Safety, Efficacy, and Pharmacokinetics of Tafamidis in Patients With Transthyretin-mediated Amyloidosis Post Orthotopic Heart Transplantation

• Status: Not yet recruiting
• Trial end date: 2024-09-30
• Target enrollment: 0
• Participant gender: All

Summary

Transthyretin cardiac amyloidosis (ATTR-CA) is a relentlessly progressive disease that can progress to end stage heart failure, at which point recently approved transthyretin production silencing or structure stabilizing therapies provide no clinical benefit. For well-selected individuals, heart transplantation is an excellent therapeutic option to improve survival. Historically, concomitant liver transplantation has been used to halt the progression of non-cardiac transthyretin amyloidosis (ATTR) manifestations, especially for individuals with TTR genotypes associated with significant neuropathy. However, despite this, patients continue to experience progressive non-cardiac manifestations, particularly gastrointestinal and neuropathic, which can have a substantial influence on post-heart transplantation morbidity. Concomitant liver transplantation is also associated with substantial morbidity and its future therapeutic role is questionable with recently established therapies for ATTR. Therefore, there is a clear unmet need to determine the utility and safety of ATTR targeted therapies for patients with recent heart transplantation for end-stage ATTR-CA. The central hypothesis of this proposal is that in patients who have received a heart transplantation for end-stage ATTR-CA, tafamidis therapy will be efficacious and well-tolerated. We aim to determine the safety and efficacy of tafamidis in stable patients who have undergone heart or combined heart/liver transplantation for ATTR (wild-type or variant) cardiac amyloidosis. The proposed study will be a single-arm intervention clinical trial with tafamidis. Because of the efficacy of tafamidis for both variant ATTR-CA and wild-type ATTR-CA, there is no clinical equipoise for an inactive-comparator placebo arm. The primary endpoint of this study will be serial change in plasma transthyretin (TTR) levels from baseline to 12 months at 3-month intervals. The secondary endpoints of this study will include serial changes in neuropathy assessments, modified body mass indices, incident transplant-specific adverse events, and pharmacokinetics of tafamidis. Observations from this study will establish the role of tafamidis use for the management of ATTR in patients after transplantation for end-stage ATTR-CA.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Texas Southwestern Medical Center

Criteria

Inclusion Criteria:

• Has received orthotopic heart transplantation for end-stage ATTRv or ATTRwt ≥12 months prior to screening. Concomitant hepatic and renal transplantation with adequate allograft function are included.

• Has a stable immunosuppressive regimen and ≤ 10 mg of prednisone (or equivalent) at time of enrollment.

• Has a Karnofsky performance status ≥ 70%

Exclusion Criteria:

• Has previously received inotersen within the past 180 days, patisiran within the past 90 days, tafamidis within the past 14 days, or diflunisal in the past 14 days.

• Participating in a clinical trial for ATTR targeted therapies.

• Has an estimated glomerular filtration rate (eGFR) ≤ 15 ml/min/1.73 m2

• Has known leptomeningeal or AL amyloidosis

• Has active post-transplant lymphoproliferative disease

• Excluding non-melanomatous skin cancers, has an active malignancy.

• Has active infection with hepatitis B, hepatitis C, human immunodeficiency virus, or cytomegalovirus (CMV). For CMV, donor/ recipient exposure status and prior treated CMV disease on stable doses of antiviral therapies are not excluded.

• Has cardiac allograft dysfunction defined by left ventricular ejection fraction (LVEF) <50% by echocardiogram within the past 3 months

• Has been treated for acute cellular or antibody mediated rejection in the past 3 months

• Has criteria to meet International Society for Heart and Lung Transplantation standardized nomenclature for severe coronary allograft vasculopathy ("ISHLT CAV3")