A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study of MGL-3196 in Patients With Heterozygous Familial Hypercholesterolemia
- Conditions
- Heterozygous Familial Hypercholesterolemia10013317
- Registration Number
- NL-OMON45499
- Lead Sponsor
- Madrigal Pharmaceuticals, Inc.
- Brief Summary
Trial is onging in other countries
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 24
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 (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;
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 (Appendix C) or WHO/Dutch Lipid Network (score >8; Appendix D);
5. Must have a fasting LDL-C *2.6 mmol/L (100 mg/dL).
Any one of the following subgroups of patients with documented history of cardiovascular disease as outlined below can be included with a fasting LDL-C of * 1.8 mmol/L (70 mg/dL):
A) Coronary Artery Disease (CAD) including one or more of the following:
* Acute myocardial infarction (MI)
* Silent myocardial infarction
* Unstable angina
* Coronary revascularization procedure (e.g. percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG])
* Clinically significant CAD diagnosed by invasive or non-invasive testing (such as coronary angiography, stress test using treadmill, stress echocardiography or nuclear imaging).
B) Previous ischemic stroke with a focal ischemic neurological deficit that persisted more than 24 hours, considered as being of atherothrombotic origin.
C) Peripheral arterial disease (one of the following criteria must be satisfied):
* Current intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) of presumed atherosclerotic origin together with ankle-brachial index equal to or less than 0.90 in either leg at rest, or
* History of intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) together with endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease,; or
* History of critical limb ischemia together with thrombolysis, endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease.
6. Must be on a stable or maximally tolerated dose (*4 weeks prior t
Patients who meet any of the following criteria will be excluded from participation in the study:
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 <30%;
4. 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;
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;
13. 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;
14. Serum alanine aminotransferase (ALT) >1.5 × ULN (one repeat allowed);
15. Estimated glomerular filtration rate <60 mL/min;
16. Creatine kinase >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 Section 5.6.1;
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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary efficacy parameter is mean percent change from baseline in LDL-C.</p><br>
- Secondary Outcome Measures
Name Time Method <p>The secondary efficacy parameters include the following:<br /><br>o Mean percent change from baseline in non-HDL-C, ApoB, TC/HDL-C ratio,<br /><br>triglycerides,<br /><br>lipoprotein(a), ApoA1/ApoB ratio, and lipoprotein particle assessment; and<br /><br>o Absolute percent change from baseline in LDL-C.<br /><br><br /><br>Safety variables to be assessed include safety laboratory tests, vital signs,<br /><br>12-lead ECG with<br /><br>rhythm strip, physical examinations, assessment of adverse events, and clinic<br /><br>assessments.</p><br>