Phase 1 Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Multiple Oral Doses of MGL-3196 in Subjects With Varying Degrees of Hepatic Impairment and Healthy Matched Control Subjects

A Phase I, Open Label, Non-randomized Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Multiple Oral Doses of MGL-3196 in Subjects With Varying Degrees of Hepatic Impairment and Healthy Matched Control Subjects With Normal Hepatic Function

The purpose of this study is to directly characterize the pharmacokinetic (PK) profiles of MGL-3196 and its major metabolite (MGL-3623) following administration of multiple oral doses (QD x 6 days) in subjects with varying degrees of hepatic impairment (HI) compared to healthy matched control subjects with normal hepatic function, including a subset of NASH subjects.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment; NASH - Nonalcoholic Steatohepatitis; Cirrhosis, Liver
• Intervention / Treatment: Drug: MGL-3196

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orlando, Florida, United States, 32809
      • Madrigal Research Center
  • Minnesota
    • Saint Paul, Minnesota, United States, 55114
      • Madrigal Research Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • Madrigal Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Capable of understanding and willing and able to sign written informed consent
• Male or female, between 18 and 85 years of age (inclusive)
• BMI between 18 and 45 kg/m2 (inclusive)

• In healthy subjects with normal hepatic function:

  • Considered by the Investigator to be healthy, based on medical and surgical history, physical examination including vital signs, 12-lead ECG, and laboratory test results
  • Match demographically with a subject in the hepatically impaired population according to gender, BMI (±20%), and age (±10 years)

• In subjects with hepatic impairment:

  • Considered by the Investigator to be clinically stable with respect to underlying HI, based on medical and surgical history, physical examination including vital signs, 12-lead ECG, and laboratory test results

• In subjects with NASH:

  • Confirmed diagnosis of NASH suggested by historical data, which include a previous liver biopsy within the last 5 years prior to randomization with evidence of NASH.
  • BMI ≥18 kg/m2

Exclusion Criteria:

• Any clinically significant concomitant disease or condition (including treatment for such conditions) that, in the opinion of the Investigator, could either interfere with the study drug, pose an unacceptable risk to the subject, or compromise interpretation of study data
• Gilbert's syndrome
• Pre-existing condition interfering with normal gastrointestinal anatomy or motility, hepatic and/or renal function that could interfere with the absorption, metabolism, and/or excretion of study drug
• eGFR <60 mL/min/1.73 m2 based on Modification of Diet in Renal Disease (MDRD) equation
• Received an investigational drug or device from another study within 30 days (or 5 half-lives, whichever is longer) prior to study drug administration

• In healthy subjects with normal hepatic function:

  • Systolic blood pressure outside the range of 90 to 150 mmHg, diastolic blood pressure outside the range of 40 to 95 mmHg or heart rate outside the range of 40 to 100 beats per minute (bpm)
  • History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months prior to screening

• In subjects with hepatic impairment:

  • Any non-hepatic acute or chronic condition (including, but not limited to, poorly controlled diabetes and encephalopathy Grade ≥3) that, in the opinion of the Investigator, would limit the subject's ability to complete and/or participate in the study
  • Acute exacerbation of HI or unstable hepatic function, as determined by the Investigator, 30 days prior to study drug administration
  • Has had a Transjugular Intrahepatic Portosystemic Shunt (TIPS) procedure performed

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 40 mg MGL-3196 Tablet; Multiple cohorts (normal, varying hepatic impairment, NASH non-cirrhosis, and NASH cirrhosis) evaluated	Drug: MGL-3196; Once daily oral dose for 6 days
Experimental: 60 mg MGL-3196 Tablet; Multiple cohorts (normal, varying hepatic impairment, NASH non-cirrhosis, and NASH cirrhosis) evaluated	Drug: MGL-3196; Once daily oral dose for 6 days
Experimental: 80 mg MGL-3196 Tablet; Multiple cohorts (normal, varying hepatic impairment, NASH non-cirrhosis, and NASH cirrhosis) evaluated	Drug: MGL-3196; Once daily oral dose for 6 days
Experimental: 100 mg MGL-3196 Tablet; Multiple cohorts (normal, varying hepatic impairment, NASH non-cirrhosis, and NASH cirrhosis) evaluated	Drug: MGL-3196; Once daily oral dose for 6 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma pharmacokinetics - Cmax	Cmax after administration	16 days
Plasma pharmacokinetics - Tmax	Tmax after administration	16 days
Plasma pharmacokinetics - AUC (0-last)	AUC (0-last) after administration	16 days
Plasma pharmacokinetics - t1/2	t1/2 after administration	16 days
Effect on the incidence of adverse events		16 days

Collaborators and Investigators

• Sponsor: Madrigal Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2018
• Primary Completion (Actual): August 4, 2021
• Study Completion (Actual): August 4, 2021

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: November 19, 2020
• First Posted (Actual): November 25, 2020

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Fibrosis; Liver Diseases; Fatty Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: MGL-3196-10

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