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

Madrigal Pharmaceuticals, Inc.116 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

116

Conditions

Heterozygous Familial Hypercholesterolemia

Interventions

MGL-3196 (resmetirom)DRUG

Oral

PlaceboDRUG

Oral

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (13)

Madrigal Research Site

Aalborg, Denmark

Madrigal Research Site

Copenhagen, Denmark

Madrigal Research Site

Esbjerg, Denmark

Outcomes

Primary Outcomes

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.

Time frame: Baseline up to Week 12

Secondary Outcomes

Mean Change From Baseline to Week 12 of Free Thyroxine (T4)

T4 was assessed at each study visit.

Time frame: Baseline up to Week 12

Mean Change From Baseline to Week 12 of Free Triiodothyronine (T3)

Free T3 was assessed at each study visit.

Time frame: Baseline up to Week 12

Mean Change From Baseline to Week 12 of Thyrotropin (TSH)

TSH was assessed at each study visit.

Time frame: 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.

Time frame: Baseline up to Week 12

Mean Change From Baseline to Week 12 of Reverse Triiodothyronine (T3)

Reverse T3 was assessed at each study visit.

Time frame: 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

Data from ClinicalTrials.gov

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Madrigal Research Site

Viborg, Denmark

Madrigal Research Site

Amsterdam, Netherlands

Madrigal Research Site

Apeldoorn, Netherlands

Madrigal Research Site

Goes, Netherlands

Madrigal Research Site

Hoorn, Netherlands

Madrigal Research Site

Nijmegen, Netherlands

...and 3 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline up to Week 12