Clinical trial NCT04136184: NEURO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Official title: A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of ION-682884 in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Keywords: Polyneuropathy
Amyloidosis
ATTR
TTR
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2019-10-23
Enrollment: 168
Sex: ALL
Minimum age (years): 18
Maximum age (years): 82
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The main objective of this study was to evaluate the efficacy of eplontersen as compared with the historical control of the placebo cohort in the NEURO-TTR trial (NCT01737398/2012-001831-30), in subjects with hereditary transthyretin-mediated amyloidosis polyneuropathy (hATTR-PN). For more information, please visit http://www.neuro-ttransform.com/.

Detailed description: This study was a multicenter, open-label study in up to 168 participants, who were randomized to receive subcutaneous (SC) injections of either eplontersen once every 4 weeks or inotersen once a week. Participants also received daily supplemental doses of the recommended daily allowance of vitamin A. Participants included in the inotersen reference arm crossed over to eplontersen at Week 37 after completing the Week 35 assessments.

Eligibility criteria: Key Inclusion Criteria:

1. Aged 18 to 82 years at the time of informed consent
2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent
3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the participant or the participantss non-pregnant female partner must be using a highly effective contraceptive method
4. Diagnosis of hereditary transthyretin-mediated polyneuropathy as defined by meeting all 3 of the following:

   * Stage 1 or Stage 2 Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage
   * Documented genetic mutation in the TTR gene
   * Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including Neuropathy Impairment Score (NIS) ≥ 10 and ≤ 130

Key Exclusion Criteria:

1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a participants unsuitable for inclusion, including but not limited to abnormal safety labs
2. Karnofsky performance status ≤ 50
3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
5. New York Heart Association (NYHA) functional classification of ≥ 3
6. Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening
7. Other types of amyloidosis
8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the Study
9. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran), off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and TUDCA, must have discontinued treatment for at least 2 weeks prior to Study Day 1
10. Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)

Primary outcomes:
measure: Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66
timeFrame: Baseline, Week 66
measure: Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
timeFrame: Baseline, Week 66
measure: Percent Change From Baseline in Serum TTR Concentration at Week 65
timeFrame: Baseline, Week 65
measure: Percent Change From Baseline in Serum TTR Concentration at Week 35
timeFrame: Baseline, Week 35
measure: Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35
timeFrame: Baseline, Week 35
Secondary outcomes:
measure: Change From Baseline in Norfolk QOL-DN at Week 35
timeFrame: Baseline, Week 35
measure: Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66
timeFrame: Baseline, Week 35, Week 66
measure: Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65
timeFrame: Baseline, Week 65
measure: Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65
timeFrame: Baseline, Week 65
measure: Change From Baseline in Modified Body Mass Index (mBMI) at Week 65
timeFrame: Baseline, Week 65
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Indianapolis
country: United States
facility: Indiana University School of Medicine - Indianapolis
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University Neurology Research Office
state: Maryland
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: New York
country: United States
facility: The Neurological Institute of New York
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospitals - Neurology Clinic
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Ciudad Autónoma De Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
state: Buenos Aires
city: Florencio Varela
country: Argentina
facility: Hospital El Cruce
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: STAT Research
city: Buenos Aires
country: Argentina
facility: Instituto Fleni
city: Nedlands
country: Australia
facility: Perron Institute for Neurological and Translational Science
state: Western Australia
city: Curitiba
country: Brazil
facility: Instituto de Neurologia de Curitiba
state: Parana
city: Curitiba
country: Brazil
facility: Instituto de Neurologia de Curitiba
state: Paraná
city: Campinas
country: Brazil
facility: Universidade Estadual de Campinas
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
city: Rio De Janeiro
country: Brazil
facility: Hospital Universitário Clementino Fraga Filho
city: São Paulo
country: Brazil
facility: Associação de Assistência à Criança Deficiente - Unidade Lar Escola
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Egkomi
country: Cyprus
facility: The Cyprus Institute of Neurology and Genetics
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse
state: Haute-Garonne
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital Bicêtre
state: Ile-De-France
city: Marseille
country: France
facility: Hôpital de la Timone
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
state: Bayern
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Heraklion
country: Greece
facility: University General Hospital of Heraklion (PAGNI)
state: Crete
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Gaetano Martino
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Lisbon
country: Portugal
facility: Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio
city: Palma De Mallorca
country: Spain
facility: Hospital Son Llàtzer
state: Illes Balears
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
city: Taoyuan City
country: Taiwan
facility: Chang Gung Memorial Hospital - Linkou Branch
state: Guishan District
city: Taichung City
country: Taiwan
facility: China Medical University Hospital
state: Taichung
city: Taipei City
country: Taiwan
facility: Taipei Veterans General Hospital
state: Taipei
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: İstanbul
country: Turkey
facility: İstanbul Üniversitesi - Istanbul Tıp Fakültesi
Study officials:
References:
citation: Coelho T, Marques W Jr, Dasgupta NR, Chao CC, Parman Y, Franca MC Jr, Guo YC, Wixner J, Ro LS, Calandra CR, Kowacs PA, Berk JL, Obici L, Barroso FA, Weiler M, Conceicao I, Jung SW, Buchele G, Brambatti M, Chen J, Hughes SG, Schneider E, Viney NJ, Masri A, Gertz MR, Ando Y, Gillmore JD, Khella S, Dyck PJB, Waddington Cruz M; NEURO-TTRansform Investigators. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. 2023 Oct 17;330(15):1448-1458. doi: 10.1001/jama.2023.18688.
citation: Coelho T, Ando Y, Benson MD, Berk JL, Waddington-Cruz M, Dyck PJ, Gillmore JD, Khella SL, Litchy WJ, Obici L, Monteiro C, Tai LJ, Viney NJ, Buchele G, Brambatti M, Jung SW, St L O'Dea L, Tsimikas S, Schneider E, Geary RS, Monia BP, Gertz M. Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-LRx (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy. Neurol Ther. 2021 Jun;10(1):375-389. doi: 10.1007/s40120-021-00235-6. Epub 2021 Feb 26.