with data available for height at Baseline.	162.67 cm STANDARD_DEVIATION 5.854 • n=20 Participants • Number analyzed is number of participants with data available for height at Baseline.	160.36 cm STANDARD_DEVIATION 6.16 • n=230 Participants • Number analyzed is number of participants with data available for height at Baseline.
Weight	73.29 kg STANDARD_DEVIATION 18.783 • n=87 Participants • Number analyzed is number of participants with data available for weight at Baseline.	72.13 kg STANDARD_DEVIATION 18.433 • n=84 Participants • Number analyzed is number of participants with data available for weight at Baseline.	75.35 kg STANDARD_DEVIATION 17.969 • n=41 Participants • Number analyzed is number of participants with data available for weight at Baseline.	71.81 kg STANDARD_DEVIATION 18.613 • n=20 Participants • Number analyzed is number of participants with data available for weight at Baseline.	73.11 kg STANDARD_DEVIATION 18.418 • n=232 Participants • Number analyzed is number of participants with data available for weight at Baseline.

PRIMARY outcome

Timeframe: Up to approximately 30 months

Population: ITT population included all randomized participants. For a participant who had not progressed and was last known to be alive, PFS was censored at the last response assessment that is stable disease (SD) or better.

Outcome measures

Outcome measures
Measure	Paclitaxel 80 mg/m^2 n=90 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=90 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Progression Free Survival (PFS)	3.7 months Interval 2.3 to 4.5	5.6 months Interval 3.8 to 6.2	2.1 months Interval 1.9 to 3.5	2.0 months Interval 1.5 to 3.3

SECONDARY outcome

Timeframe: From the first dose of study drug through 30 days after the last dose of study drug (Up to approximately 54 months)

Population: Safety population included all participants who received at least 1 dose of study drug.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

Outcome measures

Outcome measures
Measure	Paclitaxel 80 mg/m^2 n=87 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=86 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Number of Participants Who Experienced at Least One Treatment-emergent Adverse Event (TEAE)	87 Participants	86 Participants	41 Participants	20 Participants

SECONDARY outcome

Timeframe: Up to approximately 54 months

Population: ITT population included all randomized participants. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.

OS is defined as the time in months from the date of randomization to the date of death.

Outcome measures

Outcome measures
Measure	Paclitaxel 80 mg/m^2 n=90 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=90 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Overall Survival (OS)	12.7 months Interval 9.8 to 19.6	13.8 months Interval 9.9 to 19.1	12.5 months Interval 9.0 to 15.7	11.1 months Interval 2.7 to 17.5

SECONDARY outcome

Timeframe: Up to 30 months

Population: ITT population included all randomized participants. For a participant who has not progressed, TTP was censored at the last response assessment that is SD or better.

TTP is defined as the time in months from the date of randomization to the date of first documentation of progression. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Paclitaxel 80 mg/m^2 n=90 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=90 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Time to Tumor Progression (TTP)	3.7 months Interval 2.5 to 5.4	5.7 months Interval 3.8 to 7.2	2.3 months Interval 1.9 to 4.2	2.2 months Interval 1.8 to 3.7

SECONDARY outcome

Timeframe: Up to 30 months

Population: Safety population included participants who received at least 1 dose of study drug.

ORR is defined as the percentage of participants who achieved a best response of a complete response (CR) or partial response (PR). Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.

Outcome measures

Outcome measures
Measure	Paclitaxel 80 mg/m^2 n=87 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=86 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Overall Response Rate (ORR)	18.4 percentage of participants	24.4 percentage of participants	4.9 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Up to 30 months

Population: Safety population included participants who received at least 1 dose of study drug.

CBR is defined as the percentage of participants with CR or PR or SD (SD of any duration). Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Paclitaxel 80 mg/m^2 n=87 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=86 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Clinical Benefit Rate (CBR)	57.5 percentage of participants	80.2 percentage of participants	34.1 percentage of participants	35.0 percentage of participants

SECONDARY outcome

Timeframe: Week 16

Population: Safety population included participants who received at least 1 dose of study drug.

CBR-16 is defined as the percentage of participants who achieved CR or PR of any duration or have SD with a duration of at least 16 weeks. Per RECIST v1.1, CR was defined as disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Outcome measures

Outcome measures
Measure	Paclitaxel 80 mg/m^2 n=87 Participants Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=86 Participants Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 Participants Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 Participants Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Clinical Benefit Rate (CBR) at Week 16 (CBR-16)	36.8 percentage of participants	51.2 percentage of participants	17.1 percentage of participants	5.0 percentage of participants

Adverse Events

Paclitaxel 80 mg/m^2

Serious events: 23 serious events

Other events: 85 other events

Deaths: 58 deaths

Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg

Serious events: 47 serious events

Other events: 86 other events

Deaths: 59 deaths

Sapanisertib 30 mg

Serious events: 14 serious events

Other events: 41 other events

Deaths: 30 deaths

Sapanisertib 4 mg + MLN1117 200 mg

Serious events: 7 serious events

Other events: 20 other events

Deaths: 16 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Paclitaxel 80 mg/m^2 n=87 participants at risk Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=86 participants at risk Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 participants at risk Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 participants at risk Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Infections and infestations Pyelonephritis	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Staphylococcal infection	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Nausea	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.3% 2/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	4.9% 2/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Vomiting	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.3% 2/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	4.9% 2/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Intestinal obstruction	3.4% 3/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Small intestinal obstruction	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal pain	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Colitis	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.3% 2/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Intestinal perforation	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Large intestinal obstruction	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Subileus	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal distension	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal hernia	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Constipation	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Diarrhoea	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Discoloured vomit	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Dyspepsia	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Faecaloma	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Haematemesis	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Ileus	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders General physical health deterioration	3.4% 3/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	3.5% 3/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Fatigue	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.3% 2/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Pyrexia	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Malaise	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.3% 2/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Pain	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Asthenia	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Death	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Non-cardiac chest pain	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Sepsis	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	3.5% 3/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Pneumonia	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	3.5% 3/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Urinary tract infection	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Abdominal abscess	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Bacteraemia	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Cellulitis	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Cystitis	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Enterocolitis infectious	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Gastroenteritis	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Kidney infection	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Infections and infestations Urosepsis	0.00% 0/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	1.2% 1/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.

Other adverse events
Measure	Paclitaxel 80 mg/m^2 n=87 participants at risk Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 13.00 weeks).	Paclitaxel 80 mg/m^2 + Sapanisertib 4 mg n=86 participants at risk Paclitaxel 80 mg/m\^2, IV, injection, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 20.14 and 18.50 weeks).	Sapanisertib 30 mg n=41 participants at risk Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 6.14 weeks).	Sapanisertib 4 mg + MLN1117 200 mg n=20 participants at risk Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was 7.43 weeks).
Gastrointestinal disorders Nausea	33.3% 29/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	61.6% 53/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	73.2% 30/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	80.0% 16/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Diarrhoea	35.6% 31/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	55.8% 48/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	36.6% 15/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	65.0% 13/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Vomiting	23.0% 20/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	27.9% 24/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	75.6% 31/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	75.0% 15/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Constipation	28.7% 25/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	23.3% 20/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	34.1% 14/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	25.0% 5/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal pain	14.9% 13/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	25.6% 22/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	14.6% 6/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	20.0% 4/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Stomatitis	4.6% 4/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	25.6% 22/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	24.4% 10/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal pain upper	6.9% 6/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	15.1% 13/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	9.8% 4/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	20.0% 4/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Dyspepsia	5.7% 5/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	15.1% 13/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.3% 3/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Gastrooesophageal reflux disease	4.6% 4/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	11.6% 10/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.3% 3/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	15.0% 3/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Dry mouth	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	9.3% 8/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	4.9% 2/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal distension	5.7% 5/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.0% 6/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Abdominal pain lower	4.6% 4/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	3.5% 3/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	15.0% 3/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Gastrointestinal disorders Haemorrhoids	5.7% 5/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.3% 2/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Fatigue	44.8% 39/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	46.5% 40/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	43.9% 18/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	35.0% 7/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Asthenia	8.0% 7/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	30.2% 26/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	22.0% 9/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	50.0% 10/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Pyrexia	13.8% 12/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	15.1% 13/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	12.2% 5/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	20.0% 4/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Oedema peripheral	20.7% 18/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	11.6% 10/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	4.9% 2/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Peripheral swelling	5.7% 5/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.8% 5/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
General disorders Chills	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.8% 5/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Decreased appetite	18.4% 16/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	38.4% 33/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	48.8% 20/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	40.0% 8/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Hyperglycaemia	9.2% 8/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	19.8% 17/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	36.6% 15/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	25.0% 5/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Hypomagnesaemia	12.6% 11/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	22.1% 19/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	17.1% 7/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Hypokalaemia	6.9% 6/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	12.8% 11/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.3% 3/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Dehydration	1.1% 1/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	9.3% 8/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	14.6% 6/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Hypophosphataemia	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	14.0% 12/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	4.9% 2/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Hypoalbuminaemia	3.4% 3/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	9.3% 8/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	9.8% 4/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Hyponatraemia	3.4% 3/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.0% 6/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	9.8% 4/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Metabolism and nutrition disorders Hypocalcaemia	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.0% 6/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Blood and lymphatic system disorders Anaemia	36.8% 32/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	55.8% 48/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	12.2% 5/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	30.0% 6/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Blood and lymphatic system disorders Neutropenia	11.5% 10/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	22.1% 19/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Blood and lymphatic system disorders Leukopenia	9.2% 8/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	14.0% 12/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Neuropathy peripheral	13.8% 12/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	25.6% 22/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.3% 3/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Dysgeusia	11.5% 10/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	17.4% 15/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	14.6% 6/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Headache	4.6% 4/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	15.1% 13/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	14.6% 6/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Dizziness	3.4% 3/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	16.3% 14/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.3% 3/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.0% 2/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Paraesthesia	6.9% 6/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	10.5% 9/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	2.4% 1/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Peripheral sensory neuropathy	8.0% 7/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	9.3% 8/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Tremor	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.8% 5/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.3% 3/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	5.0% 1/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Nervous system disorders Taste disorder	2.3% 2/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	7.0% 6/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	4.9% 2/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	0.00% 0/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.
Respiratory, thoracic and mediastinal disorders Dyspnoea	20.7% 18/87 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	29.1% 25/86 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	14.6% 6/41 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.	15.0% 3/20 • Up to the end of study (approximately up to 54 months) At each visit investigator had to document any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study treatment. All-cause mortality:ITT population(n= 90,90,41,20). Serious and other(non-serious) AEs:Safety population.