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The purpose of this study is to evaluate the efficacy and safety of inotersen given for 65 weeks in participants with Familial Amyloid Polyneuropathy (FAP).
FAP is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP.
Inotersen (also known as ISIS 420915) is an antisense drug that was designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein would result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.
The purpose of this study is to determine if inotersen can slow or stop the nerve damage caused by TTR deposits. This study will enroll late Stage 1 and early Stage 2 FAP participants. Participants will receive either inotersen or placebo for 65 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Inotersen | Active Comparator | 300 mg inotersen administered subcutaneously (SC) 3 times on alternate days in the first week and then once-weekly for 64 weeks |
|
| Placebo | Active Comparator | Placebo administered SC 3 times on alternate days in the first week and then once-weekly for 64 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Inotersen | Drug |
|
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline In The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66 | 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 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates lower function. | Baseline and 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 136, and a higher Norfolk QoL-DN score indicates poorer QoL. | Baseline and Week 66 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66 | The Norfolk QoL-DN symptoms score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN symptoms domain score has a range of 0-32, and a higher Norfolk QoL-DN score indicates poorer QoL. | Baseline and Week 66 |
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Inclusion Criteria:
Stage 1 and Stage 2 FAP participants with the following:
Females of child-bearing potential must use appropriate contraception and be non-pregnant and non-lactating. Males engaging in relations of child-bearing potential are to use appropriate contraception
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, Irvine | Orange | California | 92868 | United States | ||
| Indiana University School of Medicine |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29972757 | Result | Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH, Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM, Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW, Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793. | |
| 41937511 |
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Participants randomized: 113 inotersen and 60 placebo; received study treatment: 112 inotersen and 60 placebo. This study consisted of a 65-week Treatment Period, 1-week End of Treatment (EOT) Period, and a 6-month Post-treatment Evaluation Period.
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| ID | Title | Description |
|---|---|---|
| FG000 | Inotersen | Participants received 3 subcutaneous (SC) doses of 300 milligrams (mg) inotersen during Week 1, followed by once-weekly SC administration for 64 weeks. |
| FG001 | Placebo |
| 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 | Yes | No | No | Study Protocol | May 13, 2016 | Nov 2, 2018 |
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| Placebo |
| Drug |
|
| Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66 |
The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer QoL. |
| Baseline and Week 66 |
| Change From Baseline In Modified Body Mass Index (mBMI) at Week 65 | The mBMI is the BMI multiplied by the serum albumin g/L | Baseline and Week 65 |
| Change From Baseline In Body Mass Index (BMI) at Week 65 | Baseline and Week 65 |
| Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66 | The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. | Baseline and Week 66 |
| Change From Baseline in Modified +7 at Week 66 | The Modified +7 score is a version of the NIS score that is a measure of neurologic impairment. The Modified +7 Score has a range of -22.32 to 102.32 and a higher NIS score indicates lower function. | Baseline and Week 66 |
| Change From Baseline in NIS+7 at Week 66 | The NIS+7 score is a version of the NIS score that is a measure of neurologic impairment. The NIS+7 Score has a range of -26.04 to 270.04 and a higher NIS score indicates lower function. | Baseline and Week 66 |
| Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set | GLS by ECHO is a measure of cardiac systolic function | Baseline and Week 65 |
| Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup | GLS by ECHO is a measure of cardiac systolic function | Baseline and Week 65 |
| Change From Baseline in Transthyretin (TTR) Level at Week 65 | Baseline and Week 65 |
| Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65 | Baseline and Week 65 |
| Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65 | Week 65 |
| Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65 | Week 65 |
| Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65 | Week 65 |
| Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65 | Week 65 |
| Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65 | Week 65 |
| Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65 | Week 65 |
| Indianapolis |
| Indiana |
| 46202 |
| United States |
| Johns Hopkins University Bayview Medical Center | Baltimore | Maryland | 21205 | United States |
| Boston University School of Medicine - Amyloid Treatment & Research Program | Boston | Massachusetts | 02118 | United States |
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| Mount Sinai Medical Center | New York | New York | 10029 | United States |
| Columbia University Medical Center - The Neurological Institute | New York | New York | 10032 | United States |
| Oregon Health & Science University | Portland | Oregon | 97239 | United States |
| Penn Presbyterian Medical Center | Philadelphia | Pennsylvania | 19104 | United States |
| FLENI | Buenos Aires | Argentina |
| Federal University of Rio de Janeiro - University Hospital | Rio de Janeiro | CEP 21941913 | Brazil |
| AACD | São Paulo | Brazil |
| UNIFESP | São Paulo | Brazil |
| CHU Henri Mondor - Department of Neurology | Créteil | 94000 | France |
| CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network | Le Kremlin-Bicêtre | 94275 | France |
| UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin | Münster | 48149 | Germany |
| Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino" | Messina | Sicily | 98124 | Italy |
| Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo | Pavia | 27100 | Italy |
| Auckland City Hospital | Auckland | New Zealand |
| CHLN - Hospital de Santa Maria | Lisbon | 1649-035 | Portugal |
| CHP-HGSA, Unidade Clinica de Paramiloidose | Porto | 4099-001 | Portugal |
| Hospital Universitari Vall D' Hebron | Barcelona | 08035 | Spain |
| Hospital Clínic | Barcelona | 08036 | Spain |
| University College London - National Amyloidosis Centre | London | NW3 2PF | United Kingdom |
| 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. |
| 35799473 | Derived | Karam C, Brown D, Yang M, Done N, Zhu JJ, Greatsinger A, Bozas A, Vera-Llonch M, Signorovitch J. Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial. Muscle Nerve. 2022 Oct;66(4):438-446. doi: 10.1002/mus.27675. Epub 2022 Aug 4. |
| 35766224 | Derived | Karam C, Brown D, Yang M, Done N, Dieye I, Bozas A, Vera Llonch M, Signorovitch J. Factors associated with increased health-related quality-of-life benefits in hereditary transthyretin amyloidosis polyneuropathy patients treated with inotersen. Muscle Nerve. 2022 Sep;66(3):319-328. doi: 10.1002/mus.27668. Epub 2022 Jul 15. |
| 34355354 | Derived | Yarlas A, Lovley A, McCausland K, Brown D, Vera-Llonch M, Conceicao I, Karam C, Khella S, Obici L, Waddington-Cruz M. Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR. Neurol Ther. 2021 Dec;10(2):865-886. doi: 10.1007/s40120-021-00268-x. Epub 2021 Aug 5. |
| 34125267 | Derived | Yarlas A, Lovley A, Brown D, Kosinski M, Vera-Llonch M. Responder analysis for neuropathic impairment and quality-of-life assessment in patients with hereditary transthyretin amyloidosis with polyneuropathy in the NEURO-TTR study. J Neurol. 2022 Jan;269(1):323-335. doi: 10.1007/s00415-021-10635-1. Epub 2021 Jun 14. |
| 32833564 | Derived | Yu RZ, Wang Y, Norris DA, Kim TW, Narayanan P, Geary RS, Monia BP, Henry SP. Immunogenicity Assessment of Inotersen, a 2'-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety. Nucleic Acid Ther. 2020 Oct;30(5):265-275. doi: 10.1089/nat.2020.0867. Epub 2020 Aug 19. |
| 32654212 | Derived | Dyck PJB, Kincaid JC, Wiesman JF, Polydefkis M, Litchy WJ, Mauermann ML, Ackermann EJ, Guthrie S, Pollock M, Jung SW, Baker BF, Dyck PJ. mNIS+7 and lower limb function in inotersen treatment of hereditary transthyretin-mediated amyloidosis. Muscle Nerve. 2020 Oct;62(4):502-508. doi: 10.1002/mus.27022. Epub 2020 Aug 13. |
| 32654156 | Derived | Dyck PJB, Coelho T, Waddington Cruz M, Brannagan TH 3rd, Khella S, Karam C, Berk JL, Polydefkis MJ, Kincaid JC, Wiesman JF, Litchy WJ, Mauermann ML, Ackermann EJ, Baker BF, Jung SW, Guthrie S, Pollock M, Dyck PJ. Neuropathy symptom and change: Inotersen treatment of hereditary transthyretin amyloidosis. Muscle Nerve. 2020 Oct;62(4):509-515. doi: 10.1002/mus.27023. Epub 2020 Aug 7. |
| 31853709 | Derived | Coelho T, Yarlas A, Waddington-Cruz M, White MK, Sikora Kessler A, Lovley A, Pollock M, Guthrie S, Ackermann EJ, Hughes SG, Karam C, Khella S, Gertz M, Merlini G, Obici L, Schmidt HH, Polydefkis M, Dyck PJB, Brannagan Iii TH, Conceicao I, Benson MD, Berk JL. Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis. J Neurol. 2020 Apr;267(4):1070-1079. doi: 10.1007/s00415-019-09671-9. Epub 2019 Dec 18. |
| 30219500 | Derived | Pinto MV, Dyck PJB, Gove LE, McCauley BM, Ackermann EJ, Hughes SG, Waddington-Cruz M, Dyck PJ. Kind and distribution of cutaneous sensation loss in hereditary transthyretin amyloidosis with polyneuropathy. J Neurol Sci. 2018 Nov 15;394:78-83. doi: 10.1016/j.jns.2018.08.031. Epub 2018 Aug 30. |
| 30169969 | Derived | Waddington-Cruz M, Ackermann EJ, Polydefkis M, Heitner SB, Dyck PJ, Barroso FA, Wang AK, Berk JL, Dyck PJB, Monia BP, Hughes SG, Tai L, Jesse Kwoh T, Jung SW, Coelho T, Benson MD, Gertz MA. Hereditary transthyretin amyloidosis: baseline characteristics of patients in the NEURO-TTR trial. Amyloid. 2018 Sep;25(3):180-188. doi: 10.1080/13506129.2018.1503593. Epub 2018 Aug 31. |
Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks.
| Received at Least 1 Dose of Study Drug | One participant in the inotersen group was ineligible, but was randomized in error. |
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| Safety Set |
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| COMPLETED |
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| NOT COMPLETED |
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Safety Set: Participants who were randomized and received at least 1 dose of study drug (inotersen or placebo). The Safety Set is the population used for the analyses of all safety measures.
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| ID | Title | Description |
|---|---|---|
| BG000 | Inotersen | Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks. |
| BG001 | Placebo | Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| 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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| Participants diagnosed with hATTR-CM | Count of Participants | Participants |
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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 The Modified Neuropathy Impairment Score (mNIS) +7 Composite Score at Week 66 | 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 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates lower function. | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Scores on a Scale | Baseline and 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 136, and a higher Norfolk QoL-DN score indicates poorer QoL. | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Scores on a Scale | Baseline and Week 66 |
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| Secondary | Change From Baseline In The Norfolk QoL-DN Questionnaire Symptoms Domain Score at Week 66 | The Norfolk QoL-DN symptoms score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN symptoms domain score has a range of 0-32, and a higher Norfolk QoL-DN score indicates poorer QoL. | This endpoint only measured participants with Stage 1 hATTR-PN in Full Analysis Set. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Scores on a Scale | Baseline and Week 66 |
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| Secondary | Change From Baseline In The Norfolk QoL-DN Questionnaire Physical Functioning/Large Fiber Neuropathy Domain Score at Week 66 | The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer QoL. | This endpoints only measured participants who had Stage 2 hATTR-PN in Full Analysis Set. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Scores on a Scale | Baseline and Week 66 |
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| Secondary | Change From Baseline In Modified Body Mass Index (mBMI) at Week 65 | The mBMI is the BMI multiplied by the serum albumin g/L | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | kg/m^2*g/L | Baseline and Week 65 |
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| Secondary | Change From Baseline In Body Mass Index (BMI) at Week 65 | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | kg/m^2 | Baseline and Week 65 |
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| Secondary | Change From Baseline in Neuropathy Impairment Score (NIS) at Week 66 | The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Scores on a Scale | Baseline and Week 66 |
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| Secondary | Change From Baseline in Modified +7 at Week 66 | The Modified +7 score is a version of the NIS score that is a measure of neurologic impairment. The Modified +7 Score has a range of -22.32 to 102.32 and a higher NIS score indicates lower function. | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Scores on a Scale | Baseline and Week 66 |
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| Secondary | Change From Baseline in NIS+7 at Week 66 | The NIS+7 score is a version of the NIS score that is a measure of neurologic impairment. The NIS+7 Score has a range of -26.04 to 270.04 and a higher NIS score indicates lower function. | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Scores on a Scale | Baseline and Week 66 |
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| Secondary | Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) at Week 65 in the CM-ECHO Set | GLS by ECHO is a measure of cardiac systolic function | The CM-ECHO Set includes the subset of the Randomized Set who had a diagnosis of TTR cardiomyopathy at study entry but are not in the ECHO subgroup, plus participants who qualified to participate in the ECHO subgroup (whether consented or not). Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Percent Change | Baseline and Week 65 |
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| Secondary | Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram ECHO at Week 65 in the ECHO Subgroup | GLS by ECHO is a measure of cardiac systolic function | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | Percent Change | Baseline and Week 65 |
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| Secondary | Change From Baseline in Transthyretin (TTR) Level at Week 65 | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | g/L | Baseline and Week 65 |
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| Secondary | Change From Baseline in Retinol Binding Protein 4 (RBP4) Level at Week 65 | The full analysis set included all randomized participants who received at least 1 injection of study drug (inotersen or placebo) and who had a Baseline and at least 1 post-Baseline efficacy assessment for the mNIS+7 score or Norfolk QoL-DN questionnaire total score. Participants analyzed = participants with evaluable data. | Posted | Mean | Standard Deviation | ug/L | Baseline and Week 65 |
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| Secondary | Maximum Measured Plasma Concentration (Cmax) Of Inotersen At Week 65 | The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result. | Posted | Mean | Standard Deviation | ug/mL | Week 65 |
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| Secondary | Time To The Maximum Plasma Concentration (Tmax) Of Inotersen At Week 65 | The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result. | Posted | Mean | Standard Deviation | hours | Week 65 |
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| Secondary | Area Under The Plasma Concentration-time Curve From 0 To 24 Hours (AUC[0-24hr]) Of Inotersen At Week 65 | The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result. | Posted | Mean | Standard Deviation | ug*hr/mL | Week 65 |
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| Secondary | Area Under The Plasma Concentration-time Curve From 0 To 168 Hours (AUC[0-168hr]) Of Inotersen At Week 65 | The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result. | Posted | Mean | Standard Deviation | ug*hr/mL | Week 65 |
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| Secondary | Plasma Clearance From 0 To 24 Hours (CL[0-24hr]/F) Of Inotersen At Week 65 | The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result. | Posted | Mean | Standard Deviation | L/hr | Week 65 |
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| Secondary | Inotersen Plasma Clearance At Steady State (CLss/F) At Week 65 | The PK Set was defined as all randomized participants who received at least 1 dose of active study drug (inotersen) and had at least 1 evaluable PK sample collected and analyzed with a reportable result. | Posted | Mean | Standard Deviation | L/hr | Week 65 |
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Week 1 to Week 91
Adverse events that first occurred or worsened after the first dose of study drug (inotersen or placebo), including serious adverse events, were summarized for each treatment group. Analysis is based on data collected while study treatment was administered and during follow-up until the day of the participant's last contact date within the study. For each treatment, a participant is counted only once within each preferred term.
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 | Inotersen | Participants received 3 SC doses of 300 mg inotersen during Week 1, followed by once-weekly SC administration for 64 weeks. | 5 | 112 | 36 | 112 | 110 | 112 |
| EG001 | Placebo | Participants received 3 SC doses of placebo during Week 1, followed by once-weekly SC administration for 64 weeks. | 0 | 60 | 13 | 60 | 60 | 60 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Bronchitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Clostridium difficile infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Encephalitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Herpes zoster | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Peritonitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Pyelonephritis acute | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Staphylococcal infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Wound infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Cellulitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Cardiac failure congestive | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Cardiac failure | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Cardiac failure acute | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Sinus arrest | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Atrioventricular block | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Bradyarrhythmia | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Pericardial effusion | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Sinus bradycardia | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Gastrointestinal hypomotility | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Haemorrhoids | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Intestinal perforation | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Mesenteric arterial occlusion | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Umbilical hernia | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Chest pain | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Gastrointestinal stoma complication | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Ankle fracture | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Hip fracture | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Pelvic fracture | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Cachexia | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Dementia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Embolic stroke | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Haemorrhage intracranial | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Myelopathy | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Myoclonus | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Neuritis | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Seizure | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Neuralgia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Confusional state | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Acute kidney injury | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Glomerulonephritis | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Renal failure | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Renal impairment | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Tubulointerstitial nephritis | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Pulmonary oedema | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Orthostatic hypotension | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Deep vein thrombosis | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Angiopathy | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Bradycardia | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Atrial fibrillation | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Conjunctival haemorrhage | Eye disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Blepharitis | Eye disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Dry mouth | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Dysphagia | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Constipation | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Chills | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Fatigue | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Gait disturbance | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Injection site bruising | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Injection site erythema | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Injection site pain | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Injection site pruritus | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Injection site reaction | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Injection site swelling | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Influenza like illness | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Oedema | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Pain | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Peripheral swelling | General disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Seasonal allergy | Immune system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Rhinitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
| |
| Fall | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Contusion | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Thermal burn | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Ligament sprain | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
| |
| Glomerular filtration rate decreased | Investigations | MedDRA (19.1) | Systematic Assessment |
| |
| Platelet count decreased | Investigations | MedDRA (19.1) | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA (19.1) | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Paraesthesia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Syncope | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Hypoaesthesia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Presyncope | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Neuralgia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Neuropathy peripheral | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Depression | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Anxiety | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Proteinuria | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Haematuria | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Dysuria | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Urinary retention | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
| |
| Hypotension | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
|
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Ionis Pharmaceuticals, Inc. | Ionis Pharmaceuticals, Inc. | 800-679-4747 | patients@ionisph.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 21, 2017 | Nov 2, 2018 | SAP_001.pdf |
| ID | Term |
|---|---|
| D028227 | Amyloid Neuropathies, Familial |
| D000686 | Amyloidosis |
| ID | Term |
|---|---|
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D009422 | Nervous System Diseases |
| D017772 | Amyloid Neuropathies |
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D028226 | Amyloidosis, Familial |
| D008661 | Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D057165 | Proteostasis Deficiencies |
Not provided
Not provided
| ID | Term |
|---|---|
| C000629536 | Inotersen |
Not provided
Not provided
Not provided
| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Black |
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| White |
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| White & Grayish-Brown |
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| Other |
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| No |
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