Study of MGL-3196 in Patients With Heterozygous Familial Hypercholesterolemia (HeFH)

A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo Controlled Study of MGL-3196 in Patients With Heterozygous Familial Hypercholesterolemia

The primary objective of this study is to determine the effect of once-daily oral MGL-3196 on the percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in participants with Heterozygous Familial Hypercholesterolemia (HeFH).

Study Overview

• Status: Completed
• Conditions: Heterozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: Placebo; Drug: MGL-3196 (resmetirom)

• Study Type: Interventional
• Enrollment (Actual): 116
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark
    • Madrigal Research Site
  • Copenhagen, Denmark
    • Madrigal Research Site
  • Esbjerg, Denmark
    • Madrigal Research Site
  • Herlev, Denmark
    • Madrigal Research Site
  • Viborg, Denmark
    • Madrigal Research Site
• Netherlands
  • Amsterdam, Netherlands
    • Madrigal Research Site
  • Apeldoorn, Netherlands
    • Madrigal Research Site
  • Goes, Netherlands
    • Madrigal Research Site
  • Hoorn, Netherlands
    • Madrigal Research Site
  • Nijmegen, Netherlands
    • Madrigal Research Site
  • Zwijndrecht, Netherlands
    • Madrigal Research Site
• Norway
  • Oslo, Norway
    • Madrigal Research Site - 1
  • Oslo, Norway
    • Madrigal Research Site - 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Must be willing to participate in the study and provide written informed consent;
• Male and female adults ≥18 years of age;
• Female participants of child bearing potential with negative serum pregnancy (beta human chorionic gonadotropin) test who are not breastfeeding, do not plan to become pregnant during the study, and agree to use effective birth control per locally agreed requirements; male participants who have sexual intercourse with a female partner of child bearing potential from the first dose of study drug until 1 month after study completion must either be surgically sterile (confirmed by documented azoospermia >90 days after the procedure) or agree to use a condom with spermicide. All male participants must agree not to donate sperm from the first dose of study drug until 1 month after study completion;
• Must have a diagnosis of HeFH by genetic testing or by having met the diagnostic criteria for definite familial hypercholesterolemia outlined by the Simon Broome Register Group or World Health Organization/Dutch Lipid Network (score >8);
• Must have had a fasting LDL-C (low density lipoprotein cholesterol) ≥2.6 mmol/L (100 mg/dL); and
• Must be on a stable or maximally tolerated dose (≥4 weeks prior to screening) of an approved statin (rosuvastatin ≤40 mg daily, atorvastatin ≤80 mg daily), with or without ezetimibe. Patients intolerant to statins were allowed.

Exclusion Criteria:

• Homozygous familial hypercholesterolemia
• LDL or plasma apheresis within 2 months prior to randomization;
• New York Heart Association class III or IV heart failure, or known left ventricular ejection fraction <30%;
• Uncontrolled cardiac arrhythmia, including confirmed QT interval corrected using Fridericia's formula >450 msec for males and >470 msec for females at the screening electrocardiogram assessment;
• Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 3 months prior to randomization;
• Type 1 diabetes, or newly diagnosed or uncontrolled type 2 diabetes (hemoglobin A1c >8%);
• History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening; Note: Significant alcohol consumption is defined as average of >20 g/day in female participants and >30 g/day in male participants;
• Hyperthyroidism;
• Thyroid replacement therapy;
• Hypothyroidism;
• Evidence of chronic liver disease;
• Hepatitis B, as defined by the presence of hepatitis B surface antigen;
• Hepatitis C, as defined by the presence of hepatitis C virus (HCV) antibody (anti-HCV) and HCV ribonucleic acid (RNA). Participants with positive anti-HCV who test negative for HCV RNA at screening will be allowed to participate in the study;
• Serum alanine aminotransferase >1.5 x upper limit of normal (ULN) (one repeat allowed);
• Estimated glomerular filtration rate <60 mL/min;
• Creatine kinase >3 x ULN (one repeat allowed);
• History of biliary diversion;
• Positive for human immunodeficiency virus infection;
• History of malignant hypertension;
• Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening or randomization and confirmed at an unscheduled visit;
• Triglycerides >5.7 mmol/L (500 mg/dL) at screening and confirmed by repeat assessment;
• Active, serious medical disease with likely life expectancy <2 years;
• Active substance abuse, including inhaled or injection drugs within the year prior to screening;
• Participation in an investigational new drug trial within the 30 days prior to randomization; or
• Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, or compromise the well-being of the participants.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching Placebo	Drug: Placebo; Oral
Experimental: MGL-3196; Study Drug	Drug: MGL-3196 (resmetirom); Oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Change in LDL-C From Baseline To Week 12	LDL-C was determined by ultracentrifugation or direct measure. Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline to Week 12 of Free Thyroxine (T4)	T4 was assessed at each study visit.	Baseline up to Week 12
Mean Change From Baseline to Week 12 of Free Triiodothyronine (T3)	Free T3 was assessed at each study visit.	Baseline up to Week 12
Mean Change From Baseline to Week 12 of Thyrotropin (TSH)	TSH was assessed at each study visit.	Baseline up to Week 12
Mean Change From Baseline to Week 12 of Thyroxine Binding Globulin (TBG)	TBG was assessed at all study visits except the Screening Visit.	Baseline up to Week 12
Mean Change From Baseline to Week 12 of Reverse Triiodothyronine (T3)	Reverse T3 was assessed at each study visit.	Baseline up to Week 12
Mean Percent Change in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) From Baseline to Week 12	Non-HDL-C were determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor	Baseline up to Week 12
Mean Percent Change In Triglycerides From Baseline To Week 12	Triglycerides were determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12
Mean Percent Change In Lipoprotein(a) (Lp[a]) From Baseline To Week 12	Lp(a) was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12
Mean Percent Change in Apolipoprotein CIII From Baseline to Week 12	Apolipoprotein CIII was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12
Mean Percent Change In Apolipoprotein B (ApoB) From Baseline To Week 12	ApoB was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12
Mean Percent Change in Apolipoprotein B/Apolipoprotein A1 (ApoB/ApoA1) Ratio From Baseline to Week 12	The ApoB/ApoA1 ratio was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12
Mean Percent Change In Cholesterol/HDL-C Ratio From Baseline to Week 12	The Cholesterol/HDL-C Ratio was determined by ultracentrifugation. LS mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12
Absolute Change in LDL-C From Baseline to Week 12	LDL-C was determined by ultracentrifugation or direct measure . Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline up to Week 12
Percent Change From Baseline in LDL-C at Week 2 and Week 4 in Patients in the 100 mg and the 60 mg Groups	LDL-C was determined by ultracentrifugation or direct measure. Least-squares (LS) mean was provided for the comparison of MGL-3196 versus placebo and it used a linear model with percent change from baseline as the dependent variable and treatment as a factor.	Baseline to Week 2 and Week 4
Percent Change in LDL-C From Baseline to Week 12 by Systemic Exposure Category	The effect on percent change in LDL-C from baseline to Week 12 was determined by patient exposure category (higher/lower). Patients taking MGL-3196 were categorized into lower and higher exposure groups. Patients in the higher exposure group must either have had estimated Week 2 AUC ≥5,000 mg∙h/L, or if Week 2 AUC <5,000 mg∙h/L but Week 4 pre-dose concentration >1.5 ng/mL (if on 60 mg MGL-3196). All other patients were in the lower exposure group.	Baseline to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total LDL Particles	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for LDL Particles.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Small LDL Particles	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Small LDL Particles.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Intermediate LDL Particles	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Intermediate LDL Particles.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Large LDL Particles	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Large LDL Particles.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12:Total Very Low-Density Lipoprotein (VLDL) and Chylomicron Particles	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for VLDL and Chylomicron Particles.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: Total HDL Particles	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for Total HDL Particles.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: LDL Particle Size	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for LDL Particle size.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: VLDL Particle Size	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for VLDL Particle Size.	Baseline up to Week 12
Mean Change in Lipid Particle Concentration From Baseline To Week 12: HDL Particle Size	The effect of once-daily oral dosing of MGL-3196 versus placebo for 12 weeks in terms of change from baseline was assessed for HDL Particle Size.	Baseline up to Week 12

Collaborators and Investigators

• Sponsor: Madrigal Pharmaceuticals, Inc.
• Investigators: Study Director: Rebecca Taub, MD, Madrigal Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Hovingh GK, Klausen IC, Heggen E, McCarty K, Zhou R, Isaac BF, Taub R, Langslet G, Kastelein JJP. Resmetirom (MGL-3196) in Patients With Heterozygous Familial Hypercholesterolemia. J Am Coll Cardiol. 2022 Mar 29;79(12):1220-1222. doi: 10.1016/j.jacc.2022.01.023. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2017
• Primary Completion (Actual): January 15, 2018
• Study Completion (Actual): January 15, 2018

Study Registration Dates

• First Submitted: January 30, 2017
• First Submitted That Met QC Criteria: January 30, 2017
• First Posted (Estimated): January 31, 2017

Study Record Updates

• Last Update Posted (Estimated): December 23, 2025
• Last Update Submitted That Met QC Criteria: December 18, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II; resmetirom
• Other Study ID Numbers: MGL-3196-06; 2016-002315-17 (EudraCT Number)

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
• product manufactured in and exported from the U.S.: Yes