E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) |
Amiloidosi da transtiretina con cardiomiopatia (amiloidosi ATTR con cardiomiopatia) |
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E.1.1.1 | Medical condition in easily understood language |
Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) |
Amiloidosi da transtiretina con cardiomiopatia (amiloidosi ATTR con cardiomiopatia) |
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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 | PT |
E.1.2 | Classification code | 10007509 |
E.1.2 | Term | Cardiac amyloidosis |
E.1.2 | System Organ Class | 10007541 - Cardiac 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 |
To evaluate the efficacy of patisiran compared with placebo treatment on functional capacity (6-minute walk test [6-MWT]) in patients with ATTR amyloidosis with cardiomyopathy |
Valutare l'efficacia di patisiran rispetto al trattamento con placebo sulla capacità funzionale (test del cammino in 6 minuti [6-MWT]) in pazienti affetti da amiloidosi ATTR con cardiomiopatia |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of patisiran compared with placebo treatment on: - Health status and health-related quality of life - Patient mortality and hospitalizations |
Valutare l’efficacia di patisiran rispetto al trattamento con placebo su: - Stato di salute e qualità della vita correlata allo stato di salute - Mortalità e ospedalizzazioni dei pazienti |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive. 2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with cardiomyopathy: Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria: a. TTR pathogenic mutation consistent with hATTR. b. Evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness >12 mm (based on central echocardiogram reading at screening). c. Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, median nerve connective sheath) confirmed by Congo Red (or equivalent) staining OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2 propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, if monoclonal gammopathy of undetermined significance (MGUS) has been excluded. d. If MGUS, confirm TTR protein in tissue with immunohistochemistry (IHC) or mass spectrometry. Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria: a. Absence of pathogenic TTR mutation. b. Evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness >12mm (based on central echocardiogram reading at screening). c. Amyloid deposits in cardiac tissue with TTR precursor identification by IHC, mass spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, if MGUS has been excluded. d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry FOR THE COMPLETE LIST, REFER TO THE PROTOCOL |
1. Età compresa tra i 18 (o l'età minima necessaria per fornire il consenso legale, a seconda di quale sia la più elevata) e gli 85 anni inclusi. 2. Diagnosi documentata di amiloidosi ATTR con cardiomiopatia, classificata come amiloidosi hATTR con cardiomiopatia o amiloidosi wtATTR con cardiomiopatia: Amiloidosi ATTR ereditaria con cardiomiopatia diagnosticata sulla base del soddisfacimento di tutti i seguenti criteri: a. Mutazione patogena della TTR coerente con hATTR. b. Evidenza di coinvolgimento cardiaco ottenuta mediante ecocardiogramma con spessore telediastolico della parete del setto interventricolare >12 mm (basato sulla lettura dell’ecocardiogramma eseguito centralmente allo screening). c. Depositi di amiloide nel tessuto cardiaco o non cardiaco (ad es. aspirato del tessuto adiposo, ghiandola salivare, guaina connettiva del nervo mediano) confermati mediante colorazione Rosso Congo (o equivalente) O scintigrafia con tecnezio (99mTc) (99mTc-3,3-difosfono-1,2-acido propanodicarbossilico [DPD-Tc] o 99mTc-pirofosfato [PYP-Tc]) con assorbimento cardiaco di grado 2 o 3, in caso di esclusione di gammopatia monoclonale di significato incerto (MGUS). d. In caso di MGUS, conferma della presenza di proteina TTR nei tessuti mediante immunoistochimica (IHC) o spettrometria di massa. Amiloidosi ATTR wild-type con cardiomiopatia diagnosticata sulla base del soddisfacimento di tutti i seguenti criteri: a. Assenza di mutazioni patogene della TTR. b. Evidenza di coinvolgimento cardiaco ottenuta mediante ecocardiogramma con spessore telediastolico della parete del setto interventricolare >12 mm (basato sulla lettura dell’ecocardiogramma eseguito centralmente allo screening). c. Depositi di amiloide nel tessuto cardiaco con identificazione del precursore della TTR mediante IHC, spettrometria di massa O scintigrafia con tecnezio (99mTc) (99mTc-3,3-difosfono-1,2-acido propanodicarbossilico [DPD-Tc] o 99mTc-pirofosfato [PYP-Tc]) con assorbimento cardiaco di grado 2 o 3, in caso di esclusione di MGUS. d. In caso di MGUS, conferma della presenza di proteina TTR nel tessuto cardiaco mediante IHC o spettrometria di massa PER L'ELENCO COMPLETO RIFERIRSI AL PROTOCOLLO |
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E.4 | Principal exclusion criteria |
1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis. 2. NYHA Class III AND ATTR amyloidosis disease Stage 3 (defined as both NT-proBNP >3000 ng/L and estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2).[Gillmore 2018] 3. NYHA Class IV at the Screening visit. 4. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to walk, or is wheelchair bound) at the Screening visit. FOR THE COMPLETE LIST, REFER TO THE PROTOCOL |
1. Soffre di amiloidosi primaria (AL) o amiloidosi leptomeningea nota. 2. Presenta una classe III secondo la NYHA E malattia amiloide ATTR allo stadio 3 (definito da NT proBNP >3000 ng/l e velocità di filtrazione glomerulare stimata [eGFR] <45 ml/min/1,73 m2) [Gillmore 2018] 3. Presenta una classe IV secondo la NYHA alla Visita di screening. 4. Ha una disabilità da polineuropatia (PND) con punteggio IIIa, IIIb o IV (necessita di assistenza alla deambulazione con bastone o stampella o è costretto sulla sedia a rotelle) alla Visita di Screening. PER L'ELENCO COMPLETO RIFERIRSI AL PROTOCOLLO |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline at Month 12 in 6-MWT |
Variazione rispetto alla baseline al Mese 12 del test 6-MWT |
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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) |
- Change from baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score - Composite endpoint of all-cause mortality, frequency of cardiovascular (CV)-related hospitalizations and change from baseline in 6-MWT over the 12-month double-blind period - Composite endpoint of all-cause mortality and frequency of all-cause hospitalizations over the 12-month double-blind period |
- Variazione rispetto alla baseline al Mese 12 del punteggio del Questionario sulla cardiomiopatia Kansas City-Sintesi complessiva (KCCQ-OS) - Indice composito di mortalità per tutte le cause, frequenza delle ospedalizzazioni per eventi cardiovascolari (CV) e variazione rispetto alla baseline del test 6-MWT nel corso del periodo in doppio cieco di 12 mesi - Indice composito di mortalità per tutte le cause e frequenza delle ospedalizzazioni per tutte le cause nel corso del periodo in doppio cieco di 12 mesi al Mese |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Month 12 (Weeks 52-53); this assessment will also be performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38 |
Al mese 12 (Settimane 52-53); tale valutazione verrà eseguita anche al Mese 6 (Settimane 25-26) e al Mese 9 (Settimane 37-38) |
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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 | Yes |
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 | 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 | 1 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 | Information not present in EudraCT |
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 |
Argentina |
Australia |
Brazil |
Colombia |
Hong Kong |
Japan |
Korea, Republic of |
Mexico |
Taiwan |
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 |