NUCRESIRAN for Transthyretin amyloidosis with cardiomyopathy (ATTR amyloidosis with cardiomyopathy)

Inclusion criteria

• {"criterion_text":"- 1. Age 18 (or age of legal consent per local regulations, whichever is older) to 85 years, inclusive.\n- 2. Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hATTR amyloidosis with cardiomyopathy or wtATTR amyloidosis with cardiomyopathy:\n- 3. Medical history of HF with at least 1 prior hospitalization for HF OR clinical evidence of HF (with or without hospitalization)\n- 4. Patients may be receiving approved TTR stabilizers for ATTR amyloidosis and may be receiving background therapy for HF but must be stable for at least 30 days prior to screening\n- 5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to randomization\n- 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\n- 7. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent"}

Exclusion criteria

• {"criterion_text":"- 1. Has known primary amyloidosis (AL amyloidosis) or leptomeningeal amyloidosis\n- 10. Female patient is pregnant, planning a pregnancy, or breastfeeding\n- 11. Unwilling or unable to limit alcohol consumption, with a history of alcohol use disorder within the last 12 months, or a history of illicit drug use within the past 5 years that could interfere with study compliance\n- 2. NYHA Class IV HF; or NYHA Class III heart failure AND ATTR Amyloidosis Disease Stage 3 (defined as NT-proBNP >3000 ng/L and eGFR <45 mL/min)\n- 3. Has a polyneuropathy disability Score IIIa, IIIb, or IV at the Screening visit.\n- 4. Has any of the following lab parameter at screening: a. AST or ALT levels ˃2.0×ULN; b. Total bilirubin >2.0×ULN; c. INR >1.5 (unless patients were on anticoagulant therapy in which case excluded if INR ˃3.5).\n- 5. Has an eGFR of <30 mL/min/1.73m2 at screening (calculation will be based on the CKD-EPI equation)\n- 6. Has known HIV infection or evidence of current or chronic HCV or HBV infection.\n- 7. Patients with current, prior or planning to receive TTR-lowering therapy, anti-TTR antibody treatment, diflunisal, or participating in another investigational study (must meet washout periods of previous treatment to be included).\n- 8. Patients with the following medical conditions: •\tsignificant non-TTR cardiomyopathies, unstable CHF, recent acute coronary syndrome, ventricular arrhythmias, pacemaker-indicated nodal dysfunction, or uncontrolled high blood pressure are excluded from the study. •\tuntreated hypo- or hyperthyroidism •\tactive infections requiring systemic antiviral, antiparasitic, or antimicrobial therapy that will not be completed before dosing •\tPrior or anticipated ( 12 months after randomization) organ transplant or implantation of LVAD •\tmultiple drug allergies or history of allergic reaction to any component of study drug •\tintolerance to SC injection •\tother medical conditions or comorbidities that could interfere with study compliance or data interpretation, or a life expectancy of <2 years due to any non-cardiovascular condition\n- 9. Unwilling to comply with the contraceptive requirements during the study;"}

Primary endpoints

• {"endpoint_text":"- Composite outcome of all-cause mortality and recurrent CV events (CV hospitalizations and urgent HF visits)","definition_or_measurement_approach":"Composite endpoint defined as occurrence of all-cause mortality and recurrent cardiovascular events, specifically cardiovascular hospitalizations and urgent heart-failure visits."}

Secondary endpoints

• {"endpoint_text":"- •Time to first CV event (CV hospitalizations and urgent HF visits) or all-cause mortality •All-cause mortality •Recurrent CV events •Change from baseline in KCCQ-OS","definition_or_measurement_approach":"Secondary endpoints include time-to-event measures (time to first CV event or all-cause mortality), counts of all-cause mortality, recurrent cardiovascular events, and change from baseline in KCCQ-OS (patient-reported health status/quality-of-life instrument)."}

Methods

• Site-based recruitment through participating hospitals and cardiology departments (multiple country-specific site documents and site lists provided).
• GP/primary care outreach (GP letter documents present for some countries).
• Patient-facing materials: Patient Information Brochures, Visual Talking Points, Clinical Trial Posting Information (country-specific versions) to inform potential participants.
• Site patient-advocacy contact lists and engagement with patient organisations (documents titled Site-Patient-advocacy_Contact-List-for-ICF, and specific patient organisation listed as a site in Italy).
• Participant engagement/digital materials: Participant Portal storyboard, Participant Engagement Content, Registration postcards, Participant cards and other retention/engagement items (documents listed in submissions).
• Concierge/participant support and travel reimbursement (Greenphire and concierge documents and third-party patient travel/reimbursement duties indicated).

Primary sponsor

Full Name

Alnylam Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD Development LP

Responsibilities

Multiple operational and study management responsibilities (codes listed in sponsorDuties: 1,2,5,6,7,8,9,10,11,12,13, etc.)

Name

Syneos Health Inc.

Responsibilities

Operational support (sponsorDuties code: 8)

Name

Medidata Solutions Inc.

Responsibilities

CRF database management and data platform duties

Name

Clario Medical Imaging Inc.

Responsibilities

Central ECG imaging reading

Name

Pharmaceutical Product Development LLC (PPD)

Responsibilities

Laboratory logistics and multiple support functions

Third parties

• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"sponsorDuties codes: 3","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"EPL Archives GmbH","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Clario Medical Imaging Inc.","duties_or_roles":"Central Medical Reading of subjects' imaging (ECG imaging reading)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"Laboratory Logistics; code:4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"sponsorDuties codes: 8","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"CRF database management; other duties (code 7)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Illingworth Research Group Limited","duties_or_roles":"Home Nursing","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Multiple operational duties (codes: 1,10,11,12,13,2,5,6,7,8,9) as listed","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"PPD Global Ltd.","duties_or_roles":"Project management duties or monitoring/regulatory","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient travel and reimbursement","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"sponsorDuties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Centogene GmbH","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"The Brigham And Women’s Hospital Inc.","duties_or_roles":"Central Medical Reading of subjects' imaging (ECHO imaging reading)","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Bioage Labs Inc.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Charles River Laboratories Montreal ULC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}