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| ID | Type | Description | Link |
|---|---|---|---|
| 2019-001698-10 | EudraCT Number |
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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/.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| Eplontersen | Experimental | Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Inotersen | Drug | Inotersen by subcutaneous injection |
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| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Key Inclusion Criteria:
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:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic - Arizona | Scottsdale | Arizona | 85259 | United States | ||
| Mayo Clinic - Jacksonville |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37768671 | Result | 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. | |
| 41937511 |
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Participants with a diagnosis of hereditary transthyretin-mediated amyloid Polyneuropathy (hATTR-PN) were randomized in a 6:1 ratio to receive eplontersen (ION-682884) or inotersen respectively. As pre-specified in the protocol, the placebo-cohort group from ISIS 420915-CS2 (NEURO-TTR) study (NCT01737398-3), which was used as an external control for efficacy analysis in this study.
Participants took part in the study at 46 investigative sites in 15 countries (Argentina, Australia, Brazil, Canada, Cyprus, France, Germany, Italy, New Zealand, Portugal, Spain, Sweden, Taiwan, Turkey, and the United States) from 11 December 2019 to 12 July 2023.
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| ID | Title | Description |
|---|---|---|
| FG000 | Inotersen | 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. |
| FG001 | Eplontersen |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 3, 2022 |
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| Eplontersen | Drug | Eplontersen by subcutaneous injection |
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| 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 |
| 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. | 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. | 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. | 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. | Baseline, Week 65 |
| Jacksonville |
| Florida |
| 32224 |
| United States |
| Indiana University School of Medicine - Indianapolis | Indianapolis | Indiana | 46202 | United States |
| University of Kansas Medical Center | Kansas City | Kansas | 66160 | United States |
| Johns Hopkins University Neurology Research Office | Baltimore | Maryland | 21224 | United States |
| Boston University School of Medicine | Boston | Massachusetts | 02118 | United States |
| Mayo Clinic - Rochester | Rochester | Minnesota | 55905 | United States |
| The Neurological Institute of New York | New York | New York | 10032 | United States |
| University of North Carolina Hospitals - Neurology Clinic | Chapel Hill | North Carolina | 27599 | United States |
| Oregon Health and Science University | Portland | Oregon | 97239 | United States |
| Penn Presbyterian Medical Center | Philadelphia | Pennsylvania | 19104 | United States |
| University of Washington Medical Center | Seattle | Washington | 98195 | United States |
| Hospital Italiano de Buenos Aires | Ciudad Autónoma de Buenos Aires | Buenos Aires | C1199ABB | Argentina |
| Hospital El Cruce | San Juan Bautista | Buenos Aires | 1888 | Argentina |
| STAT Research | Buenos Aires | C1023AAB | Argentina |
| Instituto Fleni | Buenos Aires | C1428 AQK | Argentina |
| Perron Institute for Neurological and Translational Science | Nedlands | Western Australia | 6009 | Australia |
| Instituto de Neurologia de Curitiba | Curitiba | Paraná | 81210-310 | Brazil |
| Universidade Estadual de Campinas | Campinas | 13083-970 | Brazil |
| Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto | Ribeirão Preto | 14049-900 | Brazil |
| Hospital Universitário Clementino Fraga Filho | Rio de Janeiro | 21941-617 | Brazil |
| Associação de Assistência à Criança Deficiente - Unidade Lar Escola | São Paulo | 04032-060 | Brazil |
| Toronto General Hospital | Toronto | Ontario | M4C 3E7 | Canada |
| The Cyprus Institute of Neurology and Genetics | Égkomi | 2371 | Cyprus |
| Centre Hospitalier Universitaire de Toulouse | Toulouse | Haute-Garonne | 31059 | France |
| Hôpital de la Timone | Marseille | 13005 | France |
| Hôpital Bicêtre | Le Kremlin-Bicêtre | Île-de-France Region | 94270 | France |
| Universitätsklinikum Würzburg | Würzburg | Bavaria | 97080 | Germany |
| Universitätsklinikum Heidelberg | Heidelberg | 69120 | Germany |
| University General Hospital of Heraklion (PAGNI) | Heraklion | Crete | 711 10 | Greece |
| Azienda Ospedaliera Universitaria Policlinico Gaetano Martino | Messina | 98124 | Italy |
| Fondazione IRCCS Istituto Neurologico Carlo Besta | Milan | 20133 | Italy |
| Fondazione IRCCS Policlinico San Matteo | Pavia | 27100 | Italy |
| Fondazione Policlinico Universitario Agostino Gemelli | Roma | 00168 | Italy |
| Auckland City Hospital | Grafton | Auckland | 1023 | New Zealand |
| Centro Hospitalar Universitário Lisboa Norte - Hospital De Santa Maria | Lisbon | 1649-028 | Portugal |
| Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio | Porto | 4099-001 | Portugal |
| Hospital Son Llàtzer | Palma de Mallorca | Balearic Islands | 07198 | Spain |
| Hospital Clínico San Carlos | Madrid | 28040 | Spain |
| Norrlands Universitetssjukhus | Umeå | 907 37 | Sweden |
| Chang Gung Memorial Hospital - Linkou Branch | Taoyuan City | Guishan District | 333 | Taiwan |
| China Medical University Hospital | Taichung | Taichung | 40447 | Taiwan |
| Taipei Veterans General Hospital | Taipei City | Taipei | 11217 | Taiwan |
| National Taiwan University Hospital | Taipei | 100 | Taiwan |
| İstanbul Üniversitesi - Istanbul Tıp Fakültesi | Istanbul | 34093 | Turkey (Türkiye) |
| Derived |
| Waddington 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. |
| 41913562 | Derived | Gillmore 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. |
| 38065307 | Derived | Masri 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. |
| 36525140 | Derived | 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. |
| 33638113 | 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. |
Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. |
| COMPLETED |
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| NOT COMPLETED |
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Randomized set included participants who were screened and who received a randomization assignment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Inotersen | 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. |
| BG001 | Eplontersen | Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Serum Transthyretin (TTR) Concentration | Mean | Standard Deviation | grams per litre (g/L) |
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| Modified Neuropathy Impairment Score Plus 7 (mNIS+7) Composite Score | The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 consists of 2 composite scores: the NIS composite score (maximum of 244 points) and the modified +7 composite score (maximum of 102.32 points). The mNIS+7 composite total score has a range of -22.32 to 346.32, and a higher score indicates lower function. | Mean | Standard Deviation | scores on a scale |
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| Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Total Score | 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. | Randomized set included participants who were screened and who received a randomization assignment. Number analyzed is the number of participants with data available for analysis. | Mean | Standard Deviation | scores on a scale |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline, Week 66 |
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| Primary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline, Week 66 |
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| Primary | 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. | FAS was defined as all randomized participants who received at least 1 injection of ION-682884/inotersen and had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized participants who received at least 1 injection of study drug and had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score. | Posted | Least Squares Mean | Standard Error | percentage | Baseline, Week 65 |
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| Primary | 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. | FAS was defined as all randomized participants who received at least 1 injection of ION-682884/inotersen and had a baseline & at least 1 post-baseline efficacy assessment for mNIS+7 score or Norfolk QOL-DN questionnaire total score. For NEURO-TTR trial, FAS included all randomized participants who received at least 1 injection of study drug and had a baseline and at least 1 post-baseline efficacy assessment for the mNIS+7 score or Norfolk QOL-DN questionnaire total score. | Posted | Least Squares Mean | Standard Error | percentage | Baseline, Week 35 |
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| Primary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline, Week 35 |
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| Secondary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline, Week 35 |
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| Secondary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline, Week 35, Week 66 |
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| Secondary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline, Week 65 |
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| Secondary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | scores on a scale | Baseline, Week 65 |
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| Secondary | 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. | FAS: all randomized participants who received at least 1 injection of ION-682884/inotersen & had a baseline & 1 post-baseline efficacy assessment for mNIS+7 score/Norfolk QOL-DN questionnaire total score. NEURO-TTR, FAS: all randomized participants who received at least 1 injection of study drug & had a baseline & 1 post-baseline efficacy assessment for the mNIS+7 or Norfolk QOL-DN questionnaire total score. Overall number analyzed = number of participants with data available for analysis. | Posted | Least Squares Mean | Standard Error | kilogram(kg)/metre(m)^2*gram(g)/litre(L) | Baseline, Week 65 |
|
Week 1 to Week 85
Safety Set (SS) included all participants who were randomized and received at least 1 injection of eplontersen or inotersen.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Eplontersen | Participants received eplontersen, 45 mg, SC, once every 4 weeks up to Week 81. | 4 | 144 | 27 | 144 | 131 | 144 |
| EG001 | Inotersen (Prior to Switch) | Participants received inotersen, 300 mg, SC, once weekly from Week 1 through Week 34. | 0 | 24 | 3 | 24 | 24 | 24 |
| EG002 | Inotersen to ION-682884 (After Switch) | Participants received eplontersen, 45 mg, SC, once every 4 weeks from Week 37 to Week 81. | 0 | 20 | 3 | 20 | 18 | 20 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute myocardial infarction | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Angina unstable | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Arrhythmia | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Atrioventricular block | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Atrioventricular block complete | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Atrioventricular block second degree | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Cardiac failure | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Cardio-respiratory arrest | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Supraventricular tachycardia | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Atrial flutter | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Bradyarrhythmia | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Vertigo | Ear and labyrinth disorders | MedDRA25.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Impaired gastric emptying | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Gastric haemorrhage | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Gastritis | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Ileus | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Adverse drug reaction | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| COVID-19 pneumonia | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| COVID-19 | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Pulmonary sepsis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Pyelonephritis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Skin infection | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Soft tissue infection | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Streptococcal sepsis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Urosepsis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Osteomyelitis chronic | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Burns third degree | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Femoral neck fracture | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Foot fracture | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Hip fracture | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Joint dislocation | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Tibia fracture | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Clostridium test positive | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Glomerular filtration rate decreased | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA25.0 | Systematic Assessment |
| |
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA25.0 | Systematic Assessment |
| |
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA25.0 | Systematic Assessment |
| |
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Lung neoplasm malignant | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA25.0 | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Cerebral haemorrhage | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Metabolic encephalopathy | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Haematuria | Renal and urinary disorders | MedDRA25.0 | Systematic Assessment |
| |
| Renal impairment | Renal and urinary disorders | MedDRA25.0 | Systematic Assessment |
| |
| Urinary retention | Renal and urinary disorders | MedDRA25.0 | Systematic Assessment |
| |
| Nephroangiosclerosis | Renal and urinary disorders | MedDRA25.0 | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Atrial fibrillation | Cardiac disorders | MedDRA25.0 | Systematic Assessment |
| |
| Vision blurred | Eye disorders | MedDRA25.0 | Systematic Assessment |
| |
| Cataract | Eye disorders | MedDRA25.0 | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Injection site pain | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Injection site erythema | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Injection site bruising | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Peripheral swelling | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Chills | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Pain | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Injection site swelling | General disorders | MedDRA25.0 | Systematic Assessment |
| |
| Immunisation reaction | Immune system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| COVID-19 | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Sinusitis | Infections and infestations | MedDRA25.0 | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Thermal burn | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA25.0 | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA25.0 | Systematic Assessment |
| |
| N-terminal prohormone brain natriuretic peptide increased | Investigations | MedDRA25.0 | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA25.0 | Systematic Assessment |
| |
| Glomerular filtration rate Decreased | Investigations | MedDRA25.0 | Systematic Assessment |
| |
| Platelet count decreased | Investigations | MedDRA25.0 | Systematic Assessment |
| |
| Vitamin A deficiency | Metabolism and nutrition disorders | MedDRA25.0 | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA25.0 | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Neuralgia | Nervous system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | MedDRA25.0 | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA25.0 | Systematic Assessment |
| |
| Depression | Psychiatric disorders | MedDRA25.0 | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | MedDRA25.0 | Systematic Assessment |
| |
| Proteinuria | Renal and urinary disorders | MedDRA25.0 | Systematic Assessment |
| |
| Urinary retention | Renal and urinary disorders | MedDRA25.0 | Systematic Assessment |
| |
| Albuminuria | Renal and urinary disorders | MedDRA25.0 | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA25.0 | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Skin ulcer | Skin and subcutaneous tissue disorders | MedDRA25.0 | Systematic Assessment |
| |
| Hypotension | Vascular disorders | MedDRA25.0 | Systematic Assessment |
|
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ionis Pharmaceuticals, Inc. | Ionis Pharmaceuticals, Inc. | 760-603-2346 | globalregulatoryaffairs@ionis.com |
| Sep 10, 2024 |
| Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D011115 | Polyneuropathies |
| D000686 | Amyloidosis |
| ID | Term |
|---|---|
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C000629536 | Inotersen |
| C000730926 | eplontersen |
Not provided
Not provided
Not provided
|
|
|
| Black or African American |
|
|
| White |
|
|
| Other |
|
|
| Multiple |
|
|
| Unknown or Not Reported |
|
|
|
|
|
Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study.
|
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
|
Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study. |
|
|
|
|
|
|
| OG001 | Placebo External Control | Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study. |
|
|
|
| OG001 | Placebo External Control | Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study. |
|
|
|
| Placebo External Control |
Participants in the external placebo arm received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks of the NEURO-TTR study. |
|
|
|
|
|
|