parallel randomized trial

SYNERGY-NASH

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study Comparing the Efficacy and Safety of Tirzepatide Versus Placebo in Patients With Nonalcoholic Steatohepatitis (NASH)

Metabolic dysfunction associated steatotic liver disease or steatohepatitis NCT04166773S000031

Design

Randomized: 190
Start year: 2019
Treatment: 52 weeks, follow-up 56 weeks
Countries: Belgium, France, Israel, Italy, Japan, Mexico, Poland, Spain, United Kingdom, United States (130 sites)
Sponsor: Eli Lilly and Company (industry)
Eligibility: age 18 to 80, BMI 27 to 50, biopsy MASH with NAS 4 or more and fibrosis F2 to F3, HbA1c up to 9.5 percent

Conduct and analysis

Blinding: double blind
Sequence generation: other adequate
Allocation concealment: central
Outcome adjudication: yes
Primary estimand: treatment policy
Analysis population: full analysis
Missing data: multiple imputation

Arms

Arm	Treatment	Background	Randomized	Analyzed	Completed treatment
A1	Tirzepatide 5 mg subcutaneous once weekly Tirzepatide 5 mg	stable non insulin glucose lowering drugs in participants with T2D; lifestyle: standard	47	47	40
A2	Tirzepatide 10 mg subcutaneous once weekly Tirzepatide 10 mg	stable non insulin glucose lowering drugs in participants with T2D; lifestyle: standard	47	47	42
A3	Tirzepatide 15 mg subcutaneous once weekly Tirzepatide 15 mg	stable non insulin glucose lowering drugs in participants with T2D; lifestyle: standard	48	48	42
A4	Placebo Placebo	stable non insulin glucose lowering drugs in participants with T2D; lifestyle: standard	48	48	37
A5	Pooled Tirzepatide groups pooled

Baseline characteristics

As printed in the trial reports or registry, per arm or for the whole trial.

Characteristic	Statistic	Tirzepatide 5 mg subcutaneous once weekly A1	Tirzepatide 10 mg subcutaneous once weekly A2	Tirzepatide 15 mg subcutaneous once weekly A3	Placebo A4
age	mean (years)	55.0	54.3	54.9	53.5
age	sd (years)	11.6	12.1	10.0	11.6
asian	n	5	6	6	5
asian	percent	11	13	12	10
black	n	0	1	0	0
black	percent		2
bmi	mean (kg/m2)	36.1	36.6	35.9	36.0
bmi	sd (kg/m2)	6.0	6.3	5.7	6.7
female	n	27	26	29	27
female	percent	57	55	60	56
fibrosis stage: f2	n	17	25	22	17
fibrosis stage: f2	percent	36	53	46	35
fibrosis stage: f3	n	30	22	26	31
fibrosis stage: f3	percent	64	47	54	65
hba1c	mean (percent)	6.6	6.4	6.4	6.8
hba1c	sd (percent)	1.3	1.1	0.9	1.2
hispanic	n	19	15	17	18
hispanic	percent	40	32	35	38
other race american indian alaska native	n	1	1	1	0
other race american indian alaska native	percent	2	2	2
other race multiple	n	0	0	0	0
other race native hawaiian pacific islander	n	0	0	0	0
weight	mean (kg)	100.7	102.6	100.0	96.0
weight	sd (kg)	22.2	23.8	18.1	21.6
white	n	41	39	41	43
white	percent	87	83	85	90

Analyses this trial contributes to

Results

138 adjudicated result lines, grouped by outcome. Open an outcome to see its values.

HbA1c change (7 lines; O01)

Week	Arm	Statistic	Estimate	SE or SD	95% CI	Detail
52	A1	change	-1.4 percent	0.2		not stated; other; diabetes:t2d; R0018381:Supplement Table S5
52	A1 vs A4	md	-1.3 percent		-1.8 to -0.8	not stated; other; diabetes:t2d; R0018381:Supplement Table S5
52	A2	change	-1.4 percent	0.2		not stated; other; diabetes:t2d; R0018381:Supplement Table S5
52	A2 vs A4	md	-1.3 percent		-1.8 to -0.9	not stated; other; diabetes:t2d; R0018381:Supplement Table S5
52	A3	change	-1.4 percent	0.2		not stated; other; diabetes:t2d; R0018381:Supplement Table S5
52	A3 vs A4	md	-1.3 percent		-1.8 to -0.8	not stated; other; diabetes:t2d; R0018381:Supplement Table S5
52	A4	change	-0.1 percent	0.2		not stated; other; diabetes:t2d; R0018381:Supplement Table S5

Percent body weight change (14 lines; O10)

Week	Arm	Statistic	Estimate	95% CI	Detail
52	A1	percent change	-11.4 percent		treatment policy; other; diabetes:t2d; R0018381:Supplement Figure S6C
52	A1	percent change	-10.7 percent		treatment policy; full analysis; R0018381:Supplement Figure S6A
52	A1 vs A4	md	-9.9 percent	-13.9 to -5.8	treatment policy; full analysis; R0018381:Supplement Figure S6A
52	A1 vs A4	md	-10.1 percent	-14.9 to -5.3	treatment policy; other; diabetes:t2d; R0018381:Supplement Figure S6C
52	A2	percent change	-13.3 percent		treatment policy; full analysis; R0018381:Supplement Figure S6A
52	A2 vs A4	md	-10.8 percent	-15.3 to -6.2	treatment policy; other; diabetes:t2d; R0018381:Supplement Figure S6C
52	A2	percent change	-12.0 percent		treatment policy; other; diabetes:t2d; R0018381:Supplement Figure S6C
52	A2 vs A4	md	-12.5 percent	-16.4 to -8.6	treatment policy; full analysis; R0018381:Supplement Figure S6A
52	A3	percent change	-13.7 percent		treatment policy; other; diabetes:t2d; R0018381:Supplement Figure S6C
52	A3	percent change	-15.6 percent		treatment policy; full analysis; R0018381:Supplement Figure S6A
52	A3 vs A4	md	-14.8 percent	-18.7 to -10.9	treatment policy; full analysis; R0018381:Supplement Figure S6A
52	A3 vs A4	md	-12.4 percent	-16.9 to -7.9	treatment policy; other; diabetes:t2d; R0018381:Supplement Figure S6C
52	A4	percent change	-0.8 percent		treatment policy; full analysis; R0018381:Supplement Figure S6A
52	A4	percent change	-1.3 percent		treatment policy; other; diabetes:t2d; R0018381:Supplement Figure S6C

Serious adverse events (4 lines; O25)

Arm	Statistic	Events / N	Detail
A1	events	5 / 47	not stated; randomized; R0018381:Table 3
A2	events	4 / 47	not stated; randomized; R0018381:Table 3
A3	events	0 / 48	not stated; randomized; R0018381:Table 3
A4	events	3 / 48	not stated; randomized; R0018381:Table 3

Discontinuation due to adverse events (8 lines; O26)

Arm	Statistic	Events / N	Detail
A1	events	2 / 47	not stated; randomized; R0018381:Table 3
A1	events	2 / 47	not stated; randomized; R0018381:Supplement Figure S1
A2	events	0 / 47	not stated; randomized; R0018381:Supplement Figure S1
A2	events	0 / 47	not stated; randomized; R0018381:Table 3
A3	events	4 / 48	not stated; randomized; R0018381:Table 3
A3	events	2 / 48	not stated; randomized; R0018381:Supplement Figure S1
A4	events	1 / 48	not stated; randomized; R0018381:Supplement Figure S1
A4	events	2 / 48	not stated; randomized; R0018381:Table 3

Nausea (4 lines; O27A)

Arm	Statistic	Events / N	Detail
A1	events	17 / 47	not stated; randomized; R0018381:Table 3
A2	events	16 / 47	not stated; randomized; R0018381:Table 3
A3	events	21 / 48	not stated; randomized; R0018381:Table 3
A4	events	6 / 48	not stated; randomized; R0018381:Table 3

Vomiting (4 lines; O27B)

Arm	Statistic	Events / N	Detail
A1	events	3 / 47	not stated; randomized; R0018381:Table 3
A2	events	3 / 47	not stated; randomized; R0018381:Table 3
A3	events	7 / 48	not stated; randomized; R0018381:Table 3
A4	events	1 / 48	not stated; randomized; R0018381:Table 3

Diarrhea (4 lines; O27C)

Arm	Statistic	Events / N	Detail
A1	events	15 / 47	not stated; randomized; R0018381:Table 3
A2	events	17 / 47	not stated; randomized; R0018381:Table 3
A3	events	13 / 48	not stated; randomized; R0018381:Table 3
A4	events	11 / 48	not stated; randomized; R0018381:Table 3

Constipation (4 lines; O27D)

Arm	Statistic	Events / N	Detail
A1	events	11 / 47	not stated; randomized; R0018381:Table 3
A2	events	9 / 47	not stated; randomized; R0018381:Table 3
A3	events	7 / 48	not stated; randomized; R0018381:Table 3
A4	events	3 / 48	not stated; randomized; R0018381:Table 3

Discontinuation due to gastrointestinal adverse events (4 lines; O27E)

Arm	Statistic	Events / N	Detail
A1	events	2 / 47	not stated; randomized; R0018381:Table 3
A2	events	0 / 47	not stated; randomized; R0018381:Table 3
A3	events	2 / 48	not stated; randomized; R0018381:Table 3
A4	events	1 / 48	not stated; randomized; R0018381:Table 3

Gallbladder and biliary disease (18 lines; O28)

Arm	Statistic	Events / N	Detail
A1	events	0 / 47	not stated; safety; cholangitis; registry:adverse_events
A1	events	0 / 47	not stated; safety; biliary colic; registry:adverse_events
A1	events	0 / 47	not stated; randomized; cholecystitis; R0018381:Supplement Table S7
A1	events	0 / 47	not stated; safety; cholelithiasis; registry:adverse_events
A2	events	1 / 47	not stated; safety; cholelithiasis; registry:adverse_events
A2	events	0 / 47	not stated; safety; biliary colic; registry:adverse_events
A2	events	1 / 47	not stated; safety; cholangitis; registry:adverse_events
A2	events	1 / 47	not stated; randomized; cholecystitis; R0018381:Supplement Table S7
A3	events	0 / 48	not stated; safety; cholangitis; registry:adverse_events
A3	events	1 / 48	not stated; safety; biliary colic; registry:adverse_events
A3	events	0 / 48	not stated; randomized; cholecystitis; R0018381:Supplement Table S7
A3	events	0 / 48	not stated; safety; cholelithiasis; registry:adverse_events
A4	events	1 / 48	not stated; randomized; R0018381:Results
A4	events	0 / 48	not stated; safety; biliary colic; registry:adverse_events
A4	events	0 / 48	not stated; safety; cholangitis; registry:adverse_events
A4	events	0 / 48	not stated; randomized; cholecystitis; R0018381:Supplement Table S7
A4	events	1 / 48	not stated; safety; cholelithiasis; registry:adverse_events
A5	events	4 /	not stated; randomized; R0018381:Results

Acute pancreatitis (8 lines; O29)

Arm	Statistic	Events / N	Detail
A1	events	1 / 47	not stated; safety; pancreatitis; registry:adverse_events
A1	events	0 / 47	not stated; randomized; R0018381:Results
A2	events	0 / 47	not stated; safety; pancreatitis; registry:adverse_events
A2	events	0 / 47	not stated; randomized; R0018381:Results
A3	events	0 / 48	not stated; safety; pancreatitis; registry:adverse_events
A3	events	0 / 48	not stated; randomized; R0018381:Results
A4	events	0 / 48	not stated; randomized; R0018381:Results
A4	events	0 / 48	not stated; safety; pancreatitis; registry:adverse_events

Death by suicide (4 lines; O35B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 47	not stated; safety; registry:adverse_events
A2	events	0 / 47	not stated; safety; registry:adverse_events
A3	events	0 / 48	not stated; randomized; R0018381:Table 3
A4	events	0 / 48	not stated; safety; registry:adverse_events

Intestinal obstruction or ileus (4 lines; O37B)

Arm	Statistic	Events / N	Detail
A1	events	0 / 47	not stated; safety; small intestinal obstruction; registry:adverse_events
A2	events	1 / 47	not stated; safety; small intestinal obstruction; registry:adverse_events
A3	events	0 / 48	not stated; safety; small intestinal obstruction; registry:adverse_events
A4	events	0 / 48	not stated; safety; small intestinal obstruction; registry:adverse_events

Resolution of steatohepatitis without worsening of fibrosis (20 lines; O60)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1 vs A4	or	7.45	2.27 to 24.44		hypothetical; other; registry:outcomes
52	A1	responders	44		47	treatment policy; full analysis; R0018381:Figure 1A
52	A1	responders	51.8		39	hypothetical; other; R0018381:Supplement Figure S2
52	A1 vs A4	rd	34	17 to 50		treatment policy; full analysis; R0018381:Figure 1A
52	A1 vs A4	rd	38.6	19.6 to 57.7		hypothetical; other; R0018381:Supplement Figure S2
52	A2	responders	56		47	treatment policy; full analysis; R0018381:Figure 1A
52	A2	responders	62.8		41	hypothetical; other; R0018381:Supplement Figure S2
52	A2	responders	63.13		41	hypothetical; other; registry:outcomes
52	A2 vs A4	or	11.86	3.59 to 39.11		hypothetical; other; registry:outcomes
52	A2 vs A4	rd	49.6	31.1 to 68.1		hypothetical; other; R0018381:Supplement Figure S2
52	A2 vs A4	rd	46	29 to 62		treatment policy; full analysis; R0018381:Figure 1A
52	A3 vs A4	or	19.63	5.73 to 67.25		hypothetical; other; registry:outcomes
52	A3	responders	73.3		40	hypothetical; other; R0018381:Supplement Figure S2
52	A3	responders	73.92		40	hypothetical; other; registry:outcomes
52	A3 vs A4	rd	60.1	42.4 to 77.9		hypothetical; other; R0018381:Supplement Figure S2
52	A3	responders	62		48	treatment policy; full analysis; R0018381:Figure 1A
52	A3 vs A4	rd	53	37 to 69		treatment policy; full analysis; R0018381:Figure 1A
52	A4	responders	13.2		35	hypothetical; other; R0018381:Supplement Figure S2
52	A4	responders	12.62		35	hypothetical; other; registry:outcomes
52	A4	responders	10		48	treatment policy; full analysis; R0018381:Figure 1A

Fibrosis improvement without worsening of steatohepatitis (31 lines; O61)

Week	Arm	Statistic	Estimate	95% CI	Events / N	Detail
52	A1	responders	67.0		17	treatment policy; other; fibrosis_stage:f2; R0018381:Supplement Figure S3
52	A1	responders	46.4		30	treatment policy; other; fibrosis_stage:f3; R0018381:Supplement Figure S3
52	A1 vs A4	rd	26.7	2.3 to 51.0		treatment policy; other; fibrosis_stage:f3; R0018381:Supplement Figure S3
52	A1	responders	59.21		39	hypothetical; other; registry:outcomes
52	A1	responders	55		47	treatment policy; full analysis; R0018381:Figure 1B
52	A1 vs A4	rd	25	5 to 46		treatment policy; full analysis; R0018381:Figure 1B
52	A1 vs A4	or	3.01	1.15 to 7.90		hypothetical; other; registry:outcomes
52	A1 vs A4	rd	26.2	4.5 to 48.0		hypothetical; other; R0016171:Results
52	A1 vs A4	rd	18.8	-15.9 to 53.6		treatment policy; other; fibrosis_stage:f2; R0018381:Supplement Figure S3
52	A2	responders	55.1		25	treatment policy; other; fibrosis_stage:f2; R0018381:Supplement Figure S3
52	A2 vs A4	or	2.37	0.92 to 6.13		hypothetical; other; registry:outcomes
52	A2	responders	42.8		22	treatment policy; other; fibrosis_stage:f3; R0018381:Supplement Figure S3
52	A2 vs A4	rd	22	1 to 42		treatment policy; full analysis; R0018381:Figure 1B
52	A2 vs A4	rd	23.0	-3.6 to 49.6		treatment policy; other; fibrosis_stage:f3; R0018381:Supplement Figure S3
52	A2 vs A4	rd	20.5	-1.3 to 42.2		hypothetical; other; R0016171:Results
52	A2	responders	53.35		41	hypothetical; other; registry:outcomes
52	A2 vs A4	rd	6.9	-24.9 to 38.7		treatment policy; other; fibrosis_stage:f2; R0018381:Supplement Figure S3
52	A2	responders	51		47	treatment policy; full analysis; R0018381:Figure 1B
52	A3	responders	51		48	treatment policy; full analysis; R0018381:Figure 1B
52	A3	responders	54.3		40	hypothetical; other; registry:outcomes
52	A3 vs A4	or	2.47	0.95 to 6.40		hypothetical; other; registry:outcomes
52	A3 vs A4	rd	21.4	-0.41 to 43.3		hypothetical; other; R0016171:Results
52	A3 vs A4	rd	27.5	2.2 to 52.7		treatment policy; other; fibrosis_stage:f3; R0018381:Supplement Figure S3
52	A3 vs A4	rd	21	1 to 42		treatment policy; full analysis; R0018381:Figure 1B
52	A3	responders	56.3		22	treatment policy; other; fibrosis_stage:f2; R0018381:Supplement Figure S3
52	A3 vs A4	rd	8.2	-24.7 to 41.1		treatment policy; other; fibrosis_stage:f2; R0018381:Supplement Figure S3
52	A3	responders	47.2		26	treatment policy; other; fibrosis_stage:f3; R0018381:Supplement Figure S3
52	A4	responders	30		48	treatment policy; full analysis; R0018381:Figure 1B
52	A4	responders	19.8		31	treatment policy; other; fibrosis_stage:f3; R0018381:Supplement Figure S3
52	A4	responders	32.51		35	hypothetical; other; registry:outcomes
52	A4	responders	48.1		17	treatment policy; other; fibrosis_stage:f2; R0018381:Supplement Figure S3