E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heterozygous Familial Hypercholesterolemia (HeFH) |
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E.1.1.1 | Medical condition in easily understood language |
HeFH is an inherited disease that causes high levels of cholesterol which can cause heart disease. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057079 |
E.1.2 | Term | Heterozygous familial hypercholesterolemia |
E.1.2 | System Organ Class | 100000012386 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
•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:
oNon-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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) or WHP/Dutch lipid network.
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 (Scientific Steering Committee 1991) or World Health Organization (WHO)/Dutch Lipid Network (score >8) Note: Patients meeting the diagnostic criteria of probable HeFH (WHO/Dutch Lipid Network score >=6, <=8) may be included, up to 10% of the total study population
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 to screening) of an approved statin (rosuvastatin <=40 mg daily, <=atorvastatin 80 mg daily), with or without ezetimibe. Patients intolerant to statins are allowed. See section 1.2.1 drug interaction studies with statins for details |
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E.4 | Principal 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 <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 (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 <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 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 |
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E.5 End points |
E.5.1 | 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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:
oNon-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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 2, Week 4, Week 8, and Week 12 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |