Trial Outcomes & Findings for Efficacy and Tolerability of Entospletinib in Combination With Systemic Corticosteroids as First-Line Therapy in Adults With Chronic Graft Versus Host Disease (cGVHD) (NCT NCT02701634)

NCT ID: NCT02701634

Last Updated: 2018-12-26

Results Overview

Best overall response rate by 24 weeks was defined as the proportion of participants who achieved a complete or partial overall response as assessed by the NIH cGVHD Activity Assessment (NCAA) within 24 weeks, in the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 66 participants
• Primary outcome timeframe: Up to 24 weeks
• Results posted on: 2018-12-26

Participant Flow

Participants were enrolled at study sites in Europe, Asia, Canada, and United States. The first participant was screened on 27 May 2016. The last study visit occurred on 06 Mar 2018.

89 participants were screened.

Participant milestones

Measure	ENTO Entospletinib (ENTO) 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo Placebo to match Entospletinib tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy
Overall Study STARTED	33	33
Overall Study COMPLETED	1	2
Overall Study NOT COMPLETED	32	31

Reasons for withdrawal

Measure	ENTO Entospletinib (ENTO) 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo Placebo to match Entospletinib tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy
Overall Study Adverse Event	2	3
Overall Study Death	1	0
Overall Study Investigator's Discretion	7	4
Overall Study Study terminated by Sponsor	15	17
Overall Study Withdrew Consent	6	7
Overall Study Randomized but not treated	1	0

Baseline Characteristics

Efficacy and Tolerability of Entospletinib in Combination With Systemic Corticosteroids as First-Line Therapy in Adults With Chronic Graft Versus Host Disease (cGVHD)

Baseline characteristics by cohort

Measure	ENTO n=33 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match ENTO tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Total n=66 Participants Total of all reporting groups
Age, Continuous	51 years STANDARD_DEVIATION 11.9 • n=5 Participants	58 years STANDARD_DEVIATION 11.4 • n=7 Participants	54 years STANDARD_DEVIATION 12.2 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	13 Participants n=7 Participants	27 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	20 Participants n=7 Participants	39 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	27 Participants n=5 Participants	28 Participants n=7 Participants	55 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · Black	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · White	23 Participants n=5 Participants	29 Participants n=7 Participants	52 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · Other	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity, Customized · Not Permitted	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment United States	11 Participants n=5 Participants	10 Participants n=7 Participants	21 Participants n=5 Participants
Region of Enrollment Spain	7 Participants n=5 Participants	10 Participants n=7 Participants	17 Participants n=5 Participants
Region of Enrollment Germany	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Region of Enrollment France	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment United Kingdom	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment South Korea	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment Canada	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 24 weeks

Population: ITT Analysis Set: all participants who were randomized into the study. Data was analyzed according to treatment randomized.

Best overall response rate by 24 weeks was defined as the proportion of participants who achieved a complete or partial overall response as assessed by the NIH cGVHD Activity Assessment (NCAA) within 24 weeks, in the setting of add-on therapy to systemic corticosteroids as part of first-line therapy for cGVHD.

Outcome measures

Measure	ENTO n=33 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Best Overall Response Rate	72.7 Percentage of participants	72.7 Percentage of participants

SECONDARY outcome

Timeframe: Baseline; Week 24

Population: Participants in the ITT Analysis Set with available data were analyzed.

The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.

Outcome measures

Measure	ENTO n=32 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=32 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks Baseline	15.0 units on a scale Standard Deviation 21.92	19.8 units on a scale Standard Deviation 22.34
Change From Baseline in the Skin Domain of the Lee Symptom Scale (LSS) at 24 Weeks Change at Week 24	-3.3 units on a scale Standard Deviation 10.31	-9.4 units on a scale Standard Deviation 14.24

SECONDARY outcome

Timeframe: Baseline; Week 24

Population: Participants in the ITT Analysis Set with available data were analyzed.

The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.

Outcome measures

Measure	ENTO n=32 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=32 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Change From Baseline in the Mouth Domain of the LSS at 24 Weeks Baseline	15.2 units on a scale Standard Deviation 18.17	16.8 units on a scale Standard Deviation 21.21
Change From Baseline in the Mouth Domain of the LSS at 24 Weeks Change at Week 24	-4.2 units on a scale Standard Deviation 16.54	-1.4 units on a scale Standard Deviation 25.34

SECONDARY outcome

Timeframe: Baseline; Week 24

Population: Participants in the ITT Analysis Set with available data were analyzed.

The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. A decrease from baseline value correlates with improvement in clinical outcome.

Outcome measures

Measure	ENTO n=32 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=32 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Change From Baseline in the Eyes Domain of the LSS at 24 Weeks Baseline	29.4 units on a scale Standard Deviation 27.52	21.4 units on a scale Standard Deviation 24.22
Change From Baseline in the Eyes Domain of the LSS at 24 Weeks Change at Week 24	10.2 units on a scale Standard Deviation 21.56	-1.4 units on a scale Standard Deviation 31.32

SECONDARY outcome

Timeframe: Baseline; Week 24

Population: Participants in the ITT Analysis Set with available data were analyzed.

The LSS is a patient-reported questionnaire used to measure symptom burden. Each of the LSS subscales ranged between 0 and 100, with higher scores indicating more severe symptoms. The total score was calculated by taking the average of the subscale scores. A decrease from baseline value correlates with improvement in clinical outcome.

Outcome measures

Measure	ENTO n=33 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Change From Baseline in the Total Score of the LSS at 24 Weeks Baseline	16.0 score on a scale Standard Deviation 9.74	14.7 score on a scale Standard Deviation 8.51
Change From Baseline in the Total Score of the LSS at 24 Weeks Change at Week 24	-0.5 score on a scale Standard Deviation 8.35	-5.4 score on a scale Standard Deviation 8.54

SECONDARY outcome

Timeframe: Up to 48 weeks

Population: ITT Analysis Set

Duration of response was defined as the time from the documentation of best overall response rate to the documentation of progressive disease. Note that flare was not considered as progressive disease in this analysis.

Outcome measures

Measure	ENTO n=33 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Duration of Response	26.3 weeks Interval 9.1 to 44.3	32.0 weeks Interval 8.1 to NA: Not reached

SECONDARY outcome

Timeframe: Baseline; Up to 48 weeks

Population: ITT Analysis Set

The percentage reduction was calculated as (systemic corticosteroid dose post baseline - baseline systemic corticosteroid dose) / baseline systemic corticosteroid dose.

Outcome measures

Measure	ENTO n=33 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Percentage of Participants Who Achieve at Least 50% Reduction in Systemic Corticosteroid Dose Relative to Baseline	72.7 Percentage of participants	63.6 Percentage of participants

SECONDARY outcome

Timeframe: Up to 48 weeks

Population: ITT Analysis Set

Second-line therapy for cGVHD was defined as receiving any therapy besides systemic corticosteroids or study drug for the treatment of cGVHD. Inhaled and topical steroids are not considered second-line therapy.

Outcome measures

Measure	ENTO n=33 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Percentage of Participants Who Initiate Second-Line Therapy for cGVHD	9.1 Percentage of participants	15.2 Percentage of participants

SECONDARY outcome

Timeframe: Up to 48 weeks

Population: Participants in the ITT Analysis Set with available data were analyzed.

Failure-free survival was defined as the time from randomization to the earliest of first documentation of systemic therapy change, nonrelapse mortality, or recurrent malignancy.

Outcome measures

Measure	ENTO n=20 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=20 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Failure-Free Survival	99.0 Days Interval 57.0 to 214.0	85.0 Days Interval 56.0 to 254.0

SECONDARY outcome

Timeframe: Up to 48 weeks plus 30 days

Population: Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.

Treatment-emergent adverse events are defined as 1 or both of the following: 1) any AEs with an onset on or after study drug or placebo start date and no later than earlier of 30 days after permanent discontinuation of study drug or placebo, 2) any AEs leading to premature discontinuation of study drug or placebo.

Outcome measures

Measure	ENTO n=32 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Percentage of Participants Who Experience Any Treatment-Emergent Adverse Events (AEs)	96.9 Percentage of participants	97.0 Percentage of participants

SECONDARY outcome

Timeframe: Up to 48 weeks plus 30 days

Population: Safety Analysis Set

Outcome measures

Measure	ENTO n=32 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event	12.5 Percentage of participants	12.1 Percentage of participants

SECONDARY outcome

Timeframe: Up to 48 weeks plus 30 days

Population: Safety Analysis Set

Outcome measures

Measure	ENTO n=32 Participants ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 Participants Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Percentage of Participants Who Experienced Treatment-Emergent Graded Laboratory Abnormalities	100.0 Percentage of participants	100.0 Percentage of participants

Adverse Events

ENTO

Serious events: 15 serious events

Other events: 31 other events

Deaths: 1 deaths

Placebo

Serious events: 11 serious events

Other events: 30 other events

Deaths: 0 deaths

Serious adverse events

Measure	ENTO n=32 participants at risk ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 participants at risk Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Blood and lymphatic system disorders Neutropenia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Cardiac disorders Coronary artery disease	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Abdominal pain	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Colitis	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Diarrhoea	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Nausea	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Small intestinal haemorrhage	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Disease recurrence	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Pain	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Pyrexia	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Anal abscess	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Bacteraemia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Cellulitis	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations H1N1 influenza	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Infection	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Listeriosis	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Otitis media acute	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Pneumonia	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Pneumonia bacterial	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Pyelonephritis acute	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Septic shock	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Staphylococcal bacteraemia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Upper respiratory tract infection	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Injury, poisoning and procedural complications Wound dehiscence	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Gamma-glutamyltransferase increased	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations General physical condition abnormal	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hyponatraemia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Myositis	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Pain in extremity	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute leukaemia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chloroma	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Obliterative bronchiolitis	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.

Other adverse events

Measure	ENTO n=32 participants at risk ENTO 400 mg or 200 mg tablet twice daily for 48 weeks in combination with systemic corticosteroids as first-line therapy	Placebo n=33 participants at risk Placebo to match entospletinib tablets for 48 weeks in combination with systemic corticosteroids as first-line therapy
Blood and lymphatic system disorders Anaemia	12.5% 4/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Blood and lymphatic system disorders Lymphopenia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Blood and lymphatic system disorders Neutropenia	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Blood and lymphatic system disorders Thrombocytopenia	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	9.1% 3/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Cardiac disorders Tachycardia	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Eye disorders Dry eye	12.5% 4/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Eye disorders Keratitis	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Eye disorders Vision blurred	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Abdominal pain	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	15.2% 5/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Abdominal pain upper	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Constipation	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	9.1% 3/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Diarrhoea	15.6% 5/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Dry mouth	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Nausea	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Gastrointestinal disorders Vomiting	12.5% 4/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Asthenia	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	9.1% 3/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Chest pain	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Fatigue	25.0% 8/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Oedema peripheral	15.6% 5/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	18.2% 6/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
General disorders Pyrexia	15.6% 5/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Candida infection	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	9.1% 3/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Cytomegalovirus infection	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Influenza	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	9.1% 3/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Lower respiratory tract infection	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Nasopharyngitis	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Oral candidiasis	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Respiratory tract infection	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Sinusitis	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Upper respiratory tract infection	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Infections and infestations Urinary tract infection	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Injury, poisoning and procedural complications Contusion	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Alanine aminotransferase increased	12.5% 4/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	15.2% 5/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Amylase increased	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Aspartate aminotransferase increased	12.5% 4/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Blood alkaline phosphatase increased	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Gamma-glutamyltransferase increased	15.6% 5/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Neutrophil count decreased	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Platelet count decreased	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Investigations Weight increased	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Decreased appetite	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hypercholesterolaemia	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hyperglycaemia	15.6% 5/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hypertriglyceridaemia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	12.1% 4/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hypokalaemia	15.6% 5/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hypomagnesaemia	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hyponatraemia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Hypophosphataemia	3.1% 1/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Metabolism and nutrition disorders Vitamin D deficiency	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Arthralgia	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	9.1% 3/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Back pain	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Muscular weakness	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Myalgia	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Myositis	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Musculoskeletal and connective tissue disorders Pain in extremity	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Nervous system disorders Dizziness	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Nervous system disorders Neuropathy peripheral	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Nervous system disorders Paraesthesia	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Psychiatric disorders Anxiety	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Psychiatric disorders Insomnia	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Renal and urinary disorders Micturition disorder	0.00% 0/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	6.1% 2/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Cough	12.5% 4/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	21.2% 7/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Respiratory, thoracic and mediastinal disorders Nasal congestion	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	0.00% 0/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Skin and subcutaneous tissue disorders Dry skin	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	9.1% 3/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Skin and subcutaneous tissue disorders Rash	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Skin and subcutaneous tissue disorders Rash maculo-papular	6.2% 2/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.
Vascular disorders Hypertension	9.4% 3/32 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.	3.0% 1/33 • Baseline up to the last dose date plus 30 days (average exposure: ENTO = 18 weeks; Placebo = 17 weeks) Safety Analysis Set: all participants who received at least 1 dose of study drug, with treatment assignments designated according to actual treatment received.

Additional Information

Gilead Clinical Study Information Center

Gilead Sciences

Phone: 1-833-445-3230 (GILEAD-0)

Email: GileadClinicalTrials@gilead.com

Results disclosure agreements

• Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
• Publication restrictions are in place

Restriction type: OTHER