Heterozygous Familial Hypercholesterolemia (HeFH) MedDRA version: 19.0 Level: LLT Classification code 10057079 Term: Heterozygous familial hypercholesterolemia System Organ Class: 100000004850
Conditions
Interventions
Product Name: MGL-3196
Product Code: MGL-3196
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: 2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)- phenyl]-3,5-dioxo-2,3,4,5-tet
Sponsors
Madrigal Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: The population for this study is male and female patients 18 years of age who have met the diagnostic criteria for HeFH outlined by the Simon Broome Register Group (Scientific Steering Committee 1991). Patients who meet all of the following criteria will be eligible to participate in the study: 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 of child bearing potential with negative serum pregnancy test who are not breastfeeding, do not plan to become pregnant during the study, and agree to use effective birth control (ie, condoms, hormonal contraception, diaphragm, intrauterine device, or sexual abstinence if this is in line with the patient’s current lifestyle) throughout the study and for at least 1 month after study completion; if using hormonal contraception, female patients should also use 1 additional form of effective birth control throughout the study. Female patients of non-child bearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or naturally sterile [>12 consecutive months without menses]); 4. 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 (Scientific Steering Committee 1991) or World Health Organization (WHO)/Dutch Lipid Network (score >8); 5. Must have a fasting LDL-C 100 mg/dL; and 6.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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 65 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 40
Exclusion criteria
Exclusion criteria: 1. Homozygous familial hypercholesterolemia; 2. Low-density lipoprotein (LDL) or plasma apheresis within 2 months prior to randomization; 3. New York Heart Association class III or IV heart failure, or known left ventricular ejection fraction 450 msec for males and >470 msec for females at the screening electrocardiogram (ECG) assessment; 5. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 3 months prior to randomization; 6. Type 1 diabetes, or newly diagnosed or uncontrolled type 2 diabetes (hemoglobin A1c [HbA1c] >8%); 7.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; 8. Hyperthyroidism; 9. Thyroid replacement therapy 10. Hypothyroidism note: If TSH is up to 1.5 x ULN on screening with normal free T4, one repeat test is allowed to confirm the elevation in TSH. If TSH and free T4 are normal upon repeat testing, patient may be included. Patients with a history of thyroid hormone replacement therapy or patients who have discontinued thyroid hormone replacement therapy (including thyroxine) 2 months prior to randomization may be included in the study if this criterion is met 11. Evidence of chronic liver disease 12. Hepatitis B, as defined by the presence of hepatitis B surface antigen (HBsAg); 13. Hepatitis C, as defined by the presence of hepatitis C virus (HCV) ribonucleic acid, or hepatitis C antibody (anti -HCV). Patients with positive anti-HCV who test negative for HCV RNA at screening will be allowed to participate in the study. 14. Serum alanine aminotransferase (ALT) >1.5 × ULN (one repeat allowed) 15. Estimated glomerular filtration rate 3 × ULN (one repeat allowed) 17. History of biliary diversion 18. Positive for human immunodeficiency virus infection 19. History of malignant hypertension 20. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening or randomization and confirmed at an unscheduled visit 21. Triglycerides >5.7 mmol/L (500 mg/dL) at screening and confirmed by repeat assessment 22. Active, serious medical disease with likely life expectancy <2 years 23. Active substance abuse, including inhaled or injection drugs within the year prior to screening 24. Use of any excluded medications or procedures listed in the protocol 25. Participation in an investigational new drug trial within the 30 days prior to randomization or 26. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to determine the effect of each of two separate treatment groups (the 100 mg group and the 60 mg group) of once daily oral dose of MGL-3196 and matching placebo on the percentage change from baseline in low density lipoprotein cholesterol (LDL-C) in patients with HeFH;Secondary Objective: •To evaluate the safety profile, including any changes in thyroid axis hormones, and tolerability of once-daily oral dosing regimen of MGL-3196 versus placebo after 12 weeks in patients with HeFH •To determine the effect of once-daily oral dosing regimen of MGL-3196 versus placebo for 12 weeks on the percent change from baseline on the following assessments in patients with HeFH: o Non-high-density lipoprotein cholesterol (non-HDL-C) oApolipoprotein B (ApoB) oTotal cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio oTriglycerides oLipoprotein(a) oApolipoprotein A1 (ApoA1)/ApoB ratio oLipoprotein particle assessment •To determine the effect of once-daily oral dose of MGL3196 versus placebo for 12 weeks on the absolute change from baseline in LDL-C in patients with HeFH •To determine the effect of all patients (100 and 60 mg groups) on per cent change from Baseline in LDL-C •To determine the effect of exposure to MGL3196 on LDL-C lowering ;Primary end point(s): The primary end point of this study is to determine the efficacy change in each of two separate treatment groups (the 100 mg group and the 60 mg group) of once daily oral dose of MGL-3196 and matching placebo on the percentage change from baseline in low density lipoprotein cholesterol (LDL-C) in patients with HeFH.;Timepoint(s) of evaluation of this end point: Baseline, Week 12 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints of this study are: •To evaluate the safety profile, including any changes in thyroid axis hormones, and tolerability of once-daily oral dosing regimen of MGL-3196 versus placebo after 12 weeks in patients with HeFH •To determine the effect of once-daily oral dosing regimen of MGL-3196 versus placebo for 12 weeks on the percent change from baseline on the following assessments in patients with HeFH: o Non-high-density lipoprotein cholesterol (non-HDL-C) o Apolipoprotein B (ApoB) o Total cholesterol /high-density lipoprotein cholesterol (HDL-C) ratio o Triglycerides o Lipoprotein(a) o Apolipoprotein A1 (ApoA1)/ApoB ratio o Lipoprotein particle assessment •To determine the effect of once-daily oral dose of MGL3196 versus placebo for 12 weeks on the absolute change from baseline in LDL-C in patients with HeFH •To determine the effect of all patients (100 and 60 mg groups) on per cent change from Baseline in LDL-C •To determine the effect of exposure to MGL3196 on LDL-C lowering;Timepoint(s) of evaluation of this end point: Week 2, Week 4, Week 8, and Week 12 | — |
Countries
Denmark, Netherlands, Norway
Contacts
Public ContactMedpace Regulatory Submissions
Medpace, Inc.
Outcome results
None listed