A clinical trial to evaluate the safety and effectiveness of MGL-3196 (resmetirom) in patients with Non-Alcoholic Steatohepatitis (NASH) and reduce progression of liver damage and resolve NASH

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Madrigal Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

18 Nov 2019 → ongoing

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-510626-89-00

EudraCT number

2018-004012-22

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Week 52 Dual Primary Objectives:
To determine the effect once-daily, oral administration of 80 mg or 100 mg MGL-3196 versus matching placebo on NASH, as measured by:
1. The resolution of NASH associated with an at least 2-point reduction in NAFLD activity score (NAS) and without worsening of fibrosis by liver biopsy after 52 weeks of treatment (Week 52 Primary endpoint) in the mITT-LB-W52 population.
Resolution includes:
- The absence of balloning (score = 0) and absent or mild lobular inflammation (score 0 to 1; associated with at least 2-point reduction in NAS).
- No worsening of fibrosis: worsening of fibrosis is defined as any progression ≥ 1 stage.
2. The histological improvement from Baseline demonstrated by at least a 1-point improvement in fibrosis by liver biopsy with no worsening of NAS at Week 52.
Month 54 Primary Objective:
Time to experiencing an adjudicated Composite Clinical Outcome event
The main study objective of the OLE:
1. to collect long-term safety information and readily available measures of response for resmetirom beyond 54 months in a manner more consistent with real world practice.

Secondary objectives 1

1. Key Secondary objective: For the Week 52 analysis, the key secondary objective is to determine the effect of once-daily, oral administration of 80 mg or 100 mg MGL-3196 versus matching placebo on the percent change from Baseline at 24 weeks in directly measured low-density lipoprotein cholesterol (LDL-C).

Conditions and MedDRA coding

Non-Alcoholic Steatohepatitis (NASH)

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Must be willing to participate in the study and provide written informed consent
2. Male and female adults ≥18 years of age.
3. Female patients are eligible if they are of reproductive potential and have a negative serum pregnancy test, are not breastfeeding, and do not plan to become pregnant during the study and agree to use 2 highly effective birth control methods (HEBCM) during the study and for at least 30 days after study drug administration OR if they are not of child bearing potential. A woman is considered of childbearing potential (WOCP) i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal (PM) state is defined as no menses for 12 months without an alternative medical cause. A high folicle stimulating hormone (FSH) level in the PM range may be used to confirm PM state in women not using hormonal contraception (HC) or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. HEBCM include: Combined (and progestogen containing HC associated with inhibition of ovulation: oral, intravaginal, transdermal; Progestogen-only HC associated with inhibition of ovulation: oral, injectable, implantable; Intrauterine device); Intrauterine hormone-releasing system; Bilateral tubal occlusion; Vasectomized partner provided that the partner is the sole sexual partner of the trial participant, and that the partner has received medical assessment of the surgical process; Sexual abstinence
4. Male subjects who are sexually active with a partner of child-bearing potential must either be sterile; practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable); use a male condom with any sexual activity; or agree to use a birth control method considered to be appropriate by the Investigator from the time of Screening until 30 days after the last dose of study drug administration. Male subjects must agree not to donate sperm for a period of 30 days after the last dose of study drug administration.
5. 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: • Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL; or ELF ≥ 9 • FibroScan with transient elastography ≥8.5 kPa; and controlled attenuation parameter ≥280 dB.m-1. • 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. NOTE: A biopsy that was obtained >6 months before the time of anticipated randomization is not eligible for study entry; a biopsy ≤6 months is potentially eligible for study entry as a baseline biopsy only after confirmation of eligibility based on Inclusion #7 by the central pathology reviewer. NOTE: Eligibility based on meeting Inclusion #5 should be determined based on historic medical and laboratory (PRO-C3/ELF, FibroScan, liver biopsy) data and should be determined prior to informed consent and screening visit.
6. MRI-PDFF fat fraction ≥8% obtained during the screening period (baseline MRI-PDFF). NOTE: To be eligible to perform the screening MRI-PDFF (Baseline MRI-PDFF) a patient must first meet Criterion #5. An eligible MRI-PDFF with fat fraction ≥8% must be obtained prior to performing the baseline liver biopsy (Criterion #7).
7. Inclusion criteria for OLE phase: 1. Patients must be willing to participate in the OLE phase and provide written informed consent.
8. Inclusion criteria for OLE phase: 2. Completed all protocol-specified visits in the Main Study and had the scheduled second liver biopsy at Month 54

Exclusion criteria 13

1. Regular use of drugs historically associated with NAFLD, which include but are not limited to the following: amiodarone, methotrexate, systemic oral glucocorticoids, tamoxifen, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids except testosterone replacement, valproic acid, and known hepatotoxins for more than 4 weeks within the last 8 weeks prior to the initial Screening
2. Pioglitazone >15 mg per day, stable treatment for ≥24 weeks prior to the eligible liver biopsy.
3. Platelet count <140,000/mm3. Patients with platelets <140,000 and ≥120,000 /mm3 are eligible if Fib-4<3.5
4. Uncontrolled cardiac arrhythmia.
5. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study
6. Weight gain or loss ≥5% total body weight within 12 weeks prior to randomization
7. Glucagon-like peptide 1 [GLP-1] agonist therapy (eg, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and albiglutide) unless stable dose for 24 weeks prior to biopsy. NOTE: GLP-1 therapeutics may not be initiated or doses increased during the first 52 weeks of the study
8. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis
9. Diagnosis of hepatocellular carcinoma (HCC)
10. Chronic liver diseases: a.Primary biliary cholangitis b.Primary sclerosing cholangitis c.Hepatitis B positive d.Hepatitis C as defined by presence of hepatitis C virus (HCV) antibody (HCV Ab) and positive HCV RNA (tested for known cured HCV infection, or positive HCV Ab at Screening). NOTE: Patients who are HCV antibody positive and HCV RNA negative who have a history of clearly documented HCV infection (history of positive HCV RNA) are eligible to participate if prior treatment for HCV was given, and they have a documented sustained virologic response (SVR) of at least two years prior to the baseline liver biopsy e.History or evidence of current active autoimmune hepatitis f.History or evidence of Wilson's disease g.History or evidence of alpha-1-antitrypsin deficiency h.Evidence of genetic hemochromatosis (hereditary, primary) i.Evidence of drug-induced liver disease, as defined on the basis of typical exposure and history j.Known bile duct obstruction k.Suspected or proven liver cancer.
11. Serum ALT >250 U/L NOTE:Given the intrinsic variability in ALT and AST in NASH patients, investigators should use the following guide in an attempt to establish a relatively stable baseline for ALT and AST. Investigator discretion is allowed. Documented historical (3 weeks to ≤ 6 months prior to study entry) ALT and AST levels consistent with the Screening ALT and AST values may help establish a stable baseline
12. Statins and/or other lipid-lowering therapies unless dose(s) is stable for ≥30 days prior to anticipated randomization. Statins must be taken in the evening for at least 2 weeks prior to randomization, and permitted statins include rosuvastatin up to 20 mg/day, atorvastatin up to 40 mg/day, pravastatin up to 40 mg/day, simvastatin up to 20 mg/day, pitavastatin up to 2 mg/day and lovastatin up to 40 mg/day. Other stable dyslipidemia therapies not specifically listed as excluded or dose-restricted such as PCSK9 inhibitors are allowed. Higher doses and other statins are excluded. Stable doses of bile acid sequestrants are permitted only if taken 4 h after or 4 h before the study drug dose.
13. Exclusion criterion for the OLE: 1. Any 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Week 52 Dual Primary endpoints: NASH Resolution Response at Week 52 Fibrosis ≥ 1 Stage Responder at Week 52
2. Time to Composite Clinical Outcome Event at Month 54

Secondary endpoints 1

1. Percent change from baseline in directly measured LDL-C at Week 24 and Week 52

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Madrigal Pharmaceuticals Inc.

Sponsor organisation

Madrigal Pharmaceuticals Inc.

Address

200 Barr Harbor Drive Suite 400

City

Conshohocken

Postcode

19428-2978

Country

United States

Scientific contact point

Organisation

Madrigal Pharmaceuticals Inc.

Contact name

Rebecca Taub

Public contact point

Organisation

Madrigal Pharmaceuticals Inc.

Contact name

Rebecca Taub

Third parties 12

Sponsor responsibilities

Article 77 compliance

Madrigal Pharmaceuticals Inc.

Article 77 implementation

Madrigal Pharmaceuticals Inc.

Locations

8 EU/EEA countries · 74 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 76 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications