Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) MedDRA version: 27.0 Level: PT Classification code 10007509 Term: Cardiac amyloidosis System Organ Class: 10007541 - Cardiac disorders
Conditions
Interventions
Product Name: vutrisiran
Product Code: ALN-TTRSC02
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: vutrisiran
CAS Number: 1867157-35-4
Current Sponsor code: ALN-
Sponsors
Alnylam Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 600 ng/L and =65 years) yes F.1.3.1 Number of subjects for this age range 300
Exclusion criteria
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 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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Composite outcome of all-cause mortality and recurrent CV events (CV hospitalizations and urgent HF visits) in both the overall population and the vutrisiran monotherapy subgroup (defined as patients not on tafamidis at study baseline). ;Timepoint(s) of evaluation of this end point: 36 months;Main Objective: To evaluate the efficacy of vutrisiran compared to placebo on reducing all-cause mortality and Cardiovascular (CV) events;Secondary Objective: To evaluate the efficacy of vutrisiran compared with placebo treatment on: - Functional capacity - Patient-reported health status and health related quality of life - All-cause mortality - Severity of clinical heart failure symptoms | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The following secondary endpoints will be defined in both the overall population and the vutrisiran monotherapy subgroup: - Change from baseline in 6-minute walk test (6-MWT) - Change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) - All-cause mortality - Change from baseline in NYHA Class ;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 NYHA Class: Weeks 24, 48, 72, 108, 132 mortality assessed over 36 month period | — |
Countries
Argentina, Australia, Austria, Belgium, Canada, Croatia, Czechia, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Netherlands, Norway, Peru, Poland, Portugal, Slovenia, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinical Trials Information Line
Alnylam Pharmaceuticals, Inc
Outcome results
None listed