Ensayos clínicos

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 hereditary ATTR amyloidosis with cardiomyopathy or wild-type ATTR amyloidosis with cardiomyopathy:
  • Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria:
    • TTR pathogenic mutation consistent with hATTR;
    • Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness >12 mm (based on central echocardiogram reading at screening);
    • 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] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, if monoclonal gammopathy of undetermined significance (MGUS) has been excluded;
    • 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:
    • Absence of pathogenic TTR mutation;
    • Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness >12mm (based on central echocardiogram reading at screening);
    • 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] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, if MGUS has been excluded;
    • If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry.
• Medical history of heart failure with at least 1 prior hospitalization for heart failure, or current clinical evidence (signs and symptoms of heart failure).
• Clinically stable with no cardiovascular related hospitalizations within 6 weeks of study start.
• Has never taken tafamidis before (tafamidis naïve) or currently on tafamidis for ≥ 6 months with evidence of disease progression while on tafamidis treatment.
• Able to complete ≥ 150 m on the 6-minute walk test.
• Screening N-terminal pro B-type natriuretic peptide (NT-proBNP), a blood marker of heart failure severity, > 300 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 m^2).[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:
  • Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper limit of normal (ULN);
  • Total bilirubin ˃ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if total bilirubin <2 × ULN
  • 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 m^2 (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 6-month wash-out prior to dosing (Day 1).
• Is currently taking doxycycline, 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 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.
• Requires treatment with calcium channel blockers (e.g., verapamil, diltiazem) or digitalis.
• Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease (e.g., prior myocardial infarction with documented history of cardiac enzymes and electrocardiogram [ECG] changes).
• Has non-amyloid disease affecting exercise testing (e.g., severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation).
• Recent or planned orthopedic procedure during the double-blind period (e.g., 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.
• Is not willing to comply with the contraceptive requirements during the study period.
• Female patient is pregnant or breast-feeding.
• 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.