A multicentre, international, phase 3, double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of daily oral dosing of tafamidis meglumine (PF-06291826) 20 mg or 80 mg in comparison to placebo in subjects diagnosed with transthyretin cardiomyopathy (TTR-CM).

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:;1.Evidence of a personally signed and dated Informed Consent Document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study and evidence of a personally signed and dated Release of Medical Information Form regarding access to medical records as well as vital status/transplant status follow-up by the site with the subject or the subject*s caregivers 30 months after study randomization. In some cases, sites may combine these two forms into one form, as is their standard practice.;2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures,;3. Age greater than or equal to 18 and less than or equal to 90 years old at the time of randomization,;4. Medical history of Heart Failure (HF) with at least 1 prior hospitalization for HF or clinical evidence of HF (without hospitalization) manifested by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral edema) that required/requires treatment with a diuretic for improvement,;5. Subject has documented TTR amyloid cardiomyopathy in accordance with institutional site standard of care, which is defined as:;a. Variant TTR amyloid cardiomyopathy defined by all of the following:;i. presence of a variant TTR genotype associated with cardiomyopathy and presenting with a cardiomyopathy phenotype (e.g., a history of congestive heart failure),;1. TTR genotyping is required at Screening unless documentation (ie original laboratory result, or copy) of a prior determination of a TTR genotype is produced.;2. Subjects with a confirmed diagnose of mutant (variant genotype) TTR-CM with concurrent monoclonal gammopathy of undetermined significance (MGUS) based on serum or urine light chain determinations, should be tested in the same manner as in the case of equivocal immunohistochemistry for subjects with wild type TTE-CM below.;ii. evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness > 12 mm,;iii. presence of amyloid deposits in biopsy tissue, such as fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac (amyloid demonstrated per appropriate stain such as Congo red or alcian blue stain).;b. Wild-type TTR amyloid cardiomyopathy defined by all of the following:
i. absence of a variant TTR genotype,
ii. evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness > 12 mm,
iii. presence of amyloid deposits in biopsy tissue, such as fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac (amyloid demonstrated per appropriate stain such as Congo red or alcin blue stain),
iv. TTR precursor protein identification by mass spectrometry. ;1. In the case where immunohistochemistry (IHC) outcome is equivocal such as staining suggestive of lambda or kappa light chains, additional confirmatory testing is required to confirm the diagnosis of TTR cardiomyopathy. This confirmatory test may be performed using one of the following: (a) mass spectrometry (b) immunohistochemistry with electron microscopy or immunoelectron microscopy or immune-gold microscopy (c) scintigraphy with tracer e.g. 99mTC-DPD [99mTC-3,3-diphosphono-1,2-propano-dicarboxylic acid], 99mTC- PYP [Pyrophosphate] and also 99mTC-HMDP [hydroxymethylene diphosphonate];6. Biopsy used to determine the presence of amyloid and demonstration of TTR precursor protein must be done during Screening or documented as having been performed previously.;7. Subject must be able to read in native language and complete self-administered questionnaires independently,;8. Subject*s symptoms of HF are optimally managed and clinically stable with no cardiovascular-related hospitalizations within 2 weeks prior to Baseline, as assessed by the Principal Investigator,;9. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active,;10. Subject must have a Screening visit NT-proBNP concentration * 600 pg/mL, (the conversion factor from conventional pg/mL to SI units is to divide by 8.45).;11. Subjects must be able to complete > 100 m on the 6-Minute Walk Test at screening.

Subjects presenting with any of the following will not be included in the study:;1. Subjects with echocardiogram assessment at Screening that is not deemed interpretable by the central echocardiogram reader for the measurement of wall thickness,;2. Subjects using non-steroidal anti-inflammatory drugs (NSAIDs) that are not allowable in the protocol within 30 days prior to the Baseline visit. ;3. Subjects with an mBMI below 600,;4. Subjects with a history of drug or alcohol abuse within the past 5 years that in the opinion of the investigator would interfere with compliance with study procedures or follow-up visits,;5. Subjects taking or have previously taken tafamidis,;6. Subjects requiring treatment with calcium channel blockers (e.g. verapamil diltiazem) or digitalis,;7. Subjects with primary (light chain) amyloidosis,;8. Subjects who have prior liver or heart transplantation,or implanted
cardiac mechanical assist device.;9. Subject has known or suspected hepatitis B, C, Human
Immunodeficiency Virus (HIV) infection positive serology for hepatitis B (HBsAg), hepatitis C (anti-HCV), or HIV,;10. Subjects with renal failure requiring dialysis and/or have an estimated glomerular filtration rate (eGFR) of < 25mL/min/1.73m2;11. Subjects with urinary retention requiring self-catheterization,;12. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.;13. Subjects who have symptoms indicative of New York Heart Association Classification IV at the Screening or Baseline visit,;14. Subjects with liver function test abnormalities (alanine transaminase and/or aspartate transaminase) greater than 2 times the upper limit of normal that are considered to be due to reduced liver function or active liver disease,;15. Subjects with participation in studies involving investigational drug(s) (Phases 1- 4) within 30 days before the current study begins and/or during study participation. For diflunisal, tauroursodeoxycholate and doxycycline this time period will be within 30 days before the Baseline visit and/or any time during study participation,;16. Subjects with other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study,;17. Subjects who are pregnant females; breastfeeding females; male subjects with partners currently pregnant, males and females of childbearing potential who are unwilling or unable to use two (2) highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days, after last dose of investigational product;;18. Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker is indicated but will not be placed,;19. Subjects with heart failure that in the opinion of the investigator is on the basis of ischemic heart disease (e.g. prior myocardial infarction with documented history of cardiac enzymes and ECG changes), or uncorrected valvular disease and not primarily due to transthyretin amyloid cardiomyopathy.