Please select the eligibility criteria that correspond to the clinical trial below.
Title: A MULTICENTER, 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)
Brief Summary: This Phase 3 study will investigate the efficacy, safety and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.


Options:
A: Inclusion Criteria:

* Patient has amyloid documented by biopsy (in accordance with institutional site standard of care).
* Patient has documentation of one of the following targeted TTR mutations: Ser77Tyr, Thr60Ala, Tyr114Cys, Leu58His, Glu89Gln, Ser77Phe, Thr49Ala, Ile107Val, Val30Ala, Gly47Ala, Gly47Glu, Leu55Arg, Lys70Asn, Ile84Thr, Ile107Met. Patients with mutations other than those listed may be enrolled only after approval by the Sponsor.
* Patient has peripheral and/or autonomic neuropathy and/or cardiomyopathy with a Karnofsky Performance Status ≥ 50.
* Patient is aged ≥18 to 75 years, inclusive.
* If female, patient is post-menopausal, surgically sterilized, or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide) throughout the study and for 3 months from the end of the study. (A condom alone is not considered an acceptable method of birth control.) If male with a female partner of childbearing potential, willing to use two acceptable methods of birth control for the duration of the study. For both females and males, acceptable birth control must be used for at least 3 months after the last dose of study medication.
* Patient is, in the opinion of the investigator, willing and able to comply with the study medication regimen and all other study requirements.

Exclusion Criteria:

* Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), defined as greater than 3-4 times/month (ibuprofen and nimesulide will be permitted).
* Patient has primary or secondary amyloidosis.
* Patient has TTR-associated amyloidosis with V30M mutation.
* If female, patient is pregnant or breast feeding.
* Patient has received prior liver transplantation.
* Patient is expected to undergo liver transplantation within 12 months after enrollment.
* Patient with positive results for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV).
* Patient has renal insufficiency (creatinine clearance \< 30 ml/min).
* Patient has liver function test abnormalities: alanine transaminases (ALT) and/or aspartate transaminases (AST) \> 2 times upper limit of normal (ULN) that in the medical judgment of the investigator are due to reduced liver function or active liver disease.
* Patient has a New York Heart Association (NYHA) Functional Classification ≥ III.
* Patient has other causes of sensorimotor neuropathy (B12 deficiency, Diabetes Mellitus, HIV treated with retroviral medications, thyroid disorders, alcohol abuse, and chronic inflammatory diseases).
* Patient has prior non-amyloid cardiac disease such as: myocardial infarction due to obstructive coronary artery disease, active non-amyloid cardiomyopathy (e.g., symptomatic left ventricular dysfunction from any cause other than amyloid, patients with a primary diagnosis of symptomatic valvular heart disease)
* Patient has a co-morbidity anticipated to limit survival to less than 12 months.
* Patient has received an investigational drug/device and/or participated in another clinical investigational study within 60 days before Baseline (Day 0).
B: Inclusion Criteria:

* Stage 1 and Stage 2 FAP participants with the following:

  1. NIS score within protocol criteria
  2. Documented transthyretin variant by genotyping
  3. Documented amyloid deposit by biopsy
* Females of child-bearing potential must use appropriate contraception and be non-pregnant and non-lactating. Males engaging in relations of child-bearing potential are to use appropriate contraception

Exclusion Criteria:

* Low Retinol level at screen
* Karnofsky performance status ≤50
* Poor Renal function
* Known type 1 or type 2 diabetes mellitus
* Other causes of sensorimotor or autonomic neuropathy (for example, autoimmune disease)
* If previously treated with Vyndaqel®, will need to have discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, will need to have discontinued treatment for 3 days prior to Study Day 1
* Previous treatment with any oligonucleotide or siRNA within 12 months of screening
* Prior liver transplant or anticipated liver transplant within 1 year of screening
* New York Heart Association (NYHA) functional classification of ≥3
* Acute Coronary Syndrome or major surgery within 3 months of screening
* Known Primary or Leptomeningeal Amyloidosis
* Anticipated survival less than 2 years
* Any other conditions in the opinion of the investigator which interfere with the participant participating in or completing the study
C: Inclusion Criteria:

* 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,
* Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness \> 12 mm,
* Presence of amyloid deposits in biopsy tissue and presence of a variant TTR genotype and/or TTR precursor protein identification by immunohistochemistry, scintigraphy or mass spectrometry

Exclusion Criteria:

* A New York Heart Association (NYHA) classification of IV.
* Presence of primary (light chain) amyloidosis.
* Prior liver or heart transplantation or implanted cardiac mechanical assist device.
D: Inclusion Criteria:

* Male or female of 18 to 85 years of age (inclusive);
* Have a diagnosis of FAP
* Neuropathy Impairment Score requirement of 5-130
* Meet Karnofsky performance status requirements
* Have adequate complete blood counts and liver function tests
* Have adequate cardiac function
* Have negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV)

Exclusion Criteria:

* Had a prior liver transplant or is planned to undergo liver transplant during the study period;
* Has untreated hypo- or hyperthyroidism;
* Has known human immunodeficiency virus (HIV) infection;
* Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated;
* Recently received an investigational agent or device
* Is currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid

Answer: C