A study to Evaluate Patisiran 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

22 Nov 2019 → 24 Dec 2025

Decision date (initial)

2024-11-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alnylam Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-508364-29-00

EudraCT number

2019-001458-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

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

Secondary objectives 1

1. To evaluate the efficacy of patisiran compared with placebo treatment on: - Health status and health-related quality of life - Patient mortality, hospitalizations, and urgent heart failure (HF) visits

Conditions and MedDRA coding

Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the United States (US) and/or the European Union (EU). Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. 1. Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.
2. 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.
3. b. Evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness >12 mm (based on central echocardiogram reading at screening).
4. 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], 99mTc-pyrophosphate [PYP-Tc] or 99mTc-hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if MGUS has been excluded.
5. d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry
6. Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria: a. Absence of pathogenic TTR mutation.
7. b. Evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness >12mm (based on central echocardiogram reading at screening).
8. 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], 99mTc-pyrophosphate [PYP-Tc] or 99mTc-hydroxymethylene diphosphonate [HMDP]) with Grade 2 or 3 cardiac uptake, if MGUS has been excluded.
9. d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry
10. 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.
11. 4. Patient meets one of the following criteria: a. Tafamidis naïve; in addition to patients who have never taken tafamidis, those who have been on tafamidis for ≤30 days total and have not received any tafamidis in the 6 months prior to baseline will be considered tafamidis naïve and may qualify for the study.
12. b. Currently on tafamidis (for ≥6 months) and has demonstrated disease progression, as determined by the Investigator. (At the time of study entry, tafamidis treatment must be on-label use of commercial tafamidis for the treatment of ATTR amyloidosis with cardiomyopathy at the approved dose in the country of use.)
13. 5. Patient is clinically stable, with no CV-related hospitalizations within 6weeks prior to randomization, as assessed by the Investigator.
14. 6. Able to complete ≥150 m on the 6-MWT at screening.
15. 7. 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.
16. 8. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent; and patient agrees to sign the medical records release form for collection of vital status.

Exclusion criteria 31

1. 1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.
2. 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. 3. NYHA Class IV at the Screening visit.
4. 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.
5. 5. Has any of the following laboratory parameter assessments at screening: a. Aspartate transaminase (AST) or alanine transaminase (ALT) levels>2.0 × the upper limit of normal (ULN).
6. b. Total bilirubin >2 × ULN.
7. c. International normalized ratio (INR)>1.5 (unless patient is on anticoagulant therapy, in which case excluded if INR>3.5).
8. 6. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] formula).
9. 7. Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection.
10. 8. Tafamidis naïve patients (at baseline) for whom the Investigator actively plans or anticipates commencing treatment with tafamidis during the 12-month double-blind period, taking into consideration clinical status, patient preference and/or commercial availability of tafamidis.
11. 9. Is currently taking diflunisal; if previously on this agent, must have at least a 30-day wash-out prior to dosing (Day 1).
12. 10. Is 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).
13. 11. Received prior TTR-lowering treatment (including patisiran) or participated in a gene therapy trial for hATTR amyloidosis.
14. 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 6 months prior to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at baseline (per inclusion Criterion 4).
15. 13. Requires chronic treatment with non-dihydropyridine calcium channel blockers (eg, verapamil, diltiazem).
16. 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 electrocardiogram [ECG] changes).
17. 15. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation).
18. 16. Recent or planned orthopedic procedure during the double-blind period (eg, lower extremity or back surgery) that could impact 6-MWT.
19. 17. Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of screening required to achieve optimal treatment of CHF).
20. 18. Had acute coronary syndrome or unstable angina within the past 3 months.
21. 19. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.
22. 20. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed.
23. 21. Has persistent elevation of systolic (>180 mmHg) and diastolic (>100 mmHg) blood pressure that is considered uncontrolled by physician.
24. 22. Has untreated hypo- or hyperthyroidism.
25. 23. Prior or planned heart, liver, or other organ transplant.
26. 24. Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
27. 25. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation; or, in the opinion of the Investigator, taking part in the study would jeopardize the safety of the patient.
28. 26. Has a history of severe hypersensitivity (eg. anaphylaxis) to any of the excipients in patisiran. Also see exclusion Criterion 11, which excludes all patients with prior TTR-lowering treatment including patisiran.
29. 27. Female patient is pregnant or breast-feeding. Female not willing to comply with contraceptive requirements.
30. 28. Has a known history of alcohol abuse within the past 2 years or daily heavy alcohol consumption (for females, more than 14 units of alcohol per week; for males, more than 21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ pint of beer])
31. 29. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline at Month 12 in 6-MWT

Secondary endpoints 3

1. 1. Change from baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score
2. 2. Composite endpoint of all-cause mortality, frequency of cardiovascular (CV) events (CV hospitalizations and urgent HF visits) and change from baseline in 6-MWT over the 12-month double-blind period
3. 3. Composite endpoint of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits over the 12-month double-blind period A135

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 16

Locations

8 EU/EEA countries · 22 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 52 files

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

Application history

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