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

Madrigal Pharmaceuticals

Status and phase: Enrolling; Phase 4

Conditions: MASH - Metabolic Dysfunction-Associated Steatohepatitis

Treatments: Drug: Rezdiffra; Drug: ACTOS/pioglitazone; Drug: Resmetirom; Drug: FARXIGA/dapagliflozin

Study type: Interventional

Funder types: Industry

Identifiers

NCT07848191

MGL-3196-33

Details and patient eligibility

About

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

Full 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.

Enrollment: 150 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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150 participants in 6 patient groups

Actos (pioglitazone) [Ongoing] | Resmetirom [New]

Other group

Description:

Experienced Actos/Pioglitazone + Resmetirom Naive (A1)

Treatment:

Drug: Resmetirom

Drug: ACTOS/pioglitazone

Farxiga (dapagliflozin) [Ongoing] | Resmetirom [New]

Other group

Description:

Experienced Farxiga/Dapagliflozin + Resmetirom Naive (A2)

Treatment:

Drug: FARXIGA/dapagliflozin

Drug: Resmetirom

REZDIFFRA [Ongoing] | Actos (pioglitazone) [New]

Other group

Description:

Experienced REZDIFFRA + Actos/Pioglitazone Naive (B1)

Treatment:

Drug: ACTOS/pioglitazone

Drug: Rezdiffra

REZDIFFRA [Ongoing] | Farxiga (dapagliflozin) [New]

Other group

Description:

Experienced REZDIFFRA + Farxiga/Dapagliflozin Naive (B2)

Treatment:

Drug: FARXIGA/dapagliflozin

Drug: Rezdiffra

Actos (pioglitazone) [New] | Resmetirom [New]

Other group

Description:

Naive Actos/Pioglitazone + Resmetirom Naive (C2)

Treatment:

Drug: Resmetirom

Drug: ACTOS/pioglitazone

Farxiga (dapagliflozin) [New] | Resmetirom [New]

Other group

Description:

Naïve Farxiga/dapagliflozin + Resmetirom Naïve (C2)

Treatment:

Drug: FARXIGA/dapagliflozin

Drug: Resmetirom