A Study of Tirzepatide (LY3298176) in Participants With Nonalcoholic Steatohepatitis (NASH) (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)

The purpose of this study is to see if the study drug, tirzepatide administered once weekly, is safe and effective as a treatment for Nonalcoholic Steatohepatitis (NASH).

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis
• Intervention / Treatment: Drug: Tirzepatide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 190
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Antwerp University Hospital
  • Bruxelles-Capitale, Région De
    • Brussels, Bruxelles-Capitale, Région De, Belgium, 1090
      • UZ Brussel
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium, 9000
      • UZ Gent
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • UZ Leuven
  • West-Vlaanderen
    • Roeselare, West-Vlaanderen, Belgium, 8800
      • AZ Delta vzw
• France
  • Paris, France, 75571
    • Hôpital Saint Antoine
  • Paris, France, 75013
    • Pitie Salpetriere University Hospital
  • Aquitaine
    • Pessac, Aquitaine, France, 33600
      • CHU Bordeaux Haut-Levêque
  • Haute-Vienne
    • Limoges, Haute-Vienne, France, 87042
      • Centre Hospitalier Universitaire de Limoges - Hôpital Dupuytren
  • Maine-et-Loire
    • Angers, Maine-et-Loire, France, 49933
      • Centre Hospitalier Universitaire d'Angers
  • Rhône
    • Pierre-Bénite, Rhône, France, 69494 Cédex
      • Centre Hospitalier Lyon Sud
  • Rhône-Alpes
    • Vénissieux, Rhône-Alpes, France, 69200
      • Groupe Hospitalier Mutualiste Les Portes du Sud
• Israel
  • Haifa, Israel, 3436212
    • Carmel Hospital
  • HaMerkaz
    • Ramat Gan, HaMerkaz, Israel, 5265601
      • Sheba Medical Center
  • HaTsafon
    • Haifa, HaTsafon, Israel, 3109601
      • Rambam Health Care Campus
    • Nahariya, HaTsafon, Israel, 2210001
      • Galilee Medical Center
  • Yerushalayim
    • Jerusalem, Yerushalayim, Israel, 9112001
      • Hadassah Medical Center
    • Jerusalem, Yerushalayim, Israel, 9778419
      • Shaare Zedek Medical Center
• Italy
  • Foggia, Italy, 71100
    • Azienda Ospedaliero Universitaria Ospedali Riuniti di Foggia
  • Latina, Italy, 04100
    • Ospedale Santa Maria Goretti
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli
  • Torino, Italy, 10126
    • Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
  • Sicilia
    • Palermo, Sicilia, Italy, 90127
      • A.O.U. Policlinico Paolo Giaccone
• Japan
  • Fukui, Japan, 918-8503
    • Fukuiken Saiseikai Hospital
  • Gifu, Japan, 500-8323
    • Gifu Municipal Hospital
  • Kumamoto, Japan, 862-8655
    • Kumamoto Shinto General Hospital
  • Kyoto, Japan, 602-8566
    • University Hospital,Kyoto Prefectural University of Medicine
  • Niigata, Japan, 951-8520
    • Niigata University Medical & Dental Hospital
  • Saga, Japan, 849-8501
    • Saga University Hospital
  • Yamagata, Japan, 990-9585
    • Yamagata University Hospital
  • Aichi-ken
    • Nagakute-shi, Aichi-ken, Japan, 480-1195
      • Aichi Medical University Hospital
  • Hokkaido
    • Sapporo-shi, Hokkaido, Japan, 062-8618
      • JCHO Hokkaido Hospital
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 236-0004
      • Yokohama City University Hospital
    • Yokohama, Kanagawa, Japan, 2458575
      • National Hospital Organization Yokohama Medical Center
  • Nara-Ken
    • Nara-Shi, Nara-Ken, Japan, 630-8305
      • JADECOM Nara City Hospital
  • Osaka
    • Higashi-cho, Hirakata-city, Osaka, Japan, 573-0153
      • Hirakata kohsai Hospital
    • Suita, Osaka, Japan, 564-0013
      • Osaka Saiseikai Suita hospital
  • Shimane
    • Izumo, Shimane, Japan, 693-0021
      • Shimane University Hospital
  • Tokyo
    • Bunkyō, Tokyo, Japan, 113-8519
      • Tokyo Medical and Dental University Medical Hospital
• Mexico
  • Cuauhtémoc, Mexico, 6700
    • Centro de Investigación y Gastroenterología
  • Distrito Federal
    • Cuautitlan Izcalli, Distrito Federal, Mexico, 54769
      • Phylasis Clinicas Research
    • Mexico City, Distrito Federal, Mexico, 3310
      • Grupo Medico Camino Sc
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64988
      • Christus Muguerza Hospital Sur
• Poland
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 02-672
      • Synexus Polska Sp. z o.o. Oddzial w Warszawie
  • Łódzkie
    • Lodz, Łódzkie, Poland, 90-127
      • Synexus Polska Oddział w Lodzi
• Spain
  • Alicante, Spain, 3004
    • Instituto de Ciencias Médicas
  • Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro Majadahonda
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Sevilla, Spain, 41003
    • Clínica nuevas Tecnologías en Diabetes y Endocrinología (NTDE)
  • Balears [Baleares]
    • Palma de Mallorca, Balears [Baleares], Spain, 7014
      • Clínica Juaneda
  • Cantabria
    • Santander, Cantabria, Spain, 39008
      • Hospital Universitario Marques de Valdecilla
  • Madrid, Comunidad De
    • Madrid, Madrid, Comunidad De, Spain, 28034
      • Hospital Universitario Ramón y Cajal
• United Kingdom
  • Birmingham, United Kingdom, B15 2SQ
    • Synexus Midlands Clinical Research Centre
  • Liverpool, United Kingdom, L9 7AL
    • Aintree University Hospital NHS Foundation Trust
  • Manchester, United Kingdom, M15 6SX
    • Synexus Manchester Clinical Research Centre
  • England
    • Birmingham, England, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital Birmingham
    • Hexham, England, United Kingdom, NE46 1QJ
      • Synexus North East Clinical Research Centre
    • London, England, United Kingdom, E1 1BB
      • Royal London Hospital
    • London, England, United Kingdom, SW17 0QT
      • St. George's Hospital
  • Lancashire
    • Chorley, Lancashire, United Kingdom, PR7 7NA
      • Synexus Clinical Research Centre - Lancashire
  • London, City Of
    • London, London, City Of, United Kingdom, SE5 9RL
      • King's College Hospital
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2UH
      • Queen's Medical Centre, Nottingham University Hospitals
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 9DU
      • John Radcliffe Hospital
  • Stockton-on-Tees
    • Stockton on Tees, Stockton-on-Tees, United Kingdom, TS19 8PE
      • Synexus North Teesside Clinical Research Centre
  • Westminster
    • London, Westminster, United Kingdom, W2 1NY
      • Imperial College London - St Mary's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • University of Alabama-The Kirklin Clinic
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Synexus Clinical Research US, Inc.
  • California
    • Fresno, California, United States, 93720
      • Fresno Clinical Research Center
    • Huntington Park, California, United States, 90255
      • National Research Institute - Huntington Park
    • La Jolla, California, United States, 92037
      • UCSD - Altman Clinical and Translational Research Institute (ACTRI)
    • Los Angeles, California, United States, 90057
      • National Research Institute - Wilshire
    • Montclair, California, United States, 91763
      • Catalina Research Institute, LLC
    • Northridge, California, United States, 91325
      • Diabetes Medical Center Of California
    • Panorama City, California, United States, 91402
      • Velocity Clinical Research, Panorama City
    • Rialto, California, United States, 92377
      • Inland Empire Clinical Trials, LLC
    • Santa Ana, California, United States, 92704
      • Velocity Clinical Research, Santa Ana
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials
    • Coral Gables, Florida, United States, 33134
      • Alliance for Multispecialty Research, LLC
    • Hollywood, Florida, United States, 33024
      • Research Centers of America ( Hollywood )
    • Jacksonville, Florida, United States, 32204
      • East Coast Institute For Research, LLC
    • Kissimmee, Florida, United States, 34741
      • IHS Health Research
    • Maitland, Florida, United States, 32751
      • Accel Research Sites - Maitland Clinical Research Unit
    • Miami, Florida, United States, 33014
      • Clinical Pharmacology of Miami
    • Orlando, Florida, United States, 32803
      • The Center for Digestive Health
    • Orlando, Florida, United States, 32806
      • Synexus Clinical Research US, Inc.
    • The Villages, Florida, United States, 32162
      • Synexus Clinical Research US, Inc.
  • Illinois
    • Chicago, Illinois, United States, 60602
      • Synexus Clinical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Hospital
  • Iowa
    • West Des Moines, Iowa, United States, 50265
      • Iowa Diabetes and Endocrinology Research Center
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton O'Neil Clinical Research Center
    • Wichita, Kansas, United States, 67207
      • Alliance for Multispecialty Research, LLC
  • Louisiana
    • Marrero, Louisiana, United States, 70072
      • Tandem Clinical Research
  • Mississippi
    • Biloxi, Mississippi, United States, 39532
      • The National Diabetes & Obesity Research Institute
    • Jackson, Mississippi, United States, 39216
      • Southern Therapy and Advanced Research (STAR) LLC
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Buffalo, New York, United States, 14203
      • Buffalo Clinical and Translational Research Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016
      • NYU Langone Health
  • North Carolina
    • Morehead City, North Carolina, United States, 28557
      • Diabetes & Endocrinology Consultants, PC
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • WR-ClinSearch, LLC
  • Texas
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes Research Center
    • Dallas, Texas, United States, 75231
      • Radiant Research - Dallas North
    • Dallas, Texas, United States, 75234-7858
      • Liver Center of Texas, PLLC
    • Denison, Texas, United States, 75020
      • Texoma Medical Center
    • Round Rock, Texas, United States, 78681
      • Texas Diabetes & Endocrinology, P.A.
    • San Antonio, Texas, United States, 78229
      • Synexus Clinical Research US, Inc.
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at Texas Liver Institute
    • San Antonio, Texas, United States, 78240
      • Endeavor Clinical Trials
  • Virginia
    • Richmond, Virginia, United States, 23294
      • National Clinical Research, Inc
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University (VCU) Medical Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center/University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• Participants must have a body mass index (BMI) ≥27 kilograms per square meter (kg/m²) and ≤50 kg/m² with stable body weight for at least 3 months

• Participants with or without type 2 diabetes mellitus (T2DM)

  • If with T2DM, hemoglobin A1c (HbA1c) ≤9.5%
• Participants must be willing to undergo baseline and endpoint liver biopsies
• Participants must have histologic diagnosis of NASH with stage 2 or 3 fibrosis by liver biopsy
• Participants must not have known or suspected alcohol abuse (>14 units/week for women and >21 units/week for men) or active substance abuse
• Participants must not have evidence of cirrhosis or other forms of liver disease
• Participants must not have heart attack, stroke, or hospitalization for congestive heart failure in the past 6 months
• Participants must not have active cancer within the last 5 years
• Participants must not have uncontrolled high blood pressure
• Participants must not have renal impairment with estimated glomerular filtration rate (eGFR) <30 milliters/minute/1.73m²; for participants on metformin, eGFR <45 mL/min/1.73m²
• Participants must not have a diagnosis of type 1 diabetes
• Participants must not have a history of pancreatitis (acute or chronic)
• Participants must not have calcitonin ≥35 nanograms per liter
• Participant must not have family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma (family is defined as a first degree relative)
• Female participants must not be pregnant, breast-feeding, or intend to become pregnant or of childbearing potential and not using adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 5 mg Tirzepatide; 5 milligrams (mg) tirzepatide administered subcutaneously (SC) once a week.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Experimental: 10 mg Tirzepatide; 10 mg tirzepatide administered SC once a week.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Experimental: 15 mg Tirzepatide; 15 mg tirzepatide administered SC once a week.	Drug: Tirzepatide; Administered SC; Other Names: LY3298176
Placebo Comparator: Placebo; Placebo administered SC once a week.	Drug: Placebo; Administered SC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Absence of Nonalcoholic Steatohepatitis (NASH) With no Worsening of Fibrosis on Liver Histology	NASH resolution is defined as the absence of fatty liver disease or simple steatosis without steatohepatitis; the absence of hepatocellular ballooning (nonalcoholic fatty liver disease (NAFLD) Activity Score (NAS) 0 for ballooning); with or without mild lobular inflammation (NAS 0 or 1 for inflammation); and any value for steatosis. No worsening of fibrosis is defined as no increase in fibrosis stage from baseline to Week 52.	Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With ≥1 Point Decrease in Fibrosis Stage With No Worsening of NASH on Liver Histology	NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8 with the higher score indicating more aggressive disease. Evaluation of fibrosis stage was based on the nonalcoholic steatohepatitis clinical research network (NASH CRN) fibrosis staging system, which was scaled from 0 to 4 stages where, 0=None to 4=Cirrhosis. Participants were evaluated with the NASH CRN scoring system with ≥1-point reduction without worsening of NASH (defined as no increase in the NAS score).	Week 52
Percentage of Participants With ≥1 Point Increase in Fibrosis Stage on Liver Histology	Participants were evaluated with the NASH CRN scoring system with ≥1 stage increase in fibrosis.	Week 52
Percentage of Participants That Achieve a ≥2 Point Decrease in NAFLD (Non-alcoholic Fatty Liver Disease) Activity Score (NAS) on Liver Histology, With ≥1 Point Reduction in at Least 2 NAS Components	Hepatic histological improvement in NAS was defined as a decrease (improvement) in NAS by ≥ 2 with at least a 1-point reduction in at least 2 NAS components (lobular inflammation, hepatocellular ballooning or steatosis). The NAS was derived as the unweighted sum of steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocellular ballooning (0 to 2) scores. The NAS ranges from 0-8, with the higher score indicating more aggressive disease.	Week 52
Mean Absolute Change From Baseline in Liver Fat Content by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF)	MRI-PDFF is an established method that enables quantification of fat content in the liver. The value of whole liver fat as assessed by MRI-PDFF is expressed in percentage (%) and ranges from 0 to 100% with higher values representing higher liver fat level. Least square (LS) mean was calculated using mixed model repeated measures (MMRM) model for post-baseline measures: Variable = Baseline + Diabetes Flag (DIABFL) + REGION1 + Treatment + Time + Treatment*Time (Type III sum of squares). Variance-Covariance structure (Change from Baseline) = Unstructured.	Baseline to Week 52
Mean Change From Baseline in Body Weight	Change in body weight at the end of 52 weeks measured in kilogram (kg) using a calibrated scale. LS mean was calculated using MMRM model for post-baseline measures: Variable = Baseline + DIABFL + REGION1 + Treatment + Time + Treatment*Time (Type III sum of squares). Variance-Covariance structure (Change from Baseline) = Unstructured.	Baseline to Week 52

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Investigators: Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Publications and helpful links

Helpful Links

• A Study of Tirzepatide (LY3298176) in Participants With Nonalcoholic Steatohepatitis (NASH)

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2019
• Primary Completion (Actual): December 11, 2023
• Study Completion (Actual): January 10, 2024

Study Registration Dates

• First Submitted: November 15, 2019
• First Submitted That Met QC Criteria: November 15, 2019
• First Posted (Actual): November 18, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 22, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Tirzepatide
• Other Study ID Numbers: 17361; I8F-MC-GPHR (Other Identifier: Eli Lilly and Company); 2019-001550-26 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• IPD Sharing Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• IPD Sharing Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No