Efficacy and Safety Evaluation of Patisiran in Transthyretin Amyloidosis with Cardiomyopathy: A Phase 3 Randomized, Double-blind, Placebo-controlled Study
- Trial ID
- 2023-508364-29-00
- Protocol
- ALN-TTR02-011
- Sponsor
- Alnylam Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind, placebo-controlled multicenter study is to evaluate the **efficacy** of patisiran compared with placebo treatment on functional capacity, specifically measured by the 6-minute walk test (6-MWT), in patients with Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy). This objective is clinically relevant as it aims to assess the potential of patisiran to improve physical endurance and mobility, which are critical factors in the quality of life and daily functioning of patients with this condition.
Secondary objectives include evaluating 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. These objectives are important for understanding the broader impact of patisiran on patient outcomes, including survival rates and healthcare utilization, which are essential for comprehensive patient management and treatment planning.
Participants
The clinical trial involves a total of **199 participants** diagnosed with **Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy)**. The study population includes both male and female subjects, aged between 18 and 85 years. Participants were selected based on specific criteria, including a documented diagnosis of ATTR amyloidosis with cardiomyopathy, either hereditary or wild-type, and the ability to complete a 6-minute walk test of at least 150 meters at screening. The trial population is characterized by a history of heart failure, with some participants having prior hospitalizations for heart failure or clinical evidence of heart failure requiring diuretic treatment. Lifestyle considerations such as diet and physical activity are not specified, but participants must be clinically stable with no cardiovascular-related hospitalizations within six weeks prior to randomization. The trial includes individuals who are either tafamidis naïve or currently on tafamidis with demonstrated disease progression. The study does not exclude vulnerable populations, and participants must be able to understand and comply with study requirements, providing written informed consent.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled multicenter study designed to evaluate the efficacy and safety of **patisiran** in patients with **Transthyretin Amyloidosis with Cardiomyopathy**. The primary objective is to assess the change from baseline at Month 12 in the 6-minute walk test (6-MWT), while secondary endpoints include changes in the Kansas City Cardiomyopathy Questionnaire Overall Summary score and composite endpoints involving all-cause mortality and cardiovascular events over a 12-month period. The trial is expected to conclude by June 2025, with recruitment having commenced in January 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, medical history, and specific diagnostic markers for **ATTR amyloidosis with cardiomyopathy**. Following randomization, participants will receive either patisiran or a placebo via intravenous infusion. The study includes regular follow-up visits to monitor safety, efficacy, and adherence to the protocol. The end-of-study visit will occur at the conclusion of the 12-month double-blind period, where final assessments will be conducted.
Participant involvement is expected to last approximately 12 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is structured to ensure rigorous data collection and analysis, maintaining the integrity of the double-blind design throughout the study duration.
Treatment
The clinical trial involves the administration of **Onpattro**, a **2 mg/mL concentrate for solution for infusion**, containing the active substance **patisiran**. Patisiran is a synthetic double-stranded siRNA oligonucleotide directed against transthyretin mRNA, classified under the ATC code N07XX12. The pharmaceutical form is a solution for infusion, and the route of administration is **intravenous use**. The dosing regimen involves a maximum daily dose of 0.3 mg/kg, with a total maximum dose of 30 mg. The treatment period extends up to 48 weeks. Patisiran is not a pediatric formulation and is designated as an orphan drug. The product is manufactured by Alnylam Netherlands B.V.
The study also utilizes **Sodium Chloride Intravenous Infusion BP 0.9% w/v** as a placebo comparator. This solution is administered intravenously, serving as a control to evaluate the efficacy of patisiran in patients with transthyretin amyloidosis with cardiomyopathy. The sodium chloride solution does not contain any active pharmaceutical ingredients specific to the treatment of the condition and is used to maintain the double-blind nature of the trial.
Efficacy
The efficacy of patisiran in patients with **Transthyretin Amyloidosis with Cardiomyopathy** will be assessed through a series of predefined endpoints. The primary endpoint is the change from baseline at Month 12 in the 6-minute walk test (6-MWT), which evaluates the functional capacity of patients. Secondary endpoints include the change from baseline at Month 12 in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score, a composite endpoint of all-cause mortality, frequency of cardiovascular events (CV hospitalizations and urgent heart failure visits), and change from baseline in 6-MWT over the 12-month double-blind period. Another secondary endpoint is a composite of all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits over the same period.
These efficacy parameters will be measured and collected at specific timepoints, with the primary assessment occurring at Month 12. The 6-MWT and KCCQ-OS are validated tools used to quantify changes in physical performance and quality of life, respectively. Data analysis will focus on comparing the changes from baseline in these measures between the patisiran and placebo groups, providing insights into the treatment's impact on patient outcomes. The trial is designed to ensure rigorous evaluation of patisiran's efficacy in improving the functional capacity and overall health status of patients with this condition.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.
- 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.
- b. Evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness >12 mm (based on central echocardiogram reading at screening).
- 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.
- d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry
- Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria: a. Absence of pathogenic TTR mutation.
- b. Evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness >12mm (based on central echocardiogram reading at screening).
- 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.
- d. If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry
- 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.
- 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.
- 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.)
- Patient is clinically stable, with no CV-related hospitalizations within 6weeks prior to randomization, as assessed by the Investigator.
- Able to complete ≥150 m on the 6-MWT at screening.
- 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.
- 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
- Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.
- 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]
- NYHA Class IV at the Screening visit.
- Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to walk, or is wheelchair bound) at the Screening visit.
- 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).
- b. Total bilirubin >2 × ULN.
- c. International normalized ratio (INR)>1.5 (unless patient is on anticoagulant therapy, in which case excluded if INR>3.5).
- Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] formula).
- Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection.
- 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.
- Is currently taking diflunisal; if previously on this agent, must have at least a 30-day wash-out prior to dosing (Day 1).
- 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).
- Received prior TTR-lowering treatment (including patisiran) or participated in a gene therapy trial for hATTR amyloidosis.
- 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).
- Requires chronic treatment with non-dihydropyridine calcium channel blockers (eg, verapamil, diltiazem).
- 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).
- Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation).
- Recent or planned orthopedic procedure during the double-blind period (eg, lower extremity or back surgery) that could impact 6-MWT.
- Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of screening required to achieve optimal treatment of CHF).
- Had acute coronary syndrome or unstable angina within the past 3 months.
- Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.
- Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed.
- Has persistent elevation of systolic (>180 mmHg) and diastolic (>100 mmHg) blood pressure that is considered uncontrolled by physician.
- Has untreated hypo- or hyperthyroidism.
- Prior or planned heart, liver, or other organ transplant.
- 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.
- 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.
- 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.
- Female patient is pregnant or breast-feeding. Female not willing to comply with contraceptive requirements.
- 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])
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 16 Jan 2020 | 10 |
 Czechia | Not Recruiting | 16 Jan 2020 | 20 |
 Denmark | Not Recruiting | 16 Jan 2020 | 17 |
 France | Not Recruiting | 16 Jan 2020 | 6 |
 Italy | Not Recruiting | 16 Jan 2020 | 9 |
 The Netherlands | Not Recruiting | 16 Jan 2020 | — |
 Portugal | Not Recruiting | 16 Jan 2020 | 1 |
 Sweden | Not Recruiting | 16 Jan 2020 | 6 |
| Netherlands | — | — | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Onpattro 2 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 0.3 | 48 | PRD6568924 |
Sodium Chloride Intravenous Infusion BP 0.9% w/v | Placebo | N/A | — | — | — | N/A |