Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant

Official title

A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of Acoramidis for Transthyretin Amyloidosis Prevention in the Young (ACT-EARLY Trial)

Overview

Transthyretin amyloidosis (ATTR) is a disease where the normally occurring transthyretin (TTR) protein falls apart and forms amyloid, a sticky plaque-like substance that accumulates in different organs in the body and can cause damage to the organ. There are two ways that the TTR protein can fall apart. One way occurs as a person ages, where the normal TTR protein can fall apart and form amyloid that may no longer be sufficiently cleared by the body. This type of ATTR is known as wild-type ATTR (ATTRwt). The other way occurs when a person inherits a defective TTR gene that causes the TTR protein to spontaneously fall apart. This form of the disease is known as variant ATTR (ATTRv) and can be detected in adults by a genetic test of their TTR gene before they age. Amyloid build-up in the heart causes the heart wall to become thick and stiff and can result in heart failure and even death. Accumulation of TTR amyloid in the heart is known as transthyretin amyloid cardiomyopathy or ATTR-CM. Amyloid can also deposit in the nerve tissues leading to nerve problems. Accumulation of TTR in the nerves is known as transthyretin amyloid polyneuropathy or ATTR-PN. Acoramidis is an experimental drug designed to bind tightly to TTR in the blood and stabilize its structure, so it does not form the harmful amyloid plaques that can cause damage to organs. This study is intended to determine if treatment with acoramidis in participants with ATTRv who have not yet developed any symptoms of disease can prevent or delay the development of ATTR-CM or ATTR-PN disease. If adults with an inherited defective TTR gene are treated early before any of the symptoms of disease have developed, it may be possible to delay the onset or prevent the disease entirely.

Detailed description

The AG10-501 ACT-EARLY study is a randomized, multicenter, double-blind, placebo-controlled study of acoramidis for prevention of ATTR (with specific reference to either its cardiomyopathic or polyneuropathic manifestations). Participants will be stratified at randomization.

The study population will be asymptomatic carriers of a known pathogenic TTR gene variant. A participant must be 18 to 75 inclusive years of age, and the age of the participant must be within 10 years younger than or older than the predicted age of disease onset (PADO) based either on family history (pedigree analysis) or, if family history is insufficient, based on a TTR Variant Actuarial table from published literature. For example, if PADO for a given individual is found to be 50 years, the age of the participant must be between 40 and 75 years inclusive.

Interventions

• Drug Acoramidis
  TTR stabilizer administered orally twice daily (BID)
• Drug Placebo oral tablet
  Non-active control administered orally twice daily (BID)

Primary outcome measures

• Time to development of ATTR (ATTR-CM or ATTR-PN, whichever occurs first; centrally adjudicated) [Time frame: Since randomization up to approximately 7 years or until the study is declared over]

Secondary outcome measures (2)

• Time to development of ATTR-CM (centrally adjudicated) [Time frame: Since randomization up to approximately 7 years or until the study is declared over]
• Time to development of ATTR-PN (centrally adjudicated) [Time frame: Since randomization up to approximately 7 years or until the study is declared over]

Eligibility criteria

Inclusion criteria

• Male or female ≥ 18 to ≤ 75 years of age inclusive.
• Participants must have an established genotype (hetero- or homozygosity) through a medically-indicated genetic test of a TTR gene variant that is known to be pathogenic or likely pathogenic (eg, V30M/p.V50M, V122I/p.V142I, T60A/p.T80A, or all other pathogenic TTR variants).
• Participant's age is within 10 years younger than or older than PADO.

Exclusion criteria

• Evidence of ATTR-CM or ATTR-PN.
• Current or past (within last 1 to 12 months, depending on specific agent) treatment with other TTR modifying therapies.
• Contraindication to or inability to undergo cardiac magnetic resonance testing.
• Major organ dysfunction, including: kidney disease, liver disease, heart disease (including cardiomyopathy), neuropathy
• Other diseases or conditions such has cancer within 5 years, untreated hyperthyroidism or hypothyroidism, type 1 diabetes, active hepatitis B or C, HIV.
• Major surgery within the past 3 months or planned during the next 12 months.
• Known hypersensitivity to acoramidis.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

United States · 40 centers

• University of California, San Diego (UCSD) - Medical Center — La Jolla
• University of California, Los Angeles (UCLA) - David Geffen School of Medicine — Los Angeles
• University of California, San Francisco (UCSF) — San Francisco
• Stanford University — Stanford
• University of Colorado Anschutz — Aurora
• Yale University School of Medicine - Section of Cardiology — New Haven
• MedStar Washington Hospital Center - MedStar Heart and Vascular Institute — Washington D.C.
• Mayo Clinic - Jacksonville — Jacksonville
• … and 32 more centers

Italy · 7 centers

• Azienda Ospedaliero-Universitaria di Bologna IRCCS Policlinico di S.Orsola — Bologna
• Azienda Ospedaliero-Universitaria Careggi — Florence
• Fondazione IRCCS Policlinico San Matteo — Pavia
• Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanità Pubblica - Ospeda — Pisa
• Azienda Ospedaliero Universitaria Policlinico Umberto I — Roma
• Fondazione Policlinico Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuo — Rome
• Azienda Ospedaliero-Universitaria Sant'Andrea — Rome

Spain · 6 centers

Center list to be confirmed — check the primary protocol.

France · 5 centers

• CHU Bordeaux - Hopital Pellegrin — Bordeaux
• AP-HP Hopital Henri Mondor — Créteil
• AP-HP Hopital Bicetre — Le Kremlin-Bicêtre
• CHU Rennes — Rennes
• CHU de Toulouse - Hopital Rangueil — Toulouse

Australia · 4 centers

• St Vincent's Hospital Sydney — Darlinghurst
• Fiona Stanley Hospital — Murdoch
• Westmead Hospital — Westmead
• Princess Alexandra Hospital — Woolloongabba

Brazil · 4 centers

• Fundacao Centro Medico de Campinas — Campinas
• Instituto do Coracao (InCor) do Hospital das Clinicas da FMUSP — Cerqueira César
• CAPED - Centro Avancado de Pesquisa, Estudos e Diagnostico — Ribeirão Preto
• Cardiopulmonar da Bahia S.A. (Hospital Cardio Pulmonar) — Salvador

Netherlands · 4 centers

Center list to be confirmed — check the primary protocol.

South Korea · 4 centers

Center list to be confirmed — check the primary protocol.

Argentina · 3 centers

• Hospital Italiano de Buenos Aires — Buenos Aires
• Hospital Britanico de Buenos Aires — Buenos Aires
• ICBA - Instituto Cardiovascular de Buenos Aires S.A. — CABA

Canada · 3 centers

• University of Calgary — Calgary
• University of British Columbia — Vancouver
• St. Michael's Hospital — Toronto

Germany · 3 centers

• Charite Universitaetsmedizin Berlin — Berlin
• Universitaetsklinikum Heidelberg — Heidelberg
• Universitaetsmedizin der Johannes Gutenberg - Universitaet Mainz — Mainz

Taiwan · 3 centers

Center list to be confirmed — check the primary protocol.

Greece · 2 centers

• Hippokration General Hospital of Athens — Athens
• General Hospital of Athens - Alexandra — Athens

Ireland · 2 centers

• The Mater Misericordiae University Hospital — Dublin
• Tallaght University Hospital - The Adelaide and Meath Hospital — Dublin

Japan · 2 centers

• Kumamoto University Hospital — Kumamoto
• Shinshu University Hospital — Nagano

Portugal · 2 centers

Center list to be confirmed — check the primary protocol.

Singapore · 2 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 2 centers

Center list to be confirmed — check the primary protocol.

Belgium · 1 center

• UZ Leuven — Leuven

Denmark · 1 center

• Aarhus University Hospital — Aarhus

Malaysia · 1 center

• University Malaya Medical Centre (UMMC) — Kuala Lumpur

Martinique · 1 center

• CHU de Fort de France — Fort-de-France

Mexico · 1 center

• National Institute of Medical Sciences and Nutrition - Salvador Zubiran(INCMNSZ) — Tlalpan

Sweden · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06563895 · AG10-501 · U1111-1307-8107 · jRCT2071250116

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗