E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA |
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E.1.1.1 | Medical condition in easily understood language |
Homozygous familial hypercholesterolemia is an inherited genetic condition which results in the presence of high levels of cholesterol in the blood |
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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 | 10057080 |
E.1.2 | Term | Homozygous familial hypercholesterolemia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to demonstrate the reduction of LDL-C with alirocumab 150 mg subcutaneous (SC) every 2 weeks (Q2W) in comparison to placebo after 12 weeks of treatment. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To evaluate the effect of alirocumab 150 mg Q2W on other lipid parameters (i.e., apolipoprotein [Apo] A-1 and B, non-high-density lipoprotein cholesterol
[non-HDL-C], total cholesterol [TC], proportion of patients with 15%, 30%, and 50% LDL-C reductions, Lp(a), HDL-C, triglycerides [TG]) in patients with HoFH
• To evaluate the safety and tolerability of alirocumab 150 mg SC Q2W in patients with HoFH
• To assess the pharmacokinetics of alirocumab 150 mg SC Q2W in patients with HoFH
• To assess the potential development of anti-drug (alirocumab) antibodies
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females ≥18 years of age at the time of the screening visit.
2. Diagnosis of HoFH homozygous familial hypercholesterolemia (HoFH)
3. Receiving a stable dose of a statin at the screening visit |
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E.4 | Principal exclusion criteria |
1. Documented evidence of a null mutation in both LDLR alleles
2. Use of a PCSK9 inhibitor within 10 weeks from screening visit.
3. Background medical LMT that has not been stable for at least 4 weeks (6 weeks for
fibrates, 24 weeks for mipomersen, 12 weeks for maximum tolerated dose of lomitapide)
before the screening visit.
4. LDL apheresis schedule/apheresis settings that have not been stable for at least 8 weeks before the screening visit or an apheresis schedule/settings that is not anticipated to be stable over the next 24 weeks.
5. Use of nutraceuticals or over-the-counter (OTC) therapies known to affect lipids, at a dose/amount that has not been stable for at least 4 weeks prior to the screening visit or between the screening and randomization visits. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percent change in LDL-C from baseline to week 12 in the ITT population for alirocumab 150 mg Q2W as compared with placebo in patients with HoFH.
The percent change in LDL-C from baseline to week 12 is defined as: 100 x (LDL-C value at week 12 -LDL-C value at baseline)
LDL-C value at baseline
For LDL-C analysis, both calculated and measured LDL-C values will be taken into account. In case both calculated and measured LDL-C values are available for the same sampling time point, the measured LDL-C will be considered. The baseline LDL-C value will be the last LDL-C value obtained before the first dose of double-blind-study drug. For randomized but not-treated patients, baseline will be defined as the last value before randomization. The LDL-C at week 12 will be the LDL-C value obtained within the week 12 analysis window, regardless of adherence to treatment (ITT estimand).
All calculated and measured LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used for the primary efficacy endpoint, if appropriate, according to the above definition. The analysis window used to allocate a time point to a measurement will be defined in the statistical analysis plan (SAP).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, Baseline, Week 12 |
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E.5.2 | Secondary end point(s) |
4.2.2.1. Key Secondary Efficacy Endpoints
• The percent change in Apo B from baseline to week 12 (ITT estimand).
• The percent change in non-HDL-C from baseline to week 12 (ITT estimand).
• The percent change in total cholesterol from baseline to week 12 (ITT estimand).
• Proportion of patients with ≥15% reduction in LDL-C at week 12 (ITT estimand).
• Proportion of patients with ≥30% reduction in LDL-C at week 12 (ITT estimand).
• The percent change in Lp(a) from baseline to week 12 (ITT estimand).
• Proportion of patients with ≥50% reduction in LDL-C at week 12 (ITT estimand).
• The percent change in HDL-C from baseline to week 12 (ITT estimand).
• The percent change in fasting TG from baseline to week 12 (ITT estimand).
• The percent change in Apo A-1 from baseline to week 12 (ITT estimand). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, Baseline, 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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
a double blind and open label treatment phase |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Canada |
Czech Republic |
France |
Germany |
Greece |
Italy |
South Africa |
Turkey |
Ukraine |
United States |
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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 | 2 |
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 | 2 |
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 |