E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Hepatic Porphyrias (AHP) |
porphyrie hépatique aiguë (PHA) |
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E.1.1.1 | Medical condition in easily understood language |
Acute hepatic porphyrias (AHP) represent a sub-group of porphyrias characterized by the occurrence of neuro-visceral attacks with or without cutaneous manifestations |
Les porphyries hépatiques aiguës (PHA) représentent un sous-groupe de porphyries caractérisées par la survenue d'attaques neuro-viscérales avec ou sans manifestations cutanées |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036182 |
E.1.2 | Term | Porphyria acute |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 | 10036184 |
E.1.2 | Term | Porphyria hepatic |
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 |
• Evaluate the effect of subcutaneous (SC) givosiran, compared to placebo, on the rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home in patients with acute intermittent porphyria (AIP) |
Évaluer l’effet du givosiran (ALN-AS1) en administration sous-cutanée (SC), par rapport au placebo, sur la fréquence des crises de porphyrie nécessitant une hospitalisation, une consultation médicale urgente ou l’administration intraveineuse (IV) d’hémine à domicile chez les patients atteints de porphyrie aiguë intermittente (PAI)
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of givosiran, compared to placebo, on: o Urinary aminolevulinic acid (ALA) levels in patients with AIP o Urinary porphobilinogen (PBG) levels in patients with AIP o Hemin usage in patients with AIP o The rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with any AHP o In patients with AIP on the symptoms of pain, nausea, and fatigue o In patients with AIP on the Physical Component Summary (PCS) of the 12-item Short-Form Health Survey (SF-12) • Evaluate the safety and tolerability of givosiran in patients with any AHP |
• Évaluer l’effet du givosiran, par rapport au placebo, sur: o les taux d’acide aminolévulinique (ALA) urinaire chez les patients atteints de PAI o les taux de porphobilinogène (PBG) urinaire chez les patients atteints de PAI o la prise d’hémine chez les patients atteints dePAI o la fréquence des crises de porphyrie nécessitant une hospitalisation, une consultation médicale urgente ou l’administration IV d’hémine à domicile chez les patients atteints de PHA o les symptômes de douleurs, nausées et fatigue chez les patients atteints de PAI o les scores agrégés physiques (PCS) du questionnaire SF-12 (12-item Short-Form Health Survey : version abrégée à 12 items du questionnaire d’état de santé) chez les patients atteints de PAI • Évaluer la sécurité d’emploi et la tolérance du givosiran chez les patients atteints de PHA
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥12 years 2. Documented diagnosis of AIP, HCP, VP, or ADP based on clinical features (eg, acute attacks of abdominal, back, chest, extremities, and/or limb pain), at least one documented urinary or plasma PBG or ALA value ≥4× upper limit of normal (ULN) within the past year prior to Screening, AND one of the following: • Documented genetic evidence of mutation in a porphyria-related gene, defined as ANY of the following: - AIP: mutation in the hydroxymethylbilane synthase gene (HMBS; also referred to as the porphobilinogen deaminase [PBGD] gene) - HCP: mutation in the coporphyrinogen oxidase (CPOX) gene - VP: mutation in the protoporphyrinogen oxidase (PPOX) gene - ADP: mutation in the aminolevulinic acid dehydratase (ALAD) homozygous or compound heterozygous genes • OR if the results of a patient’s genetic testing do not identify a mutation in a porphyria-related gene (<5% of cases), a patient may be eligible for the study if they have both clinical features and diagnostic biochemical criteria consistent with AHP 3. Have active disease, with at least 2 porphyria attacks requiring hospitalization, urgent healthcare visit or treatment with IV hemin at home within the 6 months prior to Screening 4. Willing to discontinue and/or not initiate use of prophylactic hemin at the time of Screening and for the duration of the study 5. Have adequate venous access for study sample collection as judged by the investigator 6. Be willing to comply with the contraceptive requirements during the study period 7. Be willing and able to comply with the study requirements and to provide written informed consent and assent in the case of patients under the age of legal consent, per local and national requirements |
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E.4 | Principal exclusion criteria |
1. Any of the following laboratory parameter assessments at Screening: a. Alanine aminotransferase (ALT) >2×ULN b. Total bilirubin >1.5× ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN c. International normalized ratio (INR) > 1.5 (patients on an anticoagulant [eg, warfarin] with an INR< 3.5 will be allowed) 2. Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula 3. On an active liver transplantation waiting list, or anticipated to undergo liver transplantation during the blinded study treatment period 4. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or to N-acetylgalactosamine (GalNAc) 5. History of intolerance to subcutaneous injection(s) 6. Known active HIV infection; or evidence of current or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection 7. Currently enrolled in another investigational device or drug study, or less than 30 days or 5 half-lives (whichever is longer) since ending another investigational device or drug study(s), or receiving other investigational agent(s) 8. Females who are pregnant, breast-feeding, or planning to become pregnant during the study 9. Any condition (eg, medical concern or alcohol or substance abuse), which in the opinion of the Investigator, would make the patient unsuitable for dosing or which could interfere with the study compliance, the patient’s safety and/or the patient’s participation in the 6-month treatment period of the study. This includes significant active and poorly controlled (unstable) cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric disorders unrelated to porphyria identified by key laboratory abnormalities or medical history. 10. History of recurrent pancreatitis, or acute pancreatitis with disease activity within the past 12 months prior to Screening 11. Has planned elective major surgery scheduled to occur during the study 12. History of serious infection within one month prior to Screening 13. Had a malignancy within 5 years prior to Screening, except for basal or squamous cell carcinoma of the skin, cervical in-situ carcinoma, or breast ductal carcinoma, that has been successfully treated |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with AIP over the 6-month treatment period |
• Fréquence annualisée des crises de porphyrie nécessitant une hospitalisation, une consultation médicale urgente ou l’administration IV d’hémine à domicile chez les patients atteints de PAI pendant la période de traitement de 6 mois |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Over the 6-month treatment period. |
pendant la période de traitement de 6 mois . |
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E.5.2 | Secondary end point(s) |
• Urinary ALA in patients with AIP at 3 months • Urinary ALA in patients with AIP at 6 months • Urinary PBG in patients with AIP at 6 months • Annualized rate of administered hemin doses in patients with AIP over the 6-month treatment period • Annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with any AHP over the 6-month treatment period • Daily worst pain score as measured by Brief Pain Inventory-Short Form (BPI-SF) numeric rating scale (NRS) in patients with AIP over the 6-month treatment period • Daily worst nausea score as measured by NRS in patients with AIP over the 6-month treatment period • Daily worst fatigue score as measured by Brief Fatigue Inventory-Short Form (BFI-SF) NRS in patients with AIP over the 6-month treatment period • Change from baseline in the PCS of the SF-12 in patients with AIP at 6 months
Safety • Incidence, severity, seriousness, and relatedness of adverse events during the 6-month treatment period and in the OLE period |
• Taux d’ALA urinaire à 3 mois chez les patients atteints de PAI • Taux d’ALA urinaire à 6 mois chez les patients atteints de PAI • Taux de PBG urinaire à 6 mois chez les patients atteints de PAI • Fréquence annualisée des doses d’hémine administrées chez les patients atteints de PAI pendant la période de traitement de 6 mois • Fréquence annualisée des crises de porphyrie nécessitant une hospitalisation, une consultation médicale urgente ou l’administration IV d’hémine à domicile chez les patients atteints de PHA sur la période de traitement de 6 mois Score quotidien de douleur la plus intense telle que mesurée par l’EEN (échelle d’évaluation numérique) du BPI-SF (Brief Pain Inventory-Short Form : questionnaire concis sur les douleurs) chez les patients atteints de PAI pendant la période de traitement de 6 mois • Score quotidien de nausée la plus intense telle que mesurée par l’EEN chez les patients atteints de PAI pendant la période de traitement de 6 mois • Score quotidien de fatigue la plus intense telle que mesurée par l’EEN du BFI-SF (Brief Fatigue Inventory-Short Form : questionnaire concis sur la fatigue) chez les patients atteints de PAI pendant la période de traitement de 6 mois • Évolution à 6 mois par rapport aux valeurs de référence des PCS du questionnaire SF-12 chez les patients atteints de PAI
Sécurité • Incidence, intensité, gravité et lien des événements indésirables pendant la période de traitement de 6 mois et la période d’extension en ouvert
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints will be measured over the 6-month double-blind treatment period |
Tous les critères d’évaluation secondaires seront mesurés pendant la période de traitement en double aveugle de 6 mois . |
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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 | No |
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) | 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 | Yes |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 |
Australia |
Belgium |
Brazil |
Bulgaria |
Canada |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
Poland |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
United Kingdom |
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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LVLS |
Dernière visite du dernier patient |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |