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

NCT04136184 | Completed Phase 3 Results FDA Drug

• 2 other identifiers: ION-682884-CS32019-001698-10
• Study Type: interventional
• Target: 168
• Locations: 16 countries
• Sites: 45

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/.

Conditions

Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

Keywords

Polyneuropathy; Amyloidosis; ATTR; TTR

Outcome Measures

Primary Outcomes (5)

• Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66

  mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. Least square (LS) mean \& standard error (SE) were analyzed using Mixed Effects Model with Repeated Measures (MMRM). As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

  Baseline, Week 66

• Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66

  The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 138, and a higher score indicates poorer quality of life. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

  Baseline, Week 66

• Percent Change From Baseline in Serum TTR Concentration at Week 65

  As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.

  Baseline, Week 65

• Percent Change From Baseline in Serum TTR Concentration at Week 35

  As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms. Overall number analyzed is the number of participants with data available for analysis.

  Baseline, Week 35

• Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35

  mNIS+7 composite score is a measure of neurologic impairment evaluating muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. mNIS+7 consists of 2 composite scores: NIS composite score (maximum of 244 points) \& the modified +7 composite score (maximum of 102.32 points). mNIS+7 composite total score range= -22.32 to 346.32. Higher score indicated a lower function. LS mean and SE were analyzed using MMRM. As pre-specified in the protocol, the efficacy of eplontersen was to be assessed by comparing participants enrolled in the eplontersen arm only with the external placebo group. There was no statistical comparison planned between the inotersen arm and the eplontersen-treated/external placebo group arms.

  Baseline, Week 35

Secondary Outcomes (5)

• Change From Baseline in Norfolk QOL-DN at Week 35

  Baseline, Week 35

• Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66

  Baseline, Week 35, Week 66

• Change From Baseline in the Physical Component Summary (PCS) Score of the 36-Item Short Form Survey (SF-36) at Week 65

  Baseline, Week 65

• Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65

  Baseline, Week 65

• Change From Baseline in Modified Body Mass Index (mBMI) at Week 65

  Baseline, Week 65

Study Arms (2)

Inotersen

ACTIVE COMPARATOR

Participants received inotersen, 300 milligrams (mg), subcutaneously (SC), once weekly up to Week 34. After Week 35 assessment, participants received eplontersen, 45 mg, SC, once every 4 weeks starting from Week 37 up to Week 81.

Drug: Inotersen; Drug: Eplontersen

Eplontersen

EXPERIMENTAL

Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81.

Drug: Eplontersen

Interventions

Inotersen DRUG

Inotersen by subcutaneous injection

Also known as: TEGSEDI, ISIS 420915

Inotersen

Eplontersen DRUG

Eplontersen by subcutaneous injection

Also known as: ION-682884, AKCEA-TTR-LRx, IONIS-TTR-LRx

Eplontersen; Inotersen

Eligibility Criteria

• Age: 18 Years - 82 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 18 to 82 years at the time of informed consent
• Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent
• 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
• 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

You may not qualify if:

• Karnofsky performance status ≤ 50
• Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
• Prior liver transplant or anticipated liver transplant within 1-yr of Screening
• New York Heart Association (NYHA) functional classification of ≥ 3
• Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening
• Other types of amyloidosis
• 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
• Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (45)

Mayo Clinic - Arizona

Scottsdale, Arizona, 85259, United States

Location

Mayo Clinic - Jacksonville

Jacksonville, Florida, 32224, United States

Location

Indiana University School of Medicine - Indianapolis

Indianapolis, Indiana, 46202, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

Johns Hopkins University Neurology Research Office

Baltimore, Maryland, 21224, United States

Location

Boston University School of Medicine

Boston, Massachusetts, 02118, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

The Neurological Institute of New York

New York, New York, 10032, United States

Location

University of North Carolina Hospitals - Neurology Clinic

Chapel Hill, North Carolina, 27599, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Penn Presbyterian Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Hospital Italiano de Buenos Aires

Ciudad Autónoma de Buenos Aires, Buenos Aires, C1199ABB, Argentina

Location

Hospital El Cruce

San Juan Bautista, Buenos Aires, 1888, Argentina

Location

STAT Research

Buenos Aires, C1023AAB, Argentina

Location

Instituto Fleni

Buenos Aires, C1428 AQK, Argentina

Location

Perron Institute for Neurological and Translational Science

Nedlands, Western Australia, 6009, Australia

Location

Instituto de Neurologia de Curitiba

Curitiba, Paraná, 81210-310, Brazil

Location

Universidade Estadual de Campinas

Campinas, 13083-970, Brazil

Location

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto

Ribeirão Preto, 14049-900, Brazil

Location

Hospital Universitário Clementino Fraga Filho

Rio de Janeiro, 21941-617, Brazil

Location

Associação de Assistência à Criança Deficiente - Unidade Lar Escola

São Paulo, 04032-060, Brazil

Location

Toronto General Hospital

Toronto, Ontario, M4C 3E7, Canada

Location

The Cyprus Institute of Neurology and Genetics

Égkomi, 2371, Cyprus

Location

Centre Hospitalier Universitaire de Toulouse

Toulouse, Haute-Garonne, 31059, France

Location

Hôpital de la Timone

Marseille, 13005, France

Location

Hôpital Bicêtre

Le Kremlin-Bicêtre, Île-de-France Region, 94270, France

Location

Universitätsklinikum Würzburg

Würzburg, Bavaria, 97080, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

University General Hospital of Heraklion (PAGNI)

Heraklion, Crete, 711 10, Greece

Location

Azienda Ospedaliera Universitaria Policlinico Gaetano Martino

Messina, 98124, Italy

Location

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, 20133, Italy

Location

Fondazione IRCCS Policlinico San Matteo

Pavia, 27100, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli

Roma, 00168, Italy

Location

Auckland City Hospital

Grafton, Auckland, 1023, New Zealand

Location

Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria

Lisbon, 1649-028, Portugal

Location

Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio

Porto, 4099-001, Portugal

Location

Hospital Son Llàtzer

Palma de Mallorca, Balearic Islands, 07198, Spain

Location

Hospital Clínico San Carlos

Madrid, 28040, Spain

Location

Norrlands Universitetssjukhus

Umeå, 907 37, Sweden

Location

Chang Gung Memorial Hospital - Linkou Branch

Taoyuan, Guishan District, 333, Taiwan

Location

China Medical University Hospital

Taichung, Taichung, 40447, Taiwan

Location

Taipei Veterans General Hospital

Taipei City, Taipei, 11217, Taiwan

Location

National Taiwan University Hospital

Taipei, 100, Taiwan

Location

İstanbul Üniversitesi - Istanbul Tıp Fakültesi

Istanbul, 34093, Turkey (Türkiye)

Location

Related Publications (3)

• 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.

  PMID: 37768671 RESULT

• Coelho T, Waddington Cruz M, Chao CC, Parman Y, Wixner J, Weiler M, Barroso FA, Dasgupta NR, Jung SW, Schneider E, Viney NJ, Dyck PJB, Ando Y, Gillmore JD, Khella S, Gertz MA, Obici L, Berk JL. Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen. Neurol Ther. 2023 Feb;12(1):267-287. doi: 10.1007/s40120-022-00414-z. Epub 2022 Dec 16.

  PMID: 36525140 DERIVED

• 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.

  PMID: 33638113 DERIVED

MeSH Terms

Conditions

Polyneuropathies; Amyloidosis

Interventions

Inotersen; eplontersen

Condition Hierarchy (Ancestors)

Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Ionis Pharmaceuticals, Inc.
• Organization: Ionis Pharmaceuticals, Inc.

globalregulatoryaffairs@ionis.com

760-603-2346

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2019
• First Posted: October 23, 2019
• Study Start: December 11, 2019
• Primary Completion: April 11, 2023
• Study Completion: July 12, 2023
• Last Updated: December 13, 2024
• Results First Posted: December 10, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (4); CY (1); FR (3); PT (2); GR (1); AU (1); AR (4); US (12); CA (1); TW (4); NZ (1); TU (1); BR (5); SE (1); ES (2); DE (2)