N1T-MC-MALO: A Master Protocol for a Randomized, Controlled, Clinical Trial of Multiple Pharmacologic Agents in Adult Participants With Metabolic Dysfunction-Associated Steatotic Liver Disease Who Are at Increased Risk of Developing Major Adverse Liver Outcomes (SYNERGY-Outcomes); N1T-MC-TZ01 Tirzepatide in participants with high-risk MASLD; N1T-MC-RT01 Retatrutide in participants with high-risk MASLD

The primary objective of this trial is to demonstrate whether the primary intervention is superior to the primary control in reducing the occurrence of major adverse liver outcomes (MALO) in adult participants with metabolic dysfunction-associated steatotic liver disease (MASLD) who are at increased risk of developing such outcomes. This master protocol evaluates multiple pharmacologic agents, specifically tirzepatide and retatrutide, compared to placebo in this high-risk population. The clinical relevance of this objective lies in addressing the progression of MASLD to serious hepatic complications, which represent significant morbidity and mortality in patients with advanced metabolic liver disease.

This clinical trial enrolled a total of **3995 participants** diagnosed with **Metabolic Dysfunction-Associated Steatotic Liver Disease**. The study population included both **male and female subjects** across **adult and elderly age groups**. Participants were selected based on the presence of **hepatic steatosis** confirmed by **MRI** and **liver fibrosis** identified through non-invasive diagnostic tests. Notably, **liver biopsy** was not required for enrollment in this trial. The trial population consisted of **patients** with confirmed liver pathology meeting specific diagnostic thresholds. No vulnerable populations were included in this study.

This clinical trial employs a master protocol design to evaluate multiple pharmacologic agents in adult participants with metabolic dysfunction-associated steatotic liver disease who are at increased risk of developing major adverse liver outcomes. The trial is designed as a randomized, controlled study classified as a Phase III clinical trial. The investigational products include tirzepatide, administered as a solution for injection in pre-filled pen via subcutaneous injection, and retatrutide (LY3437943 sodium), administered as a solution for injection via subcutaneous injection. Both active substances are of protein origin. Placebo controls matching the investigational products are utilized to maintain blinding and enable comparison with the primary intervention. The study is categorized as a Category 2 trial, as it assesses a non-authorized investigational medicinal product and a new indication for an authorized investigational medicinal product to investigate safety and efficacy.

The primary objective of the trial is to demonstrate whether the primary intervention is superior to the primary control in reducing the occurrence of major adverse liver outcomes. The primary endpoint is the time to first occurrence of any component of the composite endpoint for major adverse liver outcomes, which includes progression to cirrhosis, development of large esophageal varices, gastric varices or development of varices requiring treatment, development of ascites, development of hepatic encephalopathy, evidence of active or recent variceal hemorrhage, increase in model for end-stage liver disease score from 12 or below to 15 or above, liver transplantation, and all-cause mortality. This composite endpoint will be assessed from baseline up to study completion, which is approximately 224 weeks.

Participants eligible for enrollment must have hepatic steatosis (liver fat) diagnosed with magnetic resonance imaging, and liver fibrosis diagnosed with non-invasive tests. Importantly, liver biopsy is not required for enrollment in this trial. The screening procedures utilize non-invasive diagnostic methods to identify participants who meet the inclusion criteria based on the presence of liver fat and fibrosis, ensuring that participants are at increased risk of developing major adverse liver outcomes without the need for invasive diagnostic procedures.

The estimated recruitment start date for the trial is March 3, 2026, with an estimated completion date of October 11, 2029. The overall trial duration is expected to extend over several years to adequately assess the long-term effects of the interventions on major adverse liver outcomes. Participant involvement will span approximately 224 weeks, during which time they will attend scheduled study visits for assessment of efficacy and safety parameters. The trial protocol may include provisions for early termination of individual participants from the study under specific conditions, such as development of unacceptable adverse events, withdrawal of consent, loss to follow-up, or investigator decision based on safety considerations or protocol non-compliance.

Tirzepatide (sponsor product code LY3298176) is administered as a solution for injection in a pre-filled pen. The active substance is tirzepatide, which is classified as a protein-based compound. The medicinal product is administered via subcutaneous injection. Multiple formulations of tirzepatide in pre-filled pen devices are utilized in this clinical trial as experimental interventions. The treatment period is defined as one week. This investigational medicinal product is manufactured by Eli Lilly and Company Limited and serves as a test intervention in the study protocol.

Retatrutide (sponsor product code LY3437943) is administered as a solution for injection. The active substance is LY3437943 sodium, which is classified as a protein-based compound. The medicinal product is administered via subcutaneous injection. Multiple formulations of retatrutide solution for injection are utilized in this clinical trial as experimental interventions. The treatment period is defined as one week. This investigational medicinal product is manufactured by Eli Lilly and Company Limited and serves as a test intervention in the study protocol.

Placebo to match LY is utilized as a control intervention in this clinical trial. The placebo is designed to match the active investigational products in appearance and administration characteristics. The treatment period for placebo administration is defined as one month. The placebo serves as a comparator to evaluate the efficacy and safety of the experimental interventions.

Efficacy will be assessed through evaluation of the time to first occurrence of any component of the composite endpoint for Major Adverse Liver Outcomes (MALO). The composite endpoint comprises 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, and all-cause mortality. Efficacy parameters will be measured from baseline up to study completion at approximately 224 weeks. The primary objective is to demonstrate whether the primary intervention is superior to the primary control in reducing the occurrence of MALO.