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 |
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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 | 10010331 - Congenital, familial and genetic disorders |
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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 is to demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [percent change] at Day 330 (Year 1) in adolescents (aged 12 to <18 years) with HoFH and elevated LDL-C |
Evaluer l’effet de l’inclisiran par rapport au placebo en termes de diminution du cholestérol LDL exprimée par la variation en pourcentage au Jour 330 (Année 1) chez les adolescents (âgés de 12 ans à < 18 ans) présentant une HF homozygote et des taux élevés de cholestérol LDL. |
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E.2.2 | Secondary objectives of the trial |
Evaluate the effect of inclisiran compared to placebo on reducing LDL-C [time-adjusted percent change] over Year 1.
Evaluate the effect of inclisiran compared to placebo (for Year 1) and long-term (up to Day 720), on lowering LDL-C, other lipoprotein and lipid parameters, and PCSK9 over time.
Evaluate the safety and tolerability of inclisiran compared to placebo (for Year 1) and long-term (up to Day 720), in adolescents (aged 12 to <18 years) with HoFH. |
Evaluer l’effet de l’inclisiran par rapport au placebo en termes de diminution du cholestérol LDL exprimée par la variation en pourcentage ajustée au cours du temps sur l’Année 1.
Evaluer l’effet de l’inclisiran sur la diminution du cholestérol LDL, d’autres lipoprotéines, des paramètres lipidiques et de la PCSK9 par rapport au placebo au cours de l’Année 1 et sur le long terme (jusqu’au Jour 720) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Homozygous Familial Hypercholesterolemia (HoFH) diagnosed by genetic confirmation.
Fasting LDL-C >130 mg/dL (3.4 mmol/L) at screening.
On maximally tolerated dose of statin (investigator’s discretion) with or without other lipid-lowering therapy; stable for ≥ 30 days before screening.
Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 at screening. |
HF homozygote confirmée par un test génétique
Taux de cholestérol LDL à jeun > 130 mg/ml (3,4 mmol/l) à la visite de sélection, mesuré par le laboratoire central.
La dose du traitement hypolipémiant (statines et/ou ézétimibe) doit être stable depuis ≥ 30 jours avant la sélection, sans modification prévue du traitement ou de la dose pendant la durée de participation à l’étude.
Débit de filtration glomérulaire estimé > 30 ml/min/1,73 m² au moment de la sélection.
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E.4 | Principal exclusion criteria |
Documented evidence of a null (negative) mutation in both LDLR alleles.
Heterozygous familial hypercholesterolemia (HeFH).
Active liver disease.
Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome.
Major adverse cardiovascular events within 1 month prior to randomization.
Previous treatment with monoclonal antibodies directed towards PCSK9 (within 90 days of screening).
Treatment with mipomersen or lomitapide (within 5 months of screening).
Recent and/or planned use of other investigational medicinal products or devices. |
HF homozygote.
Maladie hépatique évolutive
Hypercholestérolémie secondaire, par exemple liée à une hypothyroïdie ou un syndrome néphrotique.
Accidents cardiovasculaires majeurs dans les 3 mois précédant la randomisation.
Traitement antérieur (dans les 90 jours avant la sélection) par anticorps monoclonaux dirigés contre la PCSK9
Utilisation prévue d'un traitement expérimental ou d'un dispositif |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage (%) change in low-density lipoprotein cholesterol (LDL-C) from baseline to Day 330. |
Variation en pourcentage du cholestérol LDL entre la baseline et le Jour 330 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline and Day 330 |
entre la baseline et le Jour 330 |
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E.5.2 | Secondary end point(s) |
Time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330.
Percent change and absolute change in LDL-C from baseline up to Day 720.
Percent change and absolute change in other lipoprotein and lipid parameters from baseline up to Day 720.
Percent change and absolute change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline up to Day 720. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, after Day 90 up to Day 330.
Baseline, up to Day 720.
Baseline, up to Day 720.
Baseline, up to Day 720. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | 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 | 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 | 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 | 9 |
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 |
Switzerland |
Canada |
Lebanon |
Serbia |
United States |
France |
Greece |
Netherlands |
Slovenia |
Türkiye |
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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 | 5 |
E.8.9.1 | In the Member State concerned days | |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |