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. 2020 Apr 20;2020(4):CD012395. doi: 10.1002/14651858.CD012395.pub2

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
Interventions
  • Inotersen 300 mg once weekly (N = 112)

  • Placebo (N = 60)


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)
Outcomes Primary outcomes (time point: week 66):
  • change from baseline in the mNIS+7Ionis score;

  • change from baseline in the Norfolk QOL‐DN total score.


Secondary outcomes (time point: week 66):
  • change from baseline in the mBMI and BMI;

  • change from baseline in the mNIS+7 individual components;

  • change from baseline in the NIS+7;

  • change from baseline in transthyretin and retinol binding protein 4.


Other assessments (safety evaluation):
  • adverse events;

  • clinical laboratory tests;

  • vital signs;

  • 12‐lead electrocardiography;

  • electroretinography.

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.
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
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.