Benson 2018.
Methods | Randomised, double‐blind, placebo‐controlled, parallel‐group | |
Participants | Outpatients Setting: 24 centres, in Argentina, Brazil (3 centres), France (2 centres), Germany, Italy (2 centres), New Zealand, Portugal (2 centres), Spain (2 centres), UK, and USA (9 centres) Number: 173 randomised participants. Efficacy analysis population: 172 participants (112 in the inotersen group, 77 in the placebo group) Mean (SD) age: 59.0 ± 12.5 years in the inotersen group, 59.5 ± 14.0 years in the placebo group Gender: males were 77/112 (69%) in the inotersen group and 41/60 (68%) in the placebo group Race: Asian 1/112 (< 1%) in the inotersen group and 3/60 (5%) in the placebo group; Black 3/112 (3%) in the inotersen group and 1/60 (2%) in the placebo group; White 105/112 (94%) in the inotersen group and 53/60 (88%) in the placebo group; Other or multiracial 3/112 (3%) in the inotersen group and 3/60 (5%) in the placebo group TTR genotype: Val30Met 56/112 (50%) in the inotersen group and 33/60 (55%) in the placebo group; non‐Val30Met 56/112 (50%) in the inotersen group and 27/60 (45%) in the placebo group Key inclusion criteria: age 18 to 82 years, stage 1 or stage 2 TTR‐FAP, NIS of 10 to 130, TTR mutation, documented amyloid deposit determined on biopsy Key exclusion criteria: clinically significant abnormalities in screening laboratory values, Karnofsky performance status of 50 or less, other causes of polyneuropathies besides TTR‐FAP, previous LT, heart failure of New York Heart Association class III or higher |
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Interventions |
Subcutaneous administration; participants received three subcutaneous injections on alternate days during the first week to reach near steady‐state drug levels, followed by one subcutaneous injection once weekly for the next 64 weeks Participants also received vitamin A supplements (approximately 3000 IU daily) |
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Outcomes | Primary outcomes (time point: week 66):
Secondary outcomes (time point: week 66):
Other assessments (safety evaluation):
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Funding | Funded by Ionis Pharmaceuticals, Inc | |
Conflicts of interest among main investigators | Merrill D Benson reported other support from Ionis Pharmaceuticals during the conduct of the study, as well as personal fees and non‐financial support from Ionis Pharmaceuticals outside the submitted work. Márcia Waddington‐Cruz reported grants and personal fees from Ionis Pharmaceuticals during the conduct of the study. John L Berk reported personal fees and non‐financial support from Alnylam Pharmaceuticals outside the submitted work. Michael Polydefkis reported grants and non‐financial support from Ionis Pharmaceuticals during the conduct of the study. Peter J Dyck reported other support from Ionis Pharmaceuticals, Inc. during the conduct of the study. Annabel K Wang reported personal fees and other support from Ionis Pharmaceuticals, Inc. during the conduct of the study. Violaine Planté‐Bordeneuve reported personal fees and non‐financial support from Ionis Pharmaceuticals during the conduct of the study. Fabio A Barroso reported grants, personal fees and non‐financial support from Ionis during the conduct of the study. Thomas H Brannagan reported grants and personal fees from Ionis during the conduct of the study. William J Litchy reported other support from Ionis Pharmaceuticals, Inc. during the conduct of the study. David Adams reported other support from Ionis during the conduct of the study. Amil M Shah reported grants from Ionis Pharmaceuticals during the conduct of the study. Scott D Solomon reported grants from Ionis during the conduct of the study. Brett P Monia reported other support from Ionis during the conduct of the study. Steven G Hughes reports personal fees and other support from Ionis Pharmaceuticals, Inc. outside the submitted work. T Jesse Kwoh reported personal fees and other support from Ionis Pharmaceuticals, Inc. outside the submitted work. Bradley W McEvoy personal fees and other support from Ionis Pharmaceuticals, Inc. outside the submitted work. Shiangtung W Jung reported personal fees and other support from Ionis Pharmaceuticals, Inc. outside the submitted work. Brenda F Baker reported personal fees and other support from Ionis Pharmaceuticals, Inc. outside the submitted work. Elizabeth J Ackermann reported personal fees and other support from Ionis Pharmaceuticals, Inc. outside the submitted work. Morie A Gertz reported personal fees from Ionis. Teresa Coelho reported non‐financial support and other from Ionis during the conduct of the study. |
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Notes | ClinicalTrials.gov Identifier: NCT01737398 Clinicaltrialsregister.eu: 2012‐001831‐30 Information obtained from both published report papers and one online clinical trial registry Maximum duration of study: 66 weeks: 65 weeks (treatment period), 1 week (post‐intervention evaluation) Dates: 2013 to 2017 |
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Risk of bias | ||
Bias | Authors' judgement | Support for judgement |
Random sequence generation (selection bias) | Low risk | Quote (form report): "Patients were randomly assigned, in a 2:1 ratio", Quote (from the final protocol): "Using an Interactive Voice/Web‐Response System (IXRS), eligible patients will be randomized 2:1 to receive ISIS 420915 or placebo, respectively"; "A permuted block schedule will be used". Comment: probably done |
Allocation concealment (selection bias) | Low risk | Quote (from the final protocol): "The Study Drug is contained in stoppered glass vials and will be provided to the Study Center by the Sponsor. The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with specific country regulatory requirements". Comment: probably done |
Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote (from the final protocol): "The Sponsor, participants, monitors, and Study Center personnel will be blinded throughout the study until all participants have completed the treatment period and the EOT [end of treatment] efficacy assessments, and the database has been locked"; "In order to ensure maintenance of the study blind, TTR, RBP4, and retinol values will not be available to the Sponsor, monitors, Investigators, Study Center Personnel, or the participants." Comment: probably done |
Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Quote (from report): "the sponsor (Ionis Pharmaceuticals) was responsible for data analysis". Quote (from the final protocol): "The Sponsor, participants, monitors, and Study Center personnel will be blinded throughout the study until all participants have completed the treatment period and the EOT efficacy assessments, and the database has been locked"; "In order to ensure maintenance of the study blind, TTR, RBP4, and retinol values will not be available to the Sponsor, monitors, Investigators, Study Center Personnel, or the participants". Comment: probably done, but data analysis was conducted by the sponsor |
Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Comment: efficacy analyses included all randomly assigned participants who received at least one dose of a trial regimen and who had at least one post‐baseline efficacy assessment for the mNIS+7 Ionis version or the Norfolk QOL‐DN score. There was no clear mention of ITT analysis. |
Selective reporting (reporting bias) | Low risk | Comment: results for all predetermined outcomes were obtained by either published report papers, online clinical trial registries, or both. |
Other bias | Unclear risk | This study was fully supported by Ionis Pharmaceuticals. |