A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis

NASH - Nonalcoholic Steatohepatitis Clinical Trial

— MAESTRO-NASH  

Official title:

A Phase 3, Multinational, Double-Blind, Randomized, Placebo-Controlled Study of MGL-3196 (Resmetirom) in Patients With Non-Alcoholic Steatohepatitis (NASH) and Fibrosis to Resolve NASH and Reduce Progression to Cirrhosis and/or Hepatic Decompensation

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03900429
• Other study ID #: MGL-3196-11
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 28, 2019
• Est. completion date: January 2028

Study information

• Verified date: February 2024
• Source: Madrigal Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A double-blind placebo controlled randomized Phase 3 study to determine if 80 or 100 mg of MGL-3196 as compared with placebo resolves NASH and/or reduces fibrosis on liver biopsy and prevents progression to cirrhosis and/or advanced liver disease

Description:

Primary and secondary endpoint population at Week 52 will be at least 900 patients, more than half fibrosis score 3 (F3), the remainder fibrosis score 2 (F2) and <10% fibrosis score F1B (F1B) based on final liver biopsy baseline fibrosis score.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1759
• Est. completion date: January 2028
• Est. primary completion date: January 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Must be willing to participate in the study and provide written informed consent.

2. Male and female adults = 18 years of age.

3. Suspected or confirmed diagnosis of NASH fibrosis suggested by the historical data. Meet one of the following criteria that is consistent with NASH liver fibrosis:

1. Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL or ELF =9

2. FibroScan with transient elastography =8.5 kPa and controlled attenuation parameter =280 dB.m-1

3. Historical liver biopsy obtained <2 years before expected randomization showing Stage 1B, 2 or 3 fibrosis with NASH based on existing pathology review, with no significant change in body weight >5% or medication that might affect NAS or fibrosis stage.

4. MRI-PDFF fat fraction =8% obtained during the screening period

5. Biopsy-proven NASH (baseline liver biopsy) based on a liver biopsy obtained =6 months before anticipated date of randomization (if the biopsy is deemed acceptable for interpretation by the central reader) with fibrosis stage 1A/1C, 1B, 2, or 3 on liver biopsy and NAS of =4 with a score of at least 1 in each of the following NAS components:

1. Steatosis (scored 0 to 3)

2. Ballooning degeneration (scored 0 to 2)

3. Lobular inflammation (scored 0 to 3)

Exclusion Criteria:

1. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to Screening.

2. Regular use of drugs historically associated with NAFLD

3. Thyroid diseases:

1. Active hyperthyroidism.

2. Untreated clinical hypothyroidism defined by thyroid stimulating hormone (TSH) >7 IU/L with symptoms of hypothyroidism or >10 IU/L without symptoms.

3. Patients who have had a thyroidectomy and are on replacement thyroxine doses >75 µg per day are allowed.

4. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study.

5. Recent significant weight gain or loss

6. HbA1c = 9.0%.

7. Glucagon-like peptide 1 [GLP-1] agonist, high dose Vitamin E (> 400 IU/day), or pioglitazone therapy unless stable dose for 24 weeks prior to biopsy.

8. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis.

9. Diagnosis of hepatocellular carcinoma (HCC).

10. MELD score =12, as determined at Screening, unless due to therapeutic anti coagulation.

11. Hepatic decompensation

12. Chronic liver diseases other than NASH

13. Active autoimmune disease

14. Serum ALT > 250 U/L.

15. Active, serious medical disease with a likely life expectancy < 2 years.

16. Participation in an investigational new drug trial in the 60 days or 5 half-lives, whichever is longer.

17. Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes.

Related Conditions & MeSH terms

• Fatty Liver
• NASH - Nonalcoholic Steatohepatitis
• Non-alcoholic Fatty Liver Disease

Intervention

Drug:
• MGL-3196
Tablet
• Placebo
Matching Tablets

Procedure:
• Liver Biopsy
A procedure in which a needle is inserted into the liver to collect a tissue sample

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Saint Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	John Hunter Hospital	New Lambton	New South Wales
Australia	The Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Mater Misericordiae	South Brisbane	Queensland
Australia	Westmead Hospital	Westmead	New South Wales
Austria	Klinikum Klagenfurt Am Wörthersee	Klagenfurt	Carinthia
Austria	Ordensklinikum Linz GmbH Barmherzige Schwestern	Linz	Upper Austria
Austria	Landesklinik St. Veit	Salzburg
Austria	Universitätsklinikum St. Pölten	St. Pölten
Austria	Medizinische Universität Wien	Vienna
Austria	Klinikum Wels-Grieskirchen	Wels
Austria	Krankenanstalt Rudolfstiftung	Wien	Vienna
Belgium	Universitair Ziekenhuis Brussel	Brussel
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Hôpital Erasme	Bruxelles	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem	Antwerpen
Belgium	Ziekenhuis Oost-Limburg'	Genk	Limburg
Belgium	Algemeen Ziekenhuis Maria Middelares	Gent	Oost-Vlaanderen
Belgium	Universitair Ziekenhuis Gent	Gent	Oost-Vlaanderen
Belgium	Centre Hospitalier Universitaire Brugmann	Laeken
Belgium	Universitair Ziekenhuis Leuven	Leuven
Belgium	Universitair Ziekenhuis Leuven	Leuven	Flemish Brabant
Belgium	AZ Delta Campus Wilgenstraat	Roeselare	West-Vlaanderen
Canada	LMC/ Manna Research - Brampton	Brampton	Ontario
Canada	William Osler Health System	Brampton	Ontario
Canada	South Shore Medical Arts	Bridgewater	Nova Scotia
Canada	University of Calgary Liver Unit	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	McMaster University	Hamilton	Ontario
Canada	Toronto General Hospital - Clinical Trials Pharmacy	Toronto	Ontario
Canada	Toronto Liver Center	Toronto	Ontario
Canada	GI Research Institute	Vancouver
Canada	Lair Centre	Vancouver
France	Centre Hospitalier Universitaire Amiens-Picardie	Amiens
France	Center Hospitalier Universitaire d'Angers	Angers	Pays De La Loire
France	Hôpital Jean-Minjoz	Besançon	Franche-Comte
France	Hôpital Avicenne	Bobigny Cedex	Ile-de-France
France	Centre Hospitalier Universitaire Estaing	Clermont-Ferrand	Auvergne
France	Hôpital Beaujon	Clichy
France	Centre Hospitalier Universitaire Henri Mondor	Créteil Cedex	Ile-de-France
France	Centre Hospitalier Régional Universitaire de Lille	Lille	Nord Pas-de-Calais
France	Hôpital Dupuytren	Limoges	Limousin
France	Hôpital de la Croix Rousse	Lyon Cedex 04	Rhone-Alpes
France	Centre Hospitalier Universitaire de Montpellier	Montpellier Cedex 5	Languedoc-Roussillon
France	Centre Hospitalier Universitaire de Nice Hôpital l'Archet	Nice Cedex 3	Provence Alpes Cote D'Azur
France	Hôpital Universitaire Pitié Salpêtrière	Paris Cedex 13
France	Assistance Publique-Hôpitaux de Paris Hôpital Cochin	Paris Cedex 14	Ile-de-France
France	Centre Hospitalier Universitaire de Rennes	Rennes Cedex 9	Bretagne
France	Les Hôpitaux Universitaires de Strasbourg - Hôpital Hautepierre	Strasbourg	Alsace
France	Nouvel Hôpital Civil	Strasbourg Cedex	Alsace
France	Centre Hospitalier Universitaire de Toulouse - Hôpital Rangueil	Toulouse Cedex	Midi-Pyrenees
France	Centre Hospitalier Universitaire de Nancy - Hôpital de Brabois	Vandœuvre-lès-Nancy
Germany	Berlin Clinical Research Center	Berlin
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	Charité Universitätsmedizin Berlin - Campus Mitte	Berlin
Germany	EPIMED	Berlin
Germany	Zentrum für Infektiologie Berlin Prenzlauer Berg	Berlin
Germany	Frankfurt Clinical Research Center	Frankfurt am main
Germany	Universitätsklinikum Frankfurt	Frankfurt am main
Germany	Universitätsklinikum des Saarlandes	Homburg
Germany	EUGASTRO	Leipzig
Germany	Leipzig Research Center	Leipzig
Germany	SIBAmed Studienzentrum	Leipzig
Germany	Universitätsmedizin der Johannes Gutenberg Universität Mainz	Mainz
Germany	Universitätsklinikum Würzburg	Würzburg
Hungary	Békés Megyei Központi Kórház Dr. Réthy Pál Tagkórház	Békéscsaba	Bekes
Hungary	Dél-pesti Centrumkórház - Országos Hematológiai és Infektológiai Intézet	Budapest
Hungary	Magyarország Research Center	Budapest
Hungary	Debreceni Egyetem Kenézy Gyula Egyetemi Kórház	Debrecen	Hajdu-Bihar
Hungary	Magyarország Research Center	Debrecen	Hajdu-Bihar
Hungary	Magyarország Egészségügyi Szolgáltató - Gyula	Gyula	Bekes
Hungary	Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház	Nyíregyháza	Szabolcs-Szatmar-Bereg
Israel	Emek Medical Center	Afula
Israel	Soroka University Medical Center	Be'er Sheva
Israel	Rambam Health Care Campus - Rambam Medical Center	Haifa
Israel	The Lady Davis Carmel Medical Center	Haifa
Israel	Hadassah University Hospital Ein Kerem	Jerusalem
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Western Galilee Hospital-Nahariya	Nahariya
Israel	Holy Family Hospital	Nazareth
Israel	Rabin Medical Center	Petah Tikva
Israel	The Chaim Sheba Medical Center	Ramat Gan	Tel Aviv
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Azienda Ospedaliera Papa Giovanni XXIII	Bergamo
Italy	Azienda Ospedaliero - Universitaria Careggi	Firenze
Italy	Azienda Ospedaliera Universitaria Policlinico Gaetano Martino	Messina
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano
Italy	Polo Universitario - L'Azienda Ospedaliera Luigi Sacco	Milano
Italy	Azienda Ospedaliera Universitaria-Maggiore della Carità di Novara	Novara
Italy	Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone	Palermo
Italy	Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)	Palermo
Italy	Azienda Ospedaliero-Universitaria Pisana Ospedale Cisanello	Pisa
Italy	Fondazione Policlinico Universitario Agostino Gemelli	Roma
Italy	Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma	Roma
Italy	Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Mexico	Centro de Investigacion y Gastroenterologia	Ciudad de México	Distrito Federal
Mexico	Centro Mexicano de Desarrollo de Estudios Clínicos	Ciudad de México	Distrito Federal
Mexico	JM Research	Cuernavaca	Morelos
Mexico	Centro Integral en Reumatología	Guadalajara	Jalisco
Mexico	Investigaciones Médicas Cisneros	Monterrey	Nuevo Leon
Poland	Polska Oddzial w Czestochowie	Czestochowa
Poland	Polska Oddzial w Gdansk	Gdansk
Poland	Polska Oddzial w Gdyni	Gdynia
Poland	Polska Oddzial w Katowicach	Katowice
Poland	Polska Oddzial w Lodz	Lódz
Poland	Polska Oddzial w Poznaniu	Poznan
Poland	Centrum Medyczne Pratia Poznan	Skórzewo
Poland	Polska Oddzial w Warszawie	Warszawa
Poland	Polska Oddzial w Wroclaw	Wroclaw
Puerto Rico	Fundación De Investigación De Diego	San Juan
Spain	Complejo Hospitalario Torrecárdenas	Almeria
Spain	Hospital de la Santa Creu i de Sant Pau	Barcelona
Spain	Hospital del Mar - Parc de Salut Mar	Barcelona
Spain	Hospital Universitari Vall d'Hebrón	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario Ramón Y Cajal	Madrid
Spain	Hospital Universitario Puerta de Hierro - Majadahonda	Majadahonda	Madrid
Spain	Complejo Hospitalario de Pontevedra	Pontevedra
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Consorci Hospital General Universitari de València	Valencia
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Switzerland	Universitatsspital Bern	Bern
Switzerland	Fondazione Epatocentro Ticino	Lugano
Switzerland	Universitatsspital Zurich	Zürich
United Kingdom	Belfast Health and Social Care Trust	Belfast	Northern Ireland
United Kingdom	Midlands Clinical Research Centre	Birmingham	England
United Kingdom	University Hospitals Birmingham NHS Foundation Trust	Birmingham	England
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge	England
United Kingdom	The Wales Clinic	Cardiff	Wales
United Kingdom	Lancashire Clinical Research Centre	Chorley	England
United Kingdom	North Teesside Clinical Research Centre	Hardwick	England
United Kingdom	The Hexham Clinic	Hexham	Northumberland, England
United Kingdom	Aintree University Hospitals NHS Foundation Trust	Liverpool
United Kingdom	Merseyside Clinical Research Centre	Liverpool	England
United Kingdom	Barts Health NHS Trust	London	England
United Kingdom	Chelsea and Westminster Hospital NHS Foundation Trust	London	England
United Kingdom	Imperial College Healthcare NHS Trust	London	England
United Kingdom	Royal Free London NHS Foundation Trust	London	England
United Kingdom	Saint George's University Hospitals NHS Foundation Trust	London
United Kingdom	Manchester Clinical Research Centre	Manchester	England
United Kingdom	The Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle Upon Tyne	England
United Kingdom	Norfolk and Norwich University Hospital	Norwich	England
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham	England
United Kingdom	Plymouth Hospitals NHS Trust	Plymouth
United Kingdom	Portsmouth Hospitals NHS Trust	Portsmouth
United Kingdom	Thames Valley Dedicated Research Centre	Reading	England
United Kingdom	Abertawe Bro Morgannwg University Health Board	Swansea	Wales
United States	Texas Digestive Disease Consultants - Gastroenterology Associates - Baton Rouge	Baton Rouge	Louisiana
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Excel Medical Clinical Trials	Boca Raton	Florida
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	South Texas Research Institute - Brownsville	Brownsville	Texas
United States	East Valley Family Physicians	Chandler	Arizona
United States	The Institute for Liver Health - Chandler	Chandler	Arizona
United States	University of North Carolina Medical Center - Chapel Hill	Charlotte	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Clinical Research - Chicago	Chicago	Illinois
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	The University of Chicago Medicine	Chicago	Illinois
United States	Consultants for Clinical Research	Cincinnati	Ohio
United States	Premier Medical Group - Clarksville	Clarksville	Tennessee
United States	Colorado Springs Family Practice	Colorado Springs	Colorado
United States	Aventiv Research - Columbus	Columbus	Ohio
United States	Dallas Research Center	Dallas	Texas
United States	Liver Center of Texas	Dallas	Texas
United States	Texas Digestive Disease Consultants - Dallas	Dallas	Texas
United States	The Liver Institute at Methodist Dallas Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	South Texas Research Institute	Edinburg	Texas
United States	South Denver Gastroenterology - Swedish Medical Center Office	Englewood	Colorado
United States	University of Kansas Medical Center Research Institute	Fairway	Kansas
United States	Cumberland Research Associates	Fayetteville	North Carolina
United States	Gastrointestinal Associates and Endoscopy Center - Madison	Flowood	Mississippi
United States	Covenant Metabolic Specialists - Fort Myers	Fort Myers	Florida
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	Texas Digestive Disease Consultants - Fort Worth	Fort Worth	Texas
United States	Fresno Clinical Research Center	Fresno	California
United States	University of Florida Hepatology Research at CTRB	Gainesville	Florida
United States	Gastro One - Germantown - Centre Oak Way	Germantown	Tennessee
United States	The Institute for Liver Health - Glendale	Glendale	Arizona
United States	Clinical Research US - Henderson	Henderson	Nevada
United States	Associates in Gastroenterology	Hermitage	Tennessee
United States	Liver Associates of Texas	Houston	Texas
United States	National Research Institute - Huntington Park	Huntington Park	California
United States	Nature Coast Clinical Research	Inverness	Florida
United States	Southern Therapy and Advanced Research	Jackson	Mississippi
United States	Kansas City Research Institute	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Gastrointestinal Associates - Knoxville	Knoxville	Tennessee
United States	University of California San Diego	La Jolla	California
United States	Florida Research Institute	Lakewood Ranch	Florida
United States	Wasatch Peak Family Practice	Layton	Utah
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	National Research Institute - Los Angeles	Los Angeles	California
United States	Ruane Clinical Research	Los Angeles	California
United States	GI Specialists of Georgia	Marietta	Georgia
United States	Awasty Research Network	Marion	Ohio
United States	Tandem Clinical Research	Marrero	Louisiana
United States	Doctor's Hospital at Renaissance	McAllen	Texas
United States	Desert Clinical Research	Mesa	Arizona
United States	Miami Dade Medical Research Institute	Miami	Florida
United States	University of Miami	Miami	Florida
United States	Lucas Research	Morehead City	North Carolina
United States	Salt Lake City Research Center	Murray	Utah
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	Mt. Sinai Medical Center	New York	New York
United States	New York Presbyterian Hospital	New York	New York
United States	Arkansas Gastroenterology	North Little Rock	Arkansas
United States	Bioclinica Research - Orlando	Orlando	Florida
United States	Stanford University School of Medicine	Palo Alto	California
United States	National Research Institute - Panorama City	Panorama City	California
United States	Plano Research Center	Plano	Texas
United States	Progressive Medical Research	Port Orange	Florida
United States	Alliance Clinical Research	Poway	California
United States	Bon Secours St. Mary's Hospital of Richmond	Richmond	Virginia
United States	Hunter Holmes McGuire Veterans Administration Medical Center	Richmond	Virginia
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Pinnacle Clinical Research - Austin	Rollingwood	Texas
United States	Saint Louis University	Saint Louis	Missouri
United States	University of Utah Hospital	Salt Lake City	Utah
United States	Pinnacle Clinical Research	San Antonio	Texas
United States	San Antonio Research Center	San Antonio	Texas
United States	The Texas Liver Institute	San Antonio	Texas
United States	Texas Digestive Disease Consultants - San Marcos	San Marcos	Texas
United States	Covenant Research	Sarasota	Florida
United States	Liver Institute Northwest	Seattle	Washington
United States	Bioclinica Research - The Villages	The Villages	Florida
United States	Kansas Medical Clinic - Gastroenterology	Topeka	Kansas
United States	Adobe Gastroenterology	Tucson	Arizona
United States	The Institute for Liver Health - Tucson	Tucson	Arizona
United States	San Fernando Valley Health Institute	Van Nuys	California
United States	Impact Research Institute	Waco	Texas
United States	Texas Digestive Disease Consultants - Bay Area Gastroenterology	Webster	Texas
United States	Clinical Trials of America	West Monroe	Louisiana

Sponsors (1)

Lead Sponsor	Collaborator
Madrigal Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Hungary,  Israel,  Italy,  Mexico,  Poland,  Puerto Rico,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Week 52 Dual Primary Objectives: To determine the effect of 80 or 100 mg MGL-3196 vs matching placebo on liver biopsy (NASH CRN score) at Week 52 compared with Baseline	Proportion with resolution of NASH (ballooning 0, inflammation 0,1) associated with at least 2-point reduction in NAFLD Activity Score (NAS) without worsening of fibrosis stage OR; Proportion with at least a 1-point improvement in fibrosis stage with no worsening of NAS	52 weeks
Primary	Month 54 Primary Objective: Time to experiencing an adjudicated Composite Clinical Outcome event (Final Primary Endpoint, at 54 months)	The Composite Clinical Outcome is composed of all-cause mortality, liver transplant, and significant hepatic events (including hepatic decompensation events [ascites, encephalopathy, or gastroesophageal variceal hemorrhage], histological progression to cirrhosis, and a confirmed increase of MELD score from <12 to =15).	up to 54 months
Secondary	Week 52 Key Secondary Objective: To determine the effect of once-daily, oral administration of MGL-3196 80 or 100 mg versus matching placebo on the percent change from Baseline at 24 weeks in directly measured low-density lipoprotein cholesterol (LDL-C)	Assess the effect of MGL-3196 80 mg or 100 mg compared to placebo on LDL-C measured by percent change from Baseline at 24 weeks.	24 weeks