A Study to Evaluate Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alnylam Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

24 Jun 2020 → ongoing

Decision date (initial)

2024-11-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alnylam Pharmaceuticals, Inc.; USA

External identifiers

EU CT number

2024-518318-25-00

EudraCT number

2019-003153-28

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To evaluate the efficacy of vutrisiran compared to placebo on reducing all-cause mortality and Cardiovascular (CV) events

Secondary objectives 1

1. 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

Conditions and MedDRA coding

Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Age 18 to 85 years
2. 2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with cardiomyopathy
3. 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. 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. 5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to randomization, as assessed by the Investigator.
6. 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. 7. Able to complete ≥150 meters on the 6-MWT at Screening.
8. 8. Have a Karnofsky performance status of ≥60%.
9. 9. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
10. 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, leftventricular assist device placement, and hospitalizations, for the duration of the DB Period of the study.

Exclusion criteria 30

1. 1. Has known primary amyloidosis(AL amyloidosis)or leptomeningeal amyloidosis
2. 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)
3. 11. Unwilling to avoid any concurrent treatment with diflunisal, ursodeoxycholic acid/tauroursodeoxycholate/doxycycline, or TTR lowering agents (eg, patisiran, inotersen)
4. 13. Requires treatment with or is unwilling to avoid any concurrent treatment with nondihydropyridine calcium channel blockers (eg, verapamil, diltiazem)
5. 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
6. 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)
7. 16. Had acute coronary syndrome or unstable angina within the past 3 months
8. 17. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation
9. 18. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed
10. 19. Has persistent elevation of systolic (>170 mmHg) or diastolic (>100 mmHg) blood pressure that is considered uncontrolled by physician
11. 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)
12. 20. Has untreated hypo- or hyperthyroidism
13. 21. Has an active infection requiring systemic antiviral, antiparasitic or antimicrobial therapy that will not be completed prior to dosing (Day 1)
14. 22. Prior or anticipated (during the first 12 months after randomization) heart, liver or other organ transplant or implantation of left-ventricular assist device
15. 23. History of multiple drug allergies; or history of allergic reaction to any component of or excipient in the study drug
16. 24. History of intolerance to SC injection(s) or significant abdominal scarring that could potentially hinder study drug administration or evaluation of local tolerability
17. 25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation
18. 26. Is not willing to comply with the contraceptive requirements during the study period
19. 27. Female patient is pregnant, planning a pregnancy, or breast-feeding
20. 28. Unwilling or unable to limit alcohol consumption throughout the course of the study
21. 29. History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator
22. 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
23. 30.History of illicit drug abuse within the past 5 years that in the opinion of the Investigator would interfere with compliance with study procedures or follow-up visits
24. 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)
25. 5. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] formula) at Screening
26. 6. Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection
27. 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
28. 8. Received prior TTR-lowering treatment (including revusiran, patisiran or inotersen) or participated in a gene therapy trial for hATTR amyloidosis
29. 9. Currently taking diflunisal; if previously on this agent, must have at least a 30-day wash-out prior to dosing (Day 1)
30. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Composite outcome of all-cause mortality and recurrent CV events (CV hospitalizations and urgent heart failure [HF] visits) in both the overall population and the vutrisiran monotherapy subgroup (defined as patients not on tafamidis at study baseline).

Secondary endpoints 1

1. 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 QuestionnaireOverall Summary (KCCQ-OS) - All-cause mortality - Change from baseline in NYHA Class

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alnylam Pharmaceuticals Inc.

Sponsor organisation

Alnylam Pharmaceuticals Inc.

Address

300 3rd Street

City

Cambridge

Postcode

02142-1103

Country

United States

Scientific contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trials Information Line

Public contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trials Information Line

Third parties 19

Locations

16 EU/EEA countries · 41 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 90 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications