E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) |
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E.1.1.1 | Medical condition in easily understood language |
Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) |
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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 vutrisiran compared to placebo on reducing all-cause mortality and Cardiovascular (CV) events |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of vutrisiran compared with placebo treatment on: - Functional capacity - Patient-reported health status and healthrelated quality of life - Cardiac structure and function - Additional assessments of death, hospitalizations, and urgent heart failure (HF) visits - Components of the primary composite outcome endpoint (all-cause mortality, and CV events) - Cardiac biomarkers |
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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 per local regulations, 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 3. Medical history of HF with at least 1 prior hospitalization for HF (not due to arrhythmia or a conduction system disturbance treated with a permanent pacemaker) OR clinical evidence of HF (with or without hospitalization) manifested by signs and symptoms of volume overload or elevated intracardiac pressures (eg, elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral edema) that currently requires treatment with a diuretic. 4. Patient meets one of the following criteria: a. Tafamidis-naïve and not actively planning to commence treatment with tafamidis during the first 12 months following randomization (per exclusion criterion #7); or b. On tafamidis (Note: must be on-label use of commercial tafamidis per an approved cardiomyopathy indication and dose in the country of use) 5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to randomization, as assessed by the Investigator. 6. Screening NT-proBNP >300 ng/L and <8500 ng/L; in patients with permanent or persistent atrial fibrillation, Screening NT-proBNP >600 ng/L and <8500 ng/L.. 7. Able to complete ≥150 meters on the 6-MWT at Screening. 8. Have a Karnofsky performance status of ≥60%. 9. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent. 10. Patient agrees to sign a separate medical records release form, where allowed by local regulations, to allow for the collection of information on vital status, cardiac transplant procedures, left-ventricular assist device placement, and hospitalizations, for the duration of the DB Period of the study. |
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E.4 | Principal exclusion criteria |
1. Has known primary amyloidosis(AL amyloidosis)or leptomeningeal amyloidosis 2. NYHA Class IV heart failure; or NYHA Class III heart failure AND ATTR Amyloidosis Disease Stage 3 (defined as NT-proBNP >3000 ng/L and eGFR <45 ml/min) 3. Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to walk due to polyneuropathy, or is wheelchair bound) at the Screening visit 4. Has any of the following laboratory parameter assessments at Screening: a. AST or ALT levels >2.0 × ULN; b. Total bilirubin >2.0 × 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 (unless patients were on anticoagulant therapy in which case excluded if INR >3.5) 5. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] formula) at Screening 6. Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection 7. Tafamidis-naïve patients (per inclusion criterion #4a) for whom the Investigator actively plans or anticipates commencing treatment with tafamidis either during the Screening Period or the first 12 months following randomization, taking into consideration clinical status, patient preference and/or commercial availability of tafamidis 8. Received prior TTR-lowering treatment (including revusiran, patisiran or inotersen) or participated in a gene therapy trial for hATTR amyloidosis 9. Currently taking diflunisal; if previously on this agent, must have at least a 30-day wash-out prior to dosing (Day 1) 10. Currently taking doxycycline, ursodeoxycholic acid or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 30-day wash-out prior to dosing (Day 1) 11. Unwilling to avoid any concurrent treatment with diflunisal, ursodeoxycholic acid/tauroursodeoxycholate/doxycycline, or TTR lowering agents (eg, patisiran, inotersen) 12. Current or future participation in another investigational device or drug study, scheduled to occur during this study, or has received an investigational agent or device within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 1). In the case of investigational TTR stabilizer drugs, washout for 3 months prior to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at baseline (inclusion criterion #4) 13. Requires treatment with or is unwilling to avoid any concurrent treatment with nondihydropyridine calcium channel blockers (eg, verapamil, diltiazem) 14. Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease (eg, prior myocardial infarction with documented history of cardiac enzymes and ECG changes) that the Investigator feels is a significant contributor or the predominant cause of the patient’s heart failure 15. Unstable congestive heart failure (CHF) (including patients who require adjustment of existing diuretics or addition of new diuretics at time of Screening for purposes of achieving optimal management of CHF) 16. Had acute coronary syndrome or unstable angina within the past 3 months 17. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation 18. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed 19. Has persistent elevation of systolic (>170 mmHg) or diastolic (>100 mmHg) blood pressure that is considered uncontrolled by physician 20. Has untreated hypo- or hyperthyroidism 21. Has an active infection requiring systemic antiviral, antiparasitic or antimicrobial therapy that will not be completed prior to dosing (Day 1) 22. Prior or anticipated (during the first 12 months after randomization) heart, liver or other organ transplant or implantation of left-ventricular assist device 23. History of multiple drug allergies; or history of allergic reaction to any component of or excipient in the study drug 24. History of intolerance to SC injection(s) or significant abdominal scarring that could potentially hinder study drug administration or evaluation of local tolerability 25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation 26. Is not willing to comply with the contraceptive requirements during the study period 27. Female patient is pregnant, planning a pregnancy, or breast-feeding 28. Unwilling or unable to limit alcohol consumption throughout the course of the study 29. History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator 30.History of illicit drug abuse within the past 5 years that in the opinion of the Investigator would interfere |
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E.5 End points |
E.5.1 | Primary end point(s) |
Composite outcome of all-cause mortality and recurrent CV events (CV hospitalizations and urgent HF visits) |
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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 in 6-minute walk test (6-MWT)
- Change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS)
- Change from baseline in mean left ventricular (LV) wall thickness (by echocardiographic assessment)
- Change from baseline in global longitudinal strain (by echocardiographic assessment)
- Composite endpoint of all-cause mortality and recurrent all-cause hospitalizations and urgent HF visits.
- All-cause mortality
- Recurrent CV events (CV hospitalizations and urgent HF visits)
- Change from baseline in N-terminal prohormone B-type natriuretic peptide (NT-proBNP) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
6-MWT: Weeks 1, 24, 48, 72, 84, 108, 132 KCCQ-OS: Weeks 1, 24, 48, 72, 84, 108, 132 echocardiogram: Weeks 48, 72, 108, 132 NT-proBNP: Weeks 12, 24, 36, 48, 72, 108, 132 mortality and CV events assessed over 36 month period
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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 | 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 | 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 | 39 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
Argentina |
Peru |
Australia |
Canada |
Israel |
Japan |
Korea, Republic of |
United Kingdom |
United States |
Austria |
Belgium |
Croatia |
Czechia |
Denmark |
France |
Germany |
Hungary |
Ireland |
Latvia |
Lithuania |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Sweden |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |