Berk 2013.

Methods	Randomised, double‐blind, placebo‐controlled, parallel‐group
Participants	Outpatients Setting: 8 centres in England, Italy, Japan (2 centres), Sweden, and the USA (3 centres) Number: 130 randomised participants (64 in the diflunisal group, 66 in the placebo group) Mean (SD) age: 60.3 ± 11.7 years in the diflunisal group, 59.2 ± 12.2 years in the placebo group Gender: males were 43/64 (67.2%) in the diflunisal group and 44/66 (66.7%) in the placebo group Race: Asian 8/64 (12.5%) in the diflunisal group and 6/66 (9.1%) in the placebo group; Black 1/64 (1.6%) in the diflunisal group and 5/66 (7.6%) in the placebo group; White 52/64 (81.3%) in the diflunisal group and 50/66 (75.8%) in the placebo group; Other 0/64 (0.0%) in the diflunisal group and 1/66 (1.5%) in the placebo group; Multiracial 3/64 (4.7%) in the diflunisal group and 4/66 (6.1%) in the placebo group TTR genotype: Val30Met 36/64 (56.3%) in the diflunisal group and 35/66 (53.0%) in the placebo group; no‐Val30Met 28/64 (43.8%) in the diflunisal group and 31/66 (47.0%) in the placebo group Key inclusion criteria: age 18 to 75 years; biopsy‐confirmed amyloid deposition by Congo Red staining; mutant TTR genopositivity by DNA sequence analysis; signs of sensorimotor or autonomic neuropathy clinically detectable by a trained neurologist; routinely spent more than 50% of waking hours out of bed or chair (Eastern Co‐operative Oncology Group performance status < 3). Key exclusion criteria: alternative causes of sensorimotor polyneuropathy; limited survival prognosis (< 2 years); prior LT; severe congestive heart failure (New York Heart Association class IV) or renal insufficiency (estimated creatinine clearance < 30 mL/min); ongoing anticoagulation
Interventions	Diflunisal 250 mg twice daily (N = 64) Placebo (N = 66) Duration of treatment period: 24 months
Outcomes	Primary outcome: difference in polyneuropathy progression between treatment groups, measured by the NIS+7 scores over a 24‐month period. Secondary outcomes: change from baseline at months 12 and 24 in the NIS and NIS‐LL; change in quality of life assessment from baseline at months 12 and 24 according to the SF‐36; change from baseline at months 12 and 24 in mBMI; change from baseline at months 12 and 24 in the KS.
Funding	Grants from the National Institute of Neurological Diseases and Stroke (grant R01‐NS051306), the Orphan Products Division of the US Food and Drug Administration (grant FD‐R‐002532), the Young Family Amyloid Research Fund, and the National Center for Advancing Translational Sciences, National Institutes of Health (grant UL1‐TR000157). Merck Sharp and Dohme Inc supplied study drug (diflunisal)
Conflicts of interest among main investigators	"Dr. Ole Suhr has received support from Pfizer for activities as Chairman of The Transthyretin Amyloidosis Outcome Survey (THAOS), ISIS, and Alnylam Pharmaceuticals. Dr. Giampaolo Merlini has received honoraria from Pfizer. Dr. Jeffery Kelly reports financial holdings in FoldRx Pharmaceuticals, Inc. Drs. Berk, Obici, Zeldenrust, Litchy, and Dyck have received honoraria from Alnylam, ISIS, and Pfizer Pharmaceuticals."
Notes	ClinicalTrials.gov Identifier: NCT00294671 EudraCT number: 2006‐001066‐16 Information obtained from both published report papers and one online clinical trial registry Duration: 24 months (treatment period) Dates: 2006 to 2012
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were randomly assigned in a 1:1 manner"; "Randomization was performed in permuted blocks of 2 to 4 stratified for mutant TTR (non‐V30M versus V30M) and study site"; "Study drug was prepackaged according to a computer‐generated randomization scheme". Comment: probably done
Allocation concealment (selection bias)	Low risk	Quotes: "randomization was performed in permuted blocks of 2 to 4 stratified for mutant TTR (non‐Val30Met versus Val30Met) and study site"; "Study drug was prepackaged according to a computer‐generated randomization scheme and dispensed by independent investigational pharmacists using sequential study IDs". Comment: probably done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quotes: "Study drug was [...] dispensed by independent investigational pharmacists using sequential study IDs"; "patients, investigators, study coordinators, and investigational pharmacists were unaware of treatment assignments"; "the randomization code was not broken at any time during the study". Comment: probably done
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Study drug was [...] dispensed by independent investigational pharmacists using sequential study IDs"; "patients, investigators, study coordinators, and investigational pharmacists were unaware of treatment assignments"; "the randomization code was not broken at any time during the study". Comment: probably done
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "analysis of missingness completely at random for the primary and secondary outcomes using the permutation test indicated dependence of dropout on the outcome values". Comment: 24 months (primary outcome): 24/64 missing from intervention group and 38/66 missing from placebo group; 67 participants discontinued study treatment before completing the 2‐year protocol (27 from the diflunisal group and 40 from the placebo group). 5 participants in the placebo group and 3 in the diflunisal group discontinued study drug and acquired diflunisal outside the study but completed 2‐year NIS+7 testing. There was a high dropout rate in this RCT.
Selective reporting (reporting bias)	Low risk	Comment: outcome measures declared in the 'methods' section are reported by either published reports, online clinical trial registries, or both.
Other bias	Low risk	Comment: we did not observe any other potential risk of bias. Merck Sharp and Dohme Inc. was only stated to support this trial by providing study drug (diflunisal) and had no role in the design and conduct of the study.