A Master Protocol of Multiple Agents in Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (SYNERGY-Outcomes)

Not Applicable

Not yet recruiting

• Conditions: Metabolic Dysfunction-Associated Steatotic Liver Disease
• Interventions: Drug: Tirzepatide; Drug: Placebo; Drug: Retatrutide

• Registration Number: NCT07165028
• Lead Sponsor: Eli Lilly and Company

Brief Summary

The main purpose of the SYNERGY-OUTCOMES study is to find out whether retatrutide and tirzepatide can prevent major adverse liver outcomes (MALO) in people with high-risk metabolic dysfunction-associated steatotic liver disease (MASLD). The study will enroll adults who have MASLD based on non-invasive tests (NITs), which indicate they are more likely to develop MALO. Participants will be randomly assigned within a Master Protocol to receive either retatrutide (N1T-MC-RT01), tirzepatide (N1T-MC-TZ01) or placebo. The trial plans to enroll about 4,500 adults and will run for approximately 224 weeks. Participants may have up to approximately 25 to 30 clinic visits throughout the study to monitor their health, complete study procedures, and assess liver function and disease progression.

Once the study is complete, eligible participants may participate in an optional 2-year extension study, in which all participants will receive either retatrutide or tirzepatide, even if they received placebo in the main study.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-08-28
• Status Verified: 2025-09
• Study First Submitted QC: 2025-09-03
• Last Update Submitted: 2025-09-03
• Study First Posted: 2025-09-10
• Last Update Posted: 2025-09-10
• Study Start: 2025-12-01
• Primary Completion: 2030-08
• Study Completion: 2032-08-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 4500

Inclusion Criteria

• Have liver fat content ≥8%
• Have ELF score of ≥9 and ≤10.8 at screening
• Have VCTE LSM ≥10 kilopascal (kPa) and <20 kPa at screening

Exclusion Criteria

• Have any other type of liver disease other than MASLD
• Have a body mass index (BMI) <25 kilogram per square meter (kg/m2)
• Prior decompensated liver disease (history of esophageal/gastric varices, ascites, hepatic encephalopathy)
• Have lost more than 11 pounds within the 3 months prior to screening
• Have a hemoglobin A1c (HbA1c) greater than 10%
• Have type 1 diabetes

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tirzepatide (TZ01)	Tirzepatide	Participants will receive tirzepatide subcutaneously (SC)
Placebo (TZ01)	Placebo	Participants will receive placebo SC
Retatrutide (RT01)	Retatrutide	Participants will receive retatrutide SC
Placebo (RT01)	Placebo	Participants will receive placebo SC

Primary Outcome Measures

Name	Time	Method
Time to First Occurrence of Any Component of the Composite Endpoint for Major Adverse Liver Outcomes (MALO)	Baseline up to Study Completion (about 224 weeks)	Composite endpoint comprised of progression to cirrhosis, development of large esophageal varices, gastric varices or development of varices needing treatment, development of ascites, development of hepatic encephalopathy, evidence of active or recent variceal hemorrhage, increase in model for end-stage liver disease (MELD) from ≤12 to ≥15, liver transplantation, all-cause mortality

Secondary Outcome Measures

Name	Time	Method
Change from Baseline in Enhanced Liver Fibrosis (ELF) Score	Baseline, Week 104
Percent Change from Baseline in Liver Fat Content (LFC)	Baseline, Week 104
Change from Baseline in Non-Alcoholic Steatohepatitis-CHECK Score (NASH-CHECK)	Baseline, Week 104
Change from Baseline in Vibration-Controlled Transient Elastography Liver Stiffness Measurement (VCTE LSM)	Baseline, Week 104
Time to Occurrence of Progression to Cirrhosis	Baseline up to Study Completion (about 224 weeks)
Change from Baseline in Aspartate Aminotransferase (AST)	Baseline, Study Completion (about 224 weeks)
Change from Baseline in Alanine Aminotransferase (ALT)	Baseline, Study Completion (about 224 weeks)
Change from Baseline in Body Weight	Baseline, Study Completion (about 224 weeks)
Time to First Occurrence of Any Component Event of the Composite Endpoint of Major Adverse Cardiovascular Events (MACE-3)	Baseline up to Study Completion (about 224 weeks)	MACE-3 composite endpoint includes nonfatal myocardial infarction, nonfatal stroke, cardiovascular death

Trial Locations

Locations (211)

Spectrum Research Institute; 🇺🇸 Gilbert, Arizona, United States

Adobe Gastroenterology; 🇺🇸 Tucson, Arizona, United States

Del Sol Research Management, LLC; 🇺🇸 Tucson, Arizona, United States

San Fernando Valley Health Institute; 🇺🇸 Canoga Park, California, United States

Ark Clinical Research - Fountain Valley; 🇺🇸 Fountain Valley, California, United States

Fresno Clinical Research Center; 🇺🇸 Fresno, California, United States

UCSD - Altman Clinical and Translational Research Institute (ACTRI); 🇺🇸 La Jolla, California, United States

Ark Clinical Research; 🇺🇸 Long Beach, California, United States

United Medical Doctors - Murrieta; 🇺🇸 Murrieta, California, United States

California Liver Research Center; 🇺🇸 Pasadena, California, United States

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