E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) |
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E.1.1.1 | Medical condition in easily understood language |
Transthyretin Amyloidosis with Cardiomyopathy (ATTR Amyloidosis with Cardiomyopathy) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007509 |
E.1.2 | Term | Cardiac amyloidosis |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 (or age of legal consent, 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: 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 end-diastolic interventricular septal wall thickness >12 mm (based on central echocardiogram reading at screening). c. Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, median nerve connective sheath) confirmed by Congo Red (or equivalent) staining 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 monoclonal gammopathy of undetermined significance (MGUS) has been excluded. d. If MGUS, confirm TTR protein in tissue with immunohistochemistry (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 end-diastolic 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
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; 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.)
5. Patient is clinically stable, with no CV-related hospitalizations within 6 weeks prior to randomization, as assessed by the Investigator. 6. Able to complete ≥150 m on the 6-MWT at screening. 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. 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. |
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E.4 | Principal exclusion criteria |
1. Has known primary amyloidosis (AL) or leptomeningeal amyloidosis. 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. NYHA Class IV at the Screening visit. 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. 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). 6. Has eGFR <30 mL/min/1.73 m2 (using the modification of diet in renal disease [MDRD] formula). 7. Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection. 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. 9. Is currently taking diflunisal; if previously on this agent, must have at least a 30-day wash-out prior to dosing (Day 1). 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). 11. Received prior TTR-lowering treatment (including patisiran) or participated in a gene therapy trial for hATTR amyloidosis. 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). 13. Requires chronic treatment with non-dihydropyridine 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 electrocardiogram [ECG] changes). 15. Has non-amyloid disease affecting exercise testing (eg, severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation). 16. Recent or planned orthopedic procedure during the double-blind period (eg, lower extremity or back surgery) that could impact 6-MWT. 17. Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of screening required to achieve optimal treatment of CHF). 18. Had acute coronary syndrome or unstable angina within the past 3 months. 19. Has history of sustained ventricular tachycardia or aborted ventricular fibrillation. 20. Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed. 21. Has persistent elevation of systolic (>180 mmHg) and diastolic (>100 mmHg) blood pressure that is considered uncontrolled by physician. 22. Has untreated hypo- or hyperthyroidism. 23. Prior or planned heart, liver, or other organ transplant. 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. 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. 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. 27. Female patient is pregnant or breast-feeding. 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]); 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline at Month 12 in 6-MWT |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Double blind period: Month 12; this assessment will also be performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) Open label extension period: Year 2 weeks 79-80, weeks 91-92, weeks 106-107; Year 3 weeks 133-134, weeks 145-146, weeks 157-158; Year 4 weeks 184-185, weeks 208-209. |
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E.5.2 | Secondary end point(s) |
-Change from baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score
-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
-Composite endpoint of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits over the 12-month double-blind period |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Double blind period: Month 12 (Weeks 52-53); this assessment will alsobe performed at Month 6 (Weeks 25-26) and Month 9 (Weeks 37-38) Open label extension period: Year 2 weeks 79-80, weeks 91-92, weeks 106-107; Year 3 weeks 133-134, weeks 145-146, weeks 157-158; Year 4 weeks 184-185, weeks 208-209. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Chile |
New Zealand |
Hong Kong |
Taiwan |
Australia |
Brazil |
Japan |
Korea, Republic of |
Mexico |
United Kingdom |
United States |
Belgium |
Netherlands |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |