Clinical trial NCT01994889: Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy
Official 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Transthyretin (TTR) Amyloid Cardiomyopathy
Keywords: amyloidosis
amyloid
transthyretin
TTR
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2013-11-26
Enrollment: 441
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Phase 3, multicenter, global, three-arm, parallel design, placebo-controlled, double-blind, randomized study to determine efficacy, safety and tolerability of tafamidis on clinical outcomes (all-cause mortality and frequency of cardiovascular-related hospitalizations) in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.

Eligibility criteria: 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.

Primary outcomes:
measure: Hierarchical Combination of All-Cause Mortality and Frequency of Cardiovascular-Related Hospitalizations
timeFrame: Baseline up to Month 30
Secondary outcomes:
measure: All-Cause Mortality
timeFrame: Baseline up to Month 30
measure: Frequency of Cardiovascular-Related Hospitalizations
timeFrame: Baseline to Month 30
measure: Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30
timeFrame: Baseline, Month 30
measure: Change From Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30
timeFrame: Baseline, Month 30
measure: Number of Participants With Cardiovascular-Related Mortality
timeFrame: Baseline up to Month 30
measure: Percentage of Participants With Stabilized Transthyretin (TTR) at Month 1
timeFrame: Month 1
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The Kirklin Clinic
state: Alabama
city: Birmingham
country: United States
facility: UAB Hospital Department of Pharmacy IDS
state: Alabama
city: Birmingham
country: United States
facility: University Hospital, University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona - Mayo Clinic Speciality Building
state: Arizona
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic Arizona - Mayo Clinic Building
state: Arizona
city: La Jolla
country: United States
facility: UCSD Clinical and Translational Research Institute, Investigational Drug Service
state: California
city: La Jolla
country: United States
facility: Altman Clinical Translational Research institute
state: California
city: La Jolla
country: United States
facility: Altman Clinical Translational Research Institute
state: California
city: La Jolla
country: United States
facility: UCSD Sulpizio Cardiovascular Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center, Investigational Drug Pharmacy Services
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Care Foundation
state: California
city: San Francisco
country: United States
facility: UCSF Cardiovascular Care and Prevention Center
state: California
city: Stanford
country: United States
facility: Stanford University Hospital and Clinics
state: California
city: Deerfield Beach
country: United States
facility: UM Sylvester at Deerfield Beach
state: Florida
city: Miami
country: United States
facility: University of Miami Hospital & Clinics
state: Florida
city: Chicago
country: United States
facility: Northwestern Medical Group
state: Illinois
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Oak Lawn
country: United States
facility: Advocate Christ Medical Centre
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland, School of Medicine
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital IDS Pharmacy
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center - Cardiovascular Center, Outpatient Clinic
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center Investigational Pharmacy Services
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center General Clinical Research Unit
state: Massachusetts
city: Ann Arbor
country: United States
facility: Michigan Medicine,University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Pharmacy Research Supp
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: New York
country: United States
facility: New York University Hospitals
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai and Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Mount Sinai Doctors Faculty Practice
state: New York
city: New York
country: United States
facility: The Mount Sinai Hospital Department of Pharmacy
state: New York
city: New York
country: United States
facility: Columbia University Medical Center Research Pharmacy
state: New York
city: New York
country: United States
facility: Columbia University Medical Center/Clinical Cardiovascular Research Laboratory for the Elderly
state: New York
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: OHSU Center for Health and Healing
state: Oregon
city: Portland
country: United States
facility: OHSU Research Pharmacy Services
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University (OHSU)
state: Oregon
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah,Health Sciences Center
state: Utah
city: Richmond
country: United States
facility: VCU Medical Center - Ambulatory Care Clinic
state: Virginia
city: Richmond
country: United States
facility: VCU Medical Center - Main Hospital
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
city: Rio de Janeiro
country: Brazil
facility: Unidade de Pesquisa Clinica / Hospital Universitario Clementino Fraga Filho / UFRJ
state: RJ
city: Calgary
country: Canada
facility: University of Calgary/Foothills Medical Centre
state: Alberta
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Brno
country: Czechia
facility: Fakultni nemocnice u sv. Anny, Nemocnicni lekarna
city: Brno
country: Czechia
facility: Nemocnice u sv. Anny v Brne
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze, Nemocnicni lekarna
city: Praha 4
country: Czechia
facility: IKEM, Ustavni lekarna
city: Praha 4
country: Czechia
facility: IKEM
city: Clamart
country: France
facility: Hopital Antoine Beclere
city: Creteil
country: France
facility: CHU Henri Mondor
city: Heidelberg
country: Germany
facility: Medical University of Heidelberg
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster
city: Bologna
country: Italy
facility: U.O. Cardiologia- Prof. Rapezzi
city: Brescia
country: Italy
facility: Unita Operativa di Cardiologia
city: Firenze
country: Italy
facility: S.O.D. Cardiologia Generale 1 - D.A.I. del Cuore e dei Vasi
city: Pavia
country: Italy
facility: Centro per lo Studio e la Cura Delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico S. Matteo
city: Kurume-shi
country: Japan
facility: Kurume University Hospital
state: Fukuoka
city: Kumamoto-city
country: Japan
facility: Kumamoto University Hospital
state: Kumamoto
city: Nagano
country: Japan
facility: Shinshu University Hospital
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta De Hierro - Majadahonda
state: Madrid
city: El Palmar
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arrixaca
state: Murcia
city: A Coruna
country: Spain
facility: Hospital Universitario A Coruna
city: Skelleftea
country: Sweden
facility: Medicin-Geriatrik kliniken-Skelleftea lasarett
city: Uppsala
country: Sweden
facility: Sjukhusvägen, Akademiska sjukhuset
city: London
country: United Kingdom
facility: St Bartholomew's Hospital-Barts Health NHS Trust
city: London
country: United Kingdom
facility: St. George's Hospital (St George's Healthcare NHS Trust)
city: London
country: United Kingdom
facility: St. George's University of London
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Tess DA, Maurer TS, Li Z, Bulawa C, Fleming J, Moody AT. Relationship of binding-site occupancy, transthyretin stabilisation and disease modification in patients with tafamidis-treated transthyretin amyloid cardiomyopathy. Amyloid. 2023 Jun;30(2):208-219. doi: 10.1080/13506129.2022.2145876. Epub 2022 Nov 18.
citation: Rozenbaum MH, Tran D, Bhambri R, Nativi-Nicolau J. Annual Cardiovascular-Related Hospitalization Days Avoided with Tafamidis in Patients with Transthyretin Amyloid Cardiomyopathy. Am J Cardiovasc Drugs. 2022 Jul;22(4):445-450. doi: 10.1007/s40256-022-00526-9. Epub 2022 Mar 30.
citation: Nativi-Nicolau J, Judge DP, Hoffman JE, Gundapaneni B, Keohane D, Sultan MB, Grogan M. How did transthyretin amyloid cardiomyopathy progress in patients who took placebo in the study ATTR-ACT? A plain language summary. Future Cardiol. 2022 Mar 17. doi: 10.2217/fca-2021-0150. Online ahead of print.
citation: Elliott P, Drachman BM, Gottlieb SS, Hoffman JE, Hummel SL, Lenihan DJ, Ebede B, Gundapaneni B, Li B, Sultan MB, Shah SJ. Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy. Circ Heart Fail. 2022 Jan;15(1):e008193. doi: 10.1161/CIRCHEARTFAILURE.120.008193. Epub 2021 Dec 20.
citation: Hanna M, Damy T, Grogan M, Stewart M, Gundapaneni B, Sultan MB, Maurer MS. Tafamidis and quality of life in people with transthyretin amyloid cardiomyopathy in the study ATTR-ACT: A plain language summary. Future Cardiol. 2022 Mar;18(3):165-172. doi: 10.2217/fca-2021-0095. Epub 2021 Nov 15.
citation: Rozenbaum MH, Garcia A, Grima D, Tran D, Bhambri R, Stewart M, Li B, Heeg B, Postma M, Masri A. Health impact of tafamidis in transthyretin amyloid cardiomyopathy patients: an analysis from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and the open-label long-term extension studies. Eur Heart J Qual Care Clin Outcomes. 2022 Aug 17;8(5):529-538. doi: 10.1093/ehjqcco/qcab031.
citation: Vong C, Boucher M, Riley S, Harnisch LO. Modeling of Survival and Frequency of Cardiovascular-Related Hospitalization in Patients with Transthyretin Amyloid Cardiomyopathy Treated with Tafamidis. Am J Cardiovasc Drugs. 2021 Sep;21(5):535-543. doi: 10.1007/s40256-021-00464-y. Epub 2021 Mar 26.
citation: Miller AB, Januzzi JL, O'Neill BJ, Gundapaneni B, Patterson TA, Sultan MB, Lopez-Sendon J. Causes of Cardiovascular Hospitalization and Death in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]). Am J Cardiol. 2021 Jun 1;148:146-150. doi: 10.1016/j.amjcard.2021.02.035. Epub 2021 Mar 3.
citation: Rapezzi C, Elliott P, Damy T, Nativi-Nicolau J, Berk JL, Velazquez EJ, Boman K, Gundapaneni B, Patterson TA, Schwartz JH, Sultan MB, Maurer MS. Efficacy of Tafamidis in Patients With Hereditary and Wild-Type Transthyretin Amyloid Cardiomyopathy: Further Analyses From ATTR-ACT. JACC Heart Fail. 2021 Feb;9(2):115-123. doi: 10.1016/j.jchf.2020.09.011. Epub 2020 Dec 9.
citation: Hanna M, Damy T, Grogan M, Stewart M, Gundapaneni B, Patterson TA, Schwartz JH, Sultan MB, Maurer MS. Impact of Tafamidis on Health-Related Quality of Life in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Am J Cardiol. 2021 Feb 15;141:98-105. doi: 10.1016/j.amjcard.2020.10.066. Epub 2020 Nov 19.
citation: Damy T, Garcia-Pavia P, Hanna M, Judge DP, Merlini G, Gundapaneni B, Patterson TA, Riley S, Schwartz JH, Sultan MB, Witteles R. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Eur J Heart Fail. 2021 Feb;23(2):277-285. doi: 10.1002/ejhf.2027. Epub 2020 Nov 12.
citation: Li B, Alvir J, Stewart M. Extrapolation of Survival Benefits in Patients with Transthyretin Amyloid Cardiomyopathy Receiving Tafamidis: Analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial. Cardiol Ther. 2020 Dec;9(2):535-540. doi: 10.1007/s40119-020-00179-2. Epub 2020 Jun 10.
citation: Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27.
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