A Study to Evaluate Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy
- Conditions
- Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)MedDRA version: 20.0Level: PTClassification code 10007509Term: Cardiac amyloidosisSystem Organ Class: 10007541 - Cardiac disordersTherapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2019-003153-28-PT
- Lead Sponsor
- Alnylam Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 600
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 the approved 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 >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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 300
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 300
1. Has known primary 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 >1.5 × 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 (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 (at baseline) for whom the Investigator actively plans or anticipates commencing treatment with tafamidis during 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. Is currently taking diflunisal; if previously on this agent, must have at least a 3-month wash-out prior to dosing (Day 1).
10. Is currently taking doxycycline 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, 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 (per 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.
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Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method