Clinical trial NCT03038022: Study of MGL-3196 in Patients With Heterozygous Familial Hypercholesterolemia (HeFH)
Official title: A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo Controlled Study of MGL-3196 in Patients With Heterozygous Familial Hypercholesterolemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heterozygous Familial Hypercholesterolemia
Lead sponsor: Madrigal Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2017-01-31
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 patients with Heterozygous Familial Hypercholesterolemia (HeFH).


Eligibility criteria: Inclusion Criteria:

* Must be willing to participate in the study and provide written informed consent;
* Male and female adults ≥18 years of age;
* Female patients 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 (ie, condoms, diaphragm, non-hormonal intrauterine device \[IUD\], or sexual abstinence \[only if this is in line with the patient's current lifestyle\]) throughout the study and for at least 1 month after study completion; hormonal contraception (estrogens stable ≥3 months) and hormonal IUDs are permitted if used with a secondary birth control measure (eg, condoms); OR female patients of non-child bearing potential (ie, surgically \[bilateral oophorectomy, hysterectomy, or tubal ligation\] or naturally sterile \[\>12 consecutive months without menses\]); male patients 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 patients 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 WHO/Dutch Lipid Network (score \>8);
* Must have a fasting LDL-C ≥ 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 ≤ 20 mg daily, atorvastatin ≤ 80 mg daily), with or without ezetimibe.

Exclusion Criteria:

* Homozygous familial hypercholesterolemia
* Low-density lipoprotein (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 (QTcF) \>450 msec for males and \>470 msec for females at the screening electrocardiogram (ECG) 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 \[HbA1c\] \>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 patients and \>30 g/day in male patients;
* Thyroid replacement therapy;
* 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). Patients with positive anti-HCV who test negative for HCV RNA at screening will be allowed to participate in the study;
* Serum alanine aminotransferase (ALT) \>1.5 × ULN (one repeat allowed);
* Estimated glomerular filtration rate \<60 mL/min;
* Creatine kinase \>3 × 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 patient.

Primary outcomes:
measure: Mean percent change from baseline in low-density lipoprotein cholesterol (LDL-C)
timeFrame: 12 Weeks
Secondary outcomes:
measure: Safety and tolerability of MGL-3196 based on Adverse Events and Changes in Laboratory Values
timeFrame: 12 Weeks
measure: Mean percent change from baseline on selected lipid parameters
timeFrame: 12 Weeks
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Madrigal Research Site
city: Viborg
country: Denmark
facility: Madrigal Research Site
Study officials:
affiliation: Madrigal Pharmaceuticals, Inc.
name: Rebecca Taub, MD
role: STUDY_DIRECTOR
References:
citation: 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.