Adams 2018.

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group
Participants	Outpatients Setting: 50 centres, in Argentina, Australia, Bulgaria, Brasil (3 centres), Canada, Cyprus, France (5 centres), Germany (3 centres), Italy (3 centres), Japan (3 centres), Korea (2 centres), Malaysia, Mexico, Netherlands, Portugal (2 centres), Spain (4 centres), Sweden, Taiwan (2 centres), Turkey, UK (2 centres), USA (11 centres) Number: 225 randomised participants (148 in the patisiran group, 77 in the placebo group) Median age (range): 62 years (24 to 83) in the patisiran group, 63 years (34 to 80) in the placebo group Gender: males were 109/148 (74%) in the patisiran group and 58/77 (75%) in the placebo group Race: Asian 27/148 (18%) in the patisiran group and 25/77 (32%) in the placebo group; Black 4/148 (3%) in the patisiran group and 1/77 (1%) in the placebo group; White 113/148 (76%) in the patisiran group and 50/77 (65%) in the placebo group; Other 1/148 (< 1%) in the patisiran group and 0/77 (0%) in the placebo group; Multiracial 2/148 (1%) in the patisiran group and 0/77 (0%) in the placebo group; missing data 1/148 (< 1%) in the patisiran group and 1/77 (1%) in the placebo group TTR genotype: Val30Met 56/148 (38%) in the patisiran group and 40/77 (52%) in the placebo group; non‐Val30Met 92/148 (62%) in the patisiran group and 37/77 (48%) in the placebo group Key inclusion criteria: age 18 to 85 years; a documented pathogenic variant in the TTR gene; a diagnosis of hereditary transthyretin amyloidosis with peripheral neuropathy, with a NIS of 5 to 130 and a PDS of IIIb or lower; adequate liver and renal function. Key exclusion criteria: prior LT or plan to undergo LT during the study period; known human immunodeficiency virus infection; history of malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated; recently received an investigational agent or device; currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid
Interventions	Patisiran 0.3 mg per kg of body weight once every 3 weeks (N = 148) Placebo (N = 77) Intravenous administration Duration of treatment period: 18 months
Outcomes	Primary outcome: change from baseline in mNIS+7Alnylam at 18 month. Secondary outcomes: change from baseline in Norfolk QOL‐DN at 18 months; change from baseline in NIS‐Weakness score at 18 months; change from baseline in R‐ODS score at 18 months; change from baseline in timed 10‐meter walk test at 18 months; change from baseline in mBMI at 18 months; change from baseline in Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score (COMPASS 31)) at 18 months.
Funding	Support from: Alnylam Pharmaceuticals
Conflicts of interest among main investigators	David Adams reported grants from Alnylam during the conduct of the study. Alejandra Gonzalez‐Duarte reported personal fees from Alnylam Pharmaceuticals outside the submitted work. William D O’Riordan reported other support from Alnylam Pharmaceuticals during the conduct of the study. Arnt V Kristen reported personal fees and other support from Alnylam Pharmaceuticals during the conduct of the study. Teresa Coelho reported personal fees and non‐financial support from Alnylam Pharmaceuticals. John L Berk reported personal fees from Alnylam Pharmaceuticals. Michelle M. Mezei reported personal fees from Alnylam during the conduct of the study. Juan Buades reported personal fees and non‐financial support from Alnylam Pharmaceuticals during the conduct of the study. Thomas H Brannagan reported grants from Alnylam during the conduct of the study, as well as personal fees from Alnylam. Yesim Parman reported other support from Alnylam Pharmaceuticals during the conduct of the study. Scott D Solomon reported grants and personal fees from Alnylam during the conduct of the study. Michael Polydefkis reported grants and personal fees from Alnyam Pharmaceuticals during the conduct of the study. Peter J Dyck reported other support from Alnylam, Inc. during the conduct of the study. Pritesh J Gandhi reported personal fees and other support from Alnylam Pharmaceuticals outside the submitted work. Jihong Chen reported personal fees from Alnylam Pharmaceuticals outside the submitted work. Andrew L Strahs reported personal fees from Alnylam Pharmaceuticals outside the submitted work. Saraswathy V Nochur reported personal fees and other support from Alnylam Pharmaceuticals outside the submitted work. Marianne T Sweetser was an employee of Alnylam Pharmaceuticals during the conduct of the study. Pushkal P Garg reported personal fees and other support from Alnylam Pharmaceuticals outside the submitted work. Akshay K Vaishnaw reported personal fees from Alnylam Pharmaceuticals outside the submitted work. Ole B Suhr, MD, PhD reports personal fees and non‐financial support from Alnylam Pharamceuticals during the conduct of the study.
Notes	ClinicalTrials.gov Identifier: NCT01960348 Clinicaltrialsregister.eu Identifier: 2013‐002987‐17 Information obtained from both published report papers and online clinical trial registries Maximum duration of study: 18 months Dates: 2013 to 2017
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote (from report): "patients were randomly assigned in a 2:1 ratio". Quote (from final protocol): "Patients will be randomized via an interactive response system (IRS)"; "Upon signing the informed consent form, the patient will be assigned a screening number by the IRS. The Investigator or his/her delegate will contact the IRS (via phone or web) after confirming that the patient fulfils all the inclusion criteria and none of the exclusion criteria. The patient will be randomized via the IRS, assigned a subject number and a study treatment". Comment: probably done
Allocation concealment (selection bias)	Low risk	Quote (from final protocol): "To maintain the blind, all IV infusion bags and lines will have amber‐colored covers added prior to leaving the pharmacy". Comment: probably done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote (from final protocol): "Only the pharmacist and designated site personnel who dispense or administer study drug will be unblinded to the study treatment. All other site personnel will be blinded to the treatment. Study personnel performing assessments related to the efficacy endpoints will be different from the Investigator and other personnel managing the patient, all of whom will also remain blinded to any clinical laboratory results that could potentially unblind them (e.g., TTR levels, vitamin A levels, thyroid function tests)." Comment: probably done
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote (from final protocol): "An Interim Analysis Committee (IAC), which will include at least 1 statistician (blinded) comprised of 2 statisticians (1 blinded and 1 unblinded) independent of the conduct of the study, will be responsible for the implementation of the interim analysis and for the calculations and recommendations surrounding whether an adjustment to the sample size is warranted, and if so, the appropriate adjustment, based on the study’s primary endpoint data from the interim analysis. The Sponsor, the CROs, and all other parties conducting the study will remain blinded to all interim analyses until study completion. The IAC will follow the procedure outlined in the committee’s charter". Comment: probably done, but it not clear if the sponsor was involved in data analysis.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote (from report): "The modified intention‐to‐treat (ITT) population included all the patients who underwent randomization and received at least one dose of patisiran or placebo". Comment: there are clear data on dropouts.
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 Alnylam Pharmaceuticals.

BMI: body mass index; EE: efficacy‐evaluable; EOT: end of treatment; ITT: intention‐to‐treat; IQR: interquartile range; KS: Kumamoto Score; LT: liver transplantation; mBMI: modified body mass index; mNIS: modified Neuropathy Impairment Score; N: number of participants; NIS: Neuropathy Impairment Score; NIS+7: Neuropathy Impairment Score plus 7 nerve tests; NIS‐LL: Neuropathy Impairment Score in the lower limbs; Norfolk QOL‐DN: Norfolk Quality of Life–Diabetic Neuropathy Questionnaire; PDS: Polyneuropathy Disability Score; R‐ODS: Rasch‐built Overall Disability Scale; RBP4: retinol binding protein 4; RCT: randomised clinical trial; SD: standard deviation; SF‐36: Short Form 36 Health Survey Questionnaire; TTR: transthyretin; TTR‐FAP: transthyretin‐familial amyloid polyneuropathy.