Hereditary Transthyretin-Mediated Amyloid PolyneuropathyPhase 3NCT04136184
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
A Phase 3 study testing Inotersen and Eplontersen in people with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy, run by Ionis Pharmaceuticals, Inc. at 45 sites in 16 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 82 years
- Conditions the study is for
- Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
- What is being tested?
- Inotersen and Eplontersen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 168 participants
- Where
- 45 sitesin 16 countries
- Study dates
- 11 Dec 2019to 12 Jul 2023
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 82 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
- 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
Show all 10Show fewer
- Other types of amyloidosis
- 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
- 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)
Trial locations and contacts
45 sites in 16 countries.
45 sites in 16 countries
United States12 sites
Johns Hopkins University Neurology Research Office
Baltimore, Maryland, 21224
Boston University School of Medicine
Boston, Massachusetts, 02118
University of North Carolina Hospitals - Neurology Clinic
Chapel Hill, North Carolina, 27599
Indiana University School of Medicine - Indianapolis
Indianapolis, Indiana, 46202
Mayo Clinic - Jacksonville
Jacksonville, Florida, 32224
University of Kansas Medical Center
Kansas City, Kansas, 66160
The Neurological Institute of New York
New York, New York, 10032
Penn Presbyterian Medical Center
Philadelphia, Pennsylvania, 19104
Oregon Health and Science University
Portland, Oregon, 97239
Mayo Clinic - Rochester
Rochester, Minnesota, 55905
Mayo Clinic - Arizona
Scottsdale, Arizona, 85259
University of Washington Medical Center
Seattle, Washington, 98195
Brazil5 sites
Universidade Estadual de Campinas
Campinas, 13083-970
Instituto de Neurologia de Curitiba
Curitiba, Paraná, 81210-310
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
Ribeirão Preto, 14049-900
Hospital Universitário Clementino Fraga Filho
Rio de Janeiro, 21941-617
Associação de Assistência à Criança Deficiente - Unidade Lar Escola
São Paulo, 04032-060
Argentina4 sites
STAT Research
Buenos Aires, C1023AAB
Instituto Fleni
Buenos Aires, C1428 AQK
Hospital Italiano de Buenos Aires
Ciudad Autónoma de Buenos Aires, Buenos Aires, C1199ABB
Hospital El Cruce
San Juan Bautista, Buenos Aires, 1888
Italy4 sites
Azienda Ospedaliera Universitaria Policlinico Gaetano Martino
Messina, 98124
Fondazione IRCCS Istituto Neurologico Carlo Besta
Milan, 20133
Fondazione IRCCS Policlinico San Matteo
Pavia, 27100
Fondazione Policlinico Universitario Agostino Gemelli
Roma, 00168
Taiwan4 sites
China Medical University Hospital
Taichung, Taichung, 40447
National Taiwan University Hospital
Taipei, 100
Taipei Veterans General Hospital
Taipei City, Taipei, 11217
Chang Gung Memorial Hospital - Linkou Branch
Taoyuan City, Guishan District, 333
France3 sites
Hôpital Bicêtre
Le Kremlin-Bicêtre, Île-de-France Region, 94270
Hôpital de la Timone
Marseille, 13005
Centre Hospitalier Universitaire de Toulouse
Toulouse, Haute-Garonne, 31059
Germany2 sites
Universitätsklinikum Heidelberg
Heidelberg, 69120
Universitätsklinikum Würzburg
Würzburg, Bavaria, 97080
Portugal2 sites
Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria
Lisbon, 1649-028
Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio
Porto, 4099-001
Spain2 sites
Hospital Clínico San Carlos
Madrid, 28040
Hospital Son Llàtzer
Palma de Mallorca, Balearic Islands, 07198
Australia1 site
Perron Institute for Neurological and Translational Science
Nedlands, Western Australia, 6009
Greece1 site
University General Hospital of Heraklion (PAGNI)
Heraklion, Crete, 711 10
Turkey (Türkiye)1 site
İstanbul Üniversitesi - Istanbul Tıp Fakültesi
Istanbul, 34093
About this study
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
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/.
Read the 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.
- Being tested
- Inotersen, Eplontersen
- Keywords
- Polyneuropathy, Amyloidosis, ATTR, TTR
- Medical subject headings
- Polyneuropathies, Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InotersenDrug
Also called TEGSEDI, ISIS 420915
Inotersen by subcutaneous injection
EplontersenDrug
Also called ION-682884, AKCEA-TTR-LRx, IONIS-TTR-LRx
Eplontersen by subcutaneous injection
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Inotersen; Drug: Eplontersen |
| Eplontersen | Experimental | Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. Receives: Drug: Eplontersen |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline, Week 35
Secondary outcomes (5)
Change From Baseline in Norfolk QOL-DN at Week 35
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.
Measured: Baseline, Week 35
Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66
NSC score is a questionnaire composed of 38 questions divided into 5 domains: muscle weakness, sensory (hypo/loss of sensation), sensory (paresthesia, hyper sensation), autonomic (gastrointestinal \& urinary incontinence), \& autonomic (non-GI/non-urinary incontinence)]. Answers to questionnaire are yes/no and if yes, then degree of severity is graded as 1 (slight +), 2 (moderate ++) and 3 (severe +++). 0=no symptom. NSC total score is a sum of scores across all 5 domains. Total score= 0-114. Higher scores=more neuropathy symptoms. 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.
Measured: 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
SF-36 comprises 36 items that yield 8 subscales and 2 summary measures (PCS and Mental component summary [MCS]). Multi-item subscales (35 items) includes: physical function=10 items, role physical =4 items, bodily pain=2 items, general health=5 items, vitality=4 items, social functioning=2 items, role emotional =3 items and mental health=5 items. 8 subscales are scored from 0-100. Higher scores indicate better health. 8 subscales are aggregated into a PCS score ranging from 0-100. Higher scores indicate better health. 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.
Measured: Baseline, Week 65
Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65
PND is a 5-stage scoring system. PND score is defined as I=sensory disturbances in limbs without motor impairment; II=difficulty walking without the need of a walking aid; IIIa=one stick or one crutch required for walking; IIIb=two sticks or two crutches needed; IV=wheelchair required or patient confined to bed. For analysis, no impairment is scored as 0, I is scored as 1, II as 2, IIIa as 3, IIIb as 4 and IV as 5. Lower scores indicate greater ambulatory 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.
Measured: Baseline, Week 65
Change From Baseline in Modified Body Mass Index (mBMI) at Week 65
mBMI is defined as body mass index in kilograms per square meter (kg/m^2) multiplied by serum albumin in grams per liter (g/L). 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.
Measured: Baseline, Week 65
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2019
- Study start11 Dec 2019
- Primary completion11 Apr 2023
- Study completion12 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Hereditary Transthyretin-Mediated Amyloid PolyneuropathyStudies of the same condition, open and under way.
- More trials run by Ionis Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 168 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ionis Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04136184
- Sponsor's protocol ID
- ION-682884-CS3
- Other IDs
- 2019-001698-10, 2019
- Status last verified
- Dec 2024
- First submitted
- 21 Oct 2019
- Last updated
- 13 Dec 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 37768671Waddington Cruz M, Berk JL, Parman Y, Gertz M, Khella S, Weiler M, Kwoh TJ, Pola M, Reicher B, Natman J, Dasgupta NR, Wixner J. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy: An Exploratory Analysis of Treatment Effect in Male and Female Patients. Muscle Nerve. 2026 Jun;73(6):1118-1127. doi: 10.1002/mus.70230. Epub 2026 Apr 6.
PubMed 41937511Gillmore JD, Adams D, Weiler M, Masri A, Obici L, Natman J, Kwoh TJ, Reicher B, Revkin J, Cruz MW, Gertz M, Chao CC. Effect of Eplontersen in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy Across Genetic Variants: An Exploratory Analysis From the NEURO-TTRansform Trial. Eur J Neurol. 2026 Apr;33(4):e70580. doi: 10.1111/ene.70580.
PubMed 41913562Masri A, Maurer MS, Claggett BL, Kulac I, Waddington Cruz M, Conceicao I, Weiler M, Berk JL, Gertz M, Gillmore JD, Rush S, Chen J, Zhou W, Kwoh J, Duran JM, Tsimikas S, Solomon SD. Effect of Eplontersen on Cardiac Structure and Function in Patients With Hereditary Transthyretin Amyloidosis. J Card Fail. 2024 Aug;30(8):973-980. doi: 10.1016/j.cardfail.2023.11.016. Epub 2023 Dec 7.
PubMed 38065307Coelho 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.
PubMed 36525140Coelho 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.
PubMed 33638113
Study at a glance
From the registry record, last updated by the sponsor on 13 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04136184
- Acronym / sponsor ID
- ION-682884-CS3
- Keywords
- Polyneuropathy, Amyloidosis, ATTR, TTR
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 168 participants (actual)
- Lead sponsor
- Ionis Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 11 Dec 2019 (actual)
- Primary completion
- 11 Apr 2023 (actual)
- Study completion
- 12 Jul 2023 (actual)
- First posted
- 23 Oct 2019 (actual)
- Results
- Posted 10 Dec 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Inotersen | Active comparator | Drug: Inotersen, Drug: EplontersenParticipants 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. |
| Eplontersen | Experimental | Drug: EplontersenParticipants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. |
Who may qualify
- Ages
- 18 to 82 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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:
Key exclusion criteria (10 listed)
- 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
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| InotersenAlso: TEGSEDI, ISIS 420915Inotersen by subcutaneous injection | Drug | Inotersen |
| EplontersenAlso: ION-682884, AKCEA-TTR-LRx, IONIS-TTR-LRxEplontersen by subcutaneous injection | Drug | Eplontersen, Inotersen |
Primary outcome
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66
Time frame: Baseline, 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.
Change From Baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66
Time frame: Baseline, 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.
Percent Change From Baseline in Serum TTR Concentration at Week 65
Time frame: Baseline, 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.
Percent Change From Baseline in Serum TTR Concentration at Week 35
Time frame: Baseline, 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.
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 35
Time frame: Baseline, 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.
5 secondary outcomes
Change From Baseline in Norfolk QOL-DN at Week 35
Time frame: Baseline, Week 35
Change From Baseline in Neuropathy Symptom and Change (NSC) Score at Weeks 35 and 66
Time frame: 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
Time frame: Baseline, Week 65
Change From Baseline in Polyneuropathy Disability (PND) Score at Week 65
Time frame: Baseline, Week 65
Change From Baseline in Modified Body Mass Index (mBMI) at Week 65
Time frame: Baseline, Week 65
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Dec 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 37768671Coelho 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.
- Derived from this study: PubMed 41937511Waddington Cruz M, Berk JL, Parman Y, Gertz M, Khella S, Weiler M, Kwoh TJ, Pola M, Reicher B, Natman J, Dasgupta NR, Wixner J. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy: An Exploratory Analysis of Treatment Effect in Male and Female Patients. Muscle Nerve. 2026 Jun;73(6):1118-1127. doi: 10.1002/mus.70230. Epub 2026 Apr 6.
- Derived from this study: PubMed 41913562Gillmore JD, Adams D, Weiler M, Masri A, Obici L, Natman J, Kwoh TJ, Reicher B, Revkin J, Cruz MW, Gertz M, Chao CC. Effect of Eplontersen in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy Across Genetic Variants: An Exploratory Analysis From the NEURO-TTRansform Trial. Eur J Neurol. 2026 Apr;33(4):e70580. doi: 10.1111/ene.70580.
- Derived from this study: PubMed 38065307Masri A, Maurer MS, Claggett BL, Kulac I, Waddington Cruz M, Conceicao I, Weiler M, Berk JL, Gertz M, Gillmore JD, Rush S, Chen J, Zhou W, Kwoh J, Duran JM, Tsimikas S, Solomon SD. Effect of Eplontersen on Cardiac Structure and Function in Patients With Hereditary Transthyretin Amyloidosis. J Card Fail. 2024 Aug;30(8):973-980. doi: 10.1016/j.cardfail.2023.11.016. Epub 2023 Dec 7.
- Derived from this study: PubMed 36525140Coelho 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.
- Derived from this study: PubMed 33638113Coelho 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.
- Individual participant dataSharing planned: No
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A Study to Assess the Long-Term Safety and Efficacy of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
45 sites in 16 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Inotersen and Eplontersen in people with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy, run by Ionis Pharmaceuticals, Inc. at 45 sites in 16 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 45 sites in United States, Brazil, Argentina, Italy, Taiwan and 11 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change From Baseline in Modified Neuropathy Impairment Score Plus 7 (mNIS+7) at Week 66 (time frame: Baseline, Week 66). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04136184, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Dec 2024; AzTrials last refreshed its copy on 26 Oct 2026.