Rezdiffra® With Concomitant Therapies Commonly Used to Treat Comorbidities in Adults With MASH and F2-F3 Fibrosis

October 15, 2026 updated by: Madrigal Pharmaceuticals, Inc.

A Phase 4, Open-label, Multi-group Study of Rezdiffra® in Combination With Concomitant Therapies Commonly Used to Treat Comorbidities in Adults With MASH and Moderate to Advanced (F2-F3) Fibrosis, Administered According to Their Approved Labeling

To determine the safety of Rezdiffra (Resmetirom) when administered alongside common prescriptions for Diabetes Metellus (Farxiga/dapagliflozin & Actos/pioglitazone)

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This Phase 4 study will evaluate the safety and tolerability of REZDIFFRA® (resmetirom) when used in combination with concomitant therapies commonly used to treat diabetes in adults with metabolic dysfunction-associated steatohepatitis (MASH) and noncirrhotic, moderate-to-advanced (F2-F3) fibrosis. The concomitant therapies evaluated in this study will include ACTOS®/pioglitazone and FARXIGA®/dapagliflozin. All study medications will be administered according to their approved labeling.

Participants will be assigned to one of six cohorts based on their existing therapy and the concomitant medication being evaluated. In Group A, participants who are receiving a stable dose of pioglitazone or dapagliflozin will initiate resmetirom. In Group B, participants who are receiving a stable dose of REZDIFFRA will initiate pioglitazone or dapagliflozin. In Group C, participants who are not currently receiving either treatment will initiate resmetirom and either pioglitazone or dapagliflozin in a staggered manner, with a 4- to 6-week run-in period between initiation of the first and second medications.

Approximately 25 participants are planned for each of the six cohorts, for a maximum planned enrollment of approximately 150 participants. Following initiation of combination treatment, participants will be followed for 24 weeks, with a safety follow-up visit approximately 4 weeks after completion of treatment.

Safety and tolerability will be characterized through assessment of treatment-emergent adverse events, physical examinations, vital signs, clinical laboratory parameters, treatment discontinuations, and dose interruptions or reductions. Exploratory assessments will evaluate changes in liver fat by MRI-PDFF, noninvasive measures of hepatic steatosis and fibrosis, and biomarkers related to MASH disease state, insulin resistance, glucose homeostasis, body weight, and liver function.

Study Type

Interventional

Enrollment (Estimated)

150

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Arizona
      • Chandler, Arizona, United States, 85224
        • Not yet recruiting
        • Arizona Liver Health - Chandler
    • Arkansas
      • North Little Rock, Arkansas, United States, 72117
        • Not yet recruiting
        • Arkansas Gastroenterology
    • California
      • Coronado, California, United States, 92118
        • Not yet recruiting
        • Southern California Research Center
      • Rialto, California, United States, 37411
        • Not yet recruiting
        • Inland Empire Liver Foundation
    • Florida
      • Lakewood Rch, Florida, United States, 34211
        • Not yet recruiting
        • Florida Research Institute
      • Miami, Florida, United States, 33176
        • Recruiting
        • Gastro Health PLLC Galloway
      • Miami, Florida, United States, 33186
        • Not yet recruiting
        • Med Research of Florida, LLC
    • Louisiana
      • Lake Charles, Louisiana, United States, 70605
        • Recruiting
        • Elevate Clinical Research
    • North Carolina
      • Morehead City, North Carolina, United States, 28557
        • Not yet recruiting
        • Centricity Research - Morehead City - Multispecialty - PPDS
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • Recruiting
        • Gastro Health Research
    • Tennessee
      • Chattanooga, Tennessee, United States, 37411
        • Not yet recruiting
        • University Diabetes and Endocrine Consultants
    • Texas
      • Arlington, Texas, United States, 76012-3216
        • Not yet recruiting
        • Texas Clinical Research Institute
      • Corpus Christi, Texas, United States, 78414
        • Not yet recruiting
        • South Texas Endocrinology & Metabolism Center
      • Dallas, Texas, United States, 75234
        • Not yet recruiting
        • The Liver Institute at Methodist Dallas Medical Center
      • McAllen, Texas, United States, 78504
        • Not yet recruiting
        • Elevate Clinical Research - McAllen - PPDS
      • San Antonio, Texas, United States, 78229
        • Not yet recruiting
        • Diabetes and Glandular Disease Clinic, PA

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria

All Subjects:

  1. Willing to participate in the study and provide written informed consent.

  2. Meets all requirements per REZDIFFRA Prescribing Information, in the opinion of the PI.

  3. Male and female adults ≥18 of age at time of screening.

  4. Evidence of hepatic steatosis consistent with MASH demonstrated by an MRI-PDFF fat fraction >5% obtained during second screening period.

  5. Evidence of moderate-to-advanced fibrosis (F2-F3) without cirrhosis.

  6. Stable medical conditions and background medications (non-concomitant medications as defined in this protocol) per PI judgement.

  7. Female subjects of reproductive potential are eligible if they have a negative serum pregnancy test (beta human chorionic gonadotropin), are not breastfeeding, and do not plan to become pregnant during the study and agree to use 1 highly effective birth control method during the study and for at least 30 days after newly introduced medication administration.

    Highly effective birth control methods include hormonal and non-hormonal intrauterine device, combination estrogen-progesterone hormonal contraception (oral, transdermal, or vaginal), tubal ligation, a vasectomized or sterile male partner, or sexual abstinence (defined as refraining from heterosexual intercourse), from Screening throughout the study, and for at least 30 days after newly introduced medication administration. Reliance on abstinence from heterosexual intercourse is acceptable only if it is the subject's habitual practice. NOTE: Female subjects who are not of child-bearing potential (ie, surgically [bilateral oophorectomy, hysterectomy] or naturally sterile [>12 consecutive months without menses]) do not require contraception during the study.

  8. Must be taking a stable dose of ACTOS/pioglitazone for at least 2 months prior to Baseline. (Group A1)

  9. Must be taking a stable dose of FARXIGA/dapagliflozin for at least 2 months prior to Baseline. (Group A2)

  10. Must be taking a stable dose of REZDIFFRA for at least 2 months prior to Baseline. (Groups B1 and B2)

  11. Must not have previously taken RESMETIROM or ACTOS/pioglitazone or FARXIGA/dapagliflozin. (Group C)

  12. For Groups A1, B1, and C1: Meets all requirements per ACTOS/pioglitazone Prescribing Information, in the opinion of the PI.

  13. For Groups B1 and C1: (ie, naïve to ACTOS/pioglitazone): HbA1c at screening ≥7.0% and ≤10.0%.

  14. For Groups A2, B2, and C2: Meets all requirements per FARXIGA/dapagliflozin Prescribing Information, in the opinion of the PI.

  15. For Groups B2 and C2 (ie, naïve to FARXIGA/dapagliflozin): HbA1c at screening ≥7.0% and ≤10.0%.

Exclusion Criteria All subjects

  1. Off label use of the commercially available study medications.

  2. Evidence of cirrhosis demonstrated by clinical, imaging, histologic, or NIT thresholds consistent with cirrhosis.

  3. Other chronic liver diseases (eg, viral hepatitis, autoimmune hepatitis, hemochromatosis).

  4. Documented history of decompensated liver disease.

  5. Use of rosuvastatin or simvastatin at a dose greater than 20 mg/day, or pravastatin or atorvastatin at a dose greater than 40 mg/day, at the time of the first dose of resmetirom. Subjects receiving a statin dose above the applicable limit during the screening period may remain eligible if the dose is reduced to the applicable maximum permitted dose before the first dose of resmetirom.

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

  7. Active or suspected bladder cancer.

  8. Diagnosis of heart failure.

  9. eGFR < 60mL/min/1.73 m2

  10. Developmental/intellectual disability, limited capacity of recognition, any history of clinically important emotional and/or psychiatric illness, inability to follow the study procedures, or 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.

  11. Individuals who are currently incarcerated or who are anticipated to be incarcerated during the study period.

    Groups B and C:

  12. Unable to secure a prescription for a concomitant medication.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Actos (pioglitazone) [Ongoing] | Resmetirom [New]

Experienced Actos/Pioglitazone + Resmetirom Naive (A1)
Drug: Resmetirom

Resmetirom - weight-based dosing:

  • <100 kg: 80 mg orally once daily.
  • ≥100 kg: 100 mg orally once daily
Drug: ACTOS/pioglitazone

Label dosing recommendations indicated for patients without congestive heart failure (15 or 30 mg orally once daily; if tolerated, increase by 15 mg increments up to a maximum of 45 mg orally once daily for additional glycemic control
Other: Farxiga (dapagliflozin) [Ongoing] | Resmetirom [New]

Experienced Farxiga/Dapagliflozin + Resmetirom Naive (A2)
Drug: Resmetirom

Resmetirom - weight-based dosing:

  • <100 kg: 80 mg orally once daily.
  • ≥100 kg: 100 mg orally once daily
Drug: FARXIGA/dapagliflozin

Label dosing recommendations indicated for glycemic control in type 2 diabetes (5 mg orally once daily; if tolerated, increase to 10 mg orally once daily for additional glycemic control)
Other: REZDIFFRA [Ongoing] | Actos (pioglitazone) [New]

Experienced REZDIFFRA + Actos/Pioglitazone Naive (B1)
Drug: ACTOS/pioglitazone

Label dosing recommendations indicated for patients without congestive heart failure (15 or 30 mg orally once daily; if tolerated, increase by 15 mg increments up to a maximum of 45 mg orally once daily for additional glycemic control

Drug: Rezdiffra

All study medications will be administered according to their labels:

• REZDIFFRA- Label weight-based dosing:

  • <100 kg: 80 mg orally once daily.
  • ≥100 kg: 100 mg orally once daily
Other: REZDIFFRA [Ongoing] | Farxiga (dapagliflozin) [New]

Experienced REZDIFFRA + Farxiga/Dapagliflozin Naive (B2)
Drug: FARXIGA/dapagliflozin

Label dosing recommendations indicated for glycemic control in type 2 diabetes (5 mg orally once daily; if tolerated, increase to 10 mg orally once daily for additional glycemic control)

Drug: Rezdiffra

All study medications will be administered according to their labels:

• REZDIFFRA- Label weight-based dosing:

  • <100 kg: 80 mg orally once daily.
  • ≥100 kg: 100 mg orally once daily
Other: Actos (pioglitazone) [New] | Resmetirom [New]

Naive Actos/Pioglitazone + Resmetirom Naive (C2)
Drug: Resmetirom

Resmetirom - weight-based dosing:

  • <100 kg: 80 mg orally once daily.
  • ≥100 kg: 100 mg orally once daily
Drug: ACTOS/pioglitazone

Label dosing recommendations indicated for patients without congestive heart failure (15 or 30 mg orally once daily; if tolerated, increase by 15 mg increments up to a maximum of 45 mg orally once daily for additional glycemic control
Other: Farxiga (dapagliflozin) [New] | Resmetirom [New]

Naïve Farxiga/dapagliflozin + Resmetirom Naïve (C2)
Drug: Resmetirom

Resmetirom - weight-based dosing:

  • <100 kg: 80 mg orally once daily.
  • ≥100 kg: 100 mg orally once daily
Drug: FARXIGA/dapagliflozin

Label dosing recommendations indicated for glycemic control in type 2 diabetes (5 mg orally once daily; if tolerated, increase to 10 mg orally once daily for additional glycemic control)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number and Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time Frame: From First Dose of newly introduced medication up to 28 weeks

The total number of TEAEs and the number and percentage of participants with at least 1 TEAE will be summarized by study group. TEAEs will also be summarized by System Organ Class and Preferred Term.
From First Dose of newly introduced medication up to 28 weeks
Number and Percentage of Participants With TEAEs by Maximum Severity
Time Frame: From First Dose of newly introduced medication up to 28 weeks

The number and percentage of participants with TEAEs will be summarized by maximum severity using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
From First Dose of newly introduced medication up to 28 weeks
Number and Percentage of Participants With TEAEs by Relationship to Study Medication
Time Frame: From First Dose of newly introduced medication up to 28 weeks

The number and percentage of participants with TEAEs assessed as Related or Not Related to each applicable study medication (REZDIFFRA/resmetirom, ACTOS/pioglitazone, or FARXIGA/dapagliflozin) will be summarized by study group.
From First Dose of newly introduced medication up to 28 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Madrigal Pharmaceuticals, Inc.

Investigators

  • Study Director: Tom Hare, Madrigal Pharmaceuticals, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 7, 2026

Primary Completion (Estimated)

November 1, 2027

Study Completion (Estimated)

November 1, 2027

Study Registration Dates

First Submitted

August 25, 2026

First Submitted That Met QC Criteria

September 23, 2026

First Posted (Actual)

September 29, 2026

Study Record Updates

Last Update Posted (Actual)

October 16, 2026

Last Update Submitted That Met QC Criteria

October 15, 2026

Last Verified

October 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MGL-3196-33

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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