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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

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This study is researching a condition called Metabolic Dysfunction-Associated Steatotic Liver Disease, which is a condition where excess fat builds up in the liver and can lead to liver scarring and damage over time. The study will test several different medications to see if they can help prevent serious liver problems from developing. The medications being studied include tirzepatide (also known by its code name LY3298176), which is given as an injection using a pre-filled pen, and retatrutide (also known as LY3437943), which is also given as an injection. Some participants will receive placebo instead of active medication. All study medications are given by injection under the skin.

The purpose of this study is to find out whether the study medications are better than placebo at reducing the occurrence of major liver-related complications. During the study, researchers will monitor participants for various liver problems including progression to cirrhosis (severe liver scarring), development of complications like varices (enlarged veins in the digestive tract), ascites (fluid buildup in the abdomen), hepatic encephalopathy (brain function problems caused by liver disease), and other serious liver conditions. The study will also track whether participants need liver transplantation or experience other serious outcomes.

Participants in this study will receive their assigned treatment over an extended period while being regularly monitored by the study team. The study requires participants to have evidence of liver fat confirmed by MRI (a type of imaging scan) and liver scarring confirmed through non-invasive tests, though a liver biopsy is not required to join the study. Throughout the study, participants will have regular check-ups and assessments to evaluate how well the treatment is working and to monitor their liver health and overall wellbeing.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Study entry

    After providing consent, you receive a study identification number and are scheduled for the first clinic visit, called the baseline visit.

  2. Step 2

    Baseline assessments and randomization

    At the baseline visit, a series of assessments are performed, including medical history, physical examination, blood tests, and imaging to document your liver condition.

    Based on the study design, you are randomly assigned to receive either tirzepatide, retatrutide, or a matching placebo. the assignment is done by the study system and you are not involved in the choice.

  3. Step 3

    Medication training

    You receive instruction on how to use a pre‑filled pen for subcutaneous injection. the training includes where to inject, how to prepare the dose, and how to record each injection.

  4. Step 4

    Initiation of study medication

    You begin the study medication immediately after the baseline visit.

    The medication is given as a subcutaneous injection once each week.

    The specific dose is defined by the study protocol and may be adjusted during the trial according to safety and response criteria.

    Treatment continues for the entire study period, which lasts up to about 224 weeks from the baseline visit.

  5. Step 5

    Regular follow‑up visits

    You attend clinic visits approximately every four weeks.

    During each visit, blood tests, liver imaging, and physical examinations are performed to monitor your health and the effect of the medication.

    The study staff review any side effects you have experienced and may adjust the dose if required.

  6. Step 6

    Ongoing self‑monitoring

    You keep a diary of each weekly injection, noting the date, time, and any symptoms you notice.

    You are instructed to report any serious or unexpected symptoms to the study team promptly.

  7. Step 7

    Study completion and final assessment

    After approximately 224 weeks, the study reaches its planned end date.

    A final set of assessments, including blood tests, imaging, and a physical exam, is performed to evaluate the overall outcome.

    The study medication is discontinued, and you receive a summary of the study results and any follow‑up recommendations.

Who can join the trial?

5 criteria

  • Must have liver fat (called hepatic steatosis) that was shown on an MRI scan, which is a special type of picture of the inside of your body.
  • Must have liver scarring (called liver fibrosis) that was shown by tests that do not require a needle or surgery, known as non‑invasive tests.
  • A liver biopsy (taking a tiny piece of liver tissue) is not needed to join the study.
  • Both men and women are allowed to take part.
  • You must be in the age groups that the study includes (the trial allows participants in the age ranges coded as 3 and 4).

Who cannot join the trial?

6 criteria

  • You have any other kind of liver disease besides Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
  • Your body mass index (BMI) is less than 25 kg/m², meaning you are below the weight range needed for the study (BMI is a measure of weight compared to height).
  • You have a history of cirrhosis (scarring of the liver) or related problems such as enlarged veins in the esophagus or stomach (esophageal/gastric varices), fluid buildup in the abdomen (ascites), brain issues caused by liver failure (hepatic encephalopathy), or a diagnosis of cirrhosis from a liver biopsy.
  • You have lost more than 11 pounds (about 5 kg) in the three months before screening.
  • Your hemoglobin A1c (HbA1c) level is greater than 10%, indicating very high average blood sugar over the past three months.
  • You have type 1 diabetes, a condition where the body does not produce insulin.
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Investigated drugs

  • Tirzepatide

    is a medication that is injected under the skin using a pre‑filled pen. It works by activating hormones that help control blood sugar and can also reduce fat and inflammation in the liver. In this study, people with high‑risk metabolic dysfunction‑associated steatotic liver disease (MASLD) receive tirzepatide to find out if it lowers the chance of serious liver problems.

  • Retatrutide

    is a medication given as an injection under the skin in a liquid form. It targets similar pathways as tirzepatide and is being tested to see if it can improve liver health and lower the risk of major adverse liver outcomes in participants with high‑risk MASLD.

What is already known about the treatment

  • Tirzepatide

    Tirzepatide is supplied as a clear solution for injection in a pre‑filled pen and is given by subcutaneous injection. It is an approved medicine for type 2 diabetes and obesity and is now being studied for high‑risk MASLD. The drug works by activating two gut hormones, GLP‑1 and GIP, which together lower blood sugar, reduce appetite, and improve liver fat. It belongs to the class of peptide hormone analogs known as dual GLP‑1/GIP receptor agonists.

  • Retatrutide

    Retatrutide is provided as a sterile solution for injection and is administered by subcutaneous injection. It is still an investigational drug that is being tested in clinical trials for people with high‑risk MASLD. The molecule activates three hormone receptors – GLP‑1, GIP, and glucagon – helping to lower blood sugar, cut appetite, and increase the breakdown of liver fat. It is classified as a triple‑agonist peptide therapeutic.

Investigated diseases

Metabolic Dysfunction-Associated Steatotic Liver Disease - A condition where excess fat accumulates in the liver because of metabolic problems such as obesity or diabetes. The fat buildup can cause the liver to become inflamed and swell. Over time, repeated inflammation may lead to the liver tissue becoming stiff and scarred. As scarring increases, the liver’s ability to filter blood and process nutrients can gradually decline.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-522674-36-00Protocol codeN1T-MC-MALOEstimated enrolment4 500 patientsSponsorEli Lilly & Co.

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