Study Design

Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT)—a clinical study in patients with ATTR-CM1
Approval of VYNDAMAX was based on ATTR-ACT, a phase 3, multicenter, international, randomized, double-blind, placebo-controlled study, which evaluated pooled VYNDAQEL® (tafamidis meglumine) doses of 20 mg and 80 mg in 441 patients with wild-type or hereditary ATTR-CM—a single VYNDAMAX 61-mg capsule is bioequivalent* to VYNDAQEL 80 mg (four 20-mg capsules) and is not interchangeable on a per-mg basis.
Two-thirds of patients in the pooled VYNDAQEL group were on the 80-mg dose.
*As determined by the predefined 90% confidence interval criteria of 80%-125% bioequivalence limits for tafamidis area under curve (AUC) and peak plasma concentration (Cmax) after repeated oral daily dosing for 7 days.2
The primary analysis was conducted using the Finkelstein-Schoenfeld method.
Inclusion criteria1
  • Patients between 18 and 90 years of age
  • Confirmation of ATTR-CM, wild-type or hereditary
  • Echocardiography with an end-diastolic interventricular septal wall thickness >12 mm
  • History of heart failure with at least 1 prior hospitalization for heart failure, or clinical evidence of heart failure (without hospitalization)§
  • NT-proBNP level ≥600 pg/mL
  • 6MWT >100 m
§Manifested in signs or symptoms of volume overload or elevated intracardiac pressures requiring treatment with a diuretic for improvement; an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level greater than or equal to 600 pg per milliliter; and a 6-minute walk-test distance exceeding 100 m.
NT-proBNP=N-terminal pro-B-type natriuretic peptide.
Exclusion criteria1
  • Heart failure unrelated to ATTR-CM
  • NYHA class IV heart failure
  • Light-chain amyloidosis
  • History of liver or heart transplantation
  • Implanted cardiac mechanical assist device3||
  • Previous VYNDAQEL treatment
  • eGFR <25 mL/min/1.73 m2
  • Liver transaminase levels >2x the upper limit of normal
  • mBMI <600
  • Concurrent treatment with NSAIDs, tauroursodeoxycholate, doxycycline, calcium channel blockers, or digitalis
||Cardiac mechanical assist device (CMAD) term utilized to cover LVAD. Patients with a permanent pacemaker or implanted cardiac defibrillator were permitted in this study.4
Select NSAIDs were permitted, eg, aspirin, ibuprofen, naproxen.
eGFR=estimated glomerular filtration rate; LVAD=left ventricular assist device; mBMI=modified body mass index.
The Finkelstein-Schoenfeld method
#Frequency of CV-related hospitalizations is used to compare patients who cannot be differentiated based on all-cause mortality.

REFERENCES
1. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016.
2. Tankisheva E. A phase 1, open-label, randomized, crossover, multiple dose, pivotal bioequivalence study to compare PF-06291826 4 × 20 mg tafamidis meglumine and 61 mg: tafamidis free acid soft gelatin capsules administered under fasted conditions to healthy volunteers. Full Clinical Study Report [protocol B3461056]. July 23, 2018.
3. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy [protocol]. N Engl J Med. 2018;379(11):1007-1016. https://nejm.org/doi/suppl/10.1056/NEJMoa1805689/suppl_file/nejmoa1805689_protocol.pdf. Accessed July 2, 2019.
4. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy [supplemental appendix]. N Engl J Med. 2018;379(11):1007-1016. https://nejm.org/doi/suppl/10.1056/NEJMoa1805689/suppl_file/nejmoa1805689_appendix.pdf. Accessed July 1, 2019.

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