Hudson 2021.

Study characteristics
Methods	Design: parallel Duration: 14 weeks Assessment: baseline and post‐intervention Country: New Zealand
Participants	Pain condition: knee OA Population: people with knee OA on a stable analgesic regime Minimum pain intensity: ≥ 20 out of 50 on WOMAC pain subscale Inclusion criteria Primary knee OA defined according to ACR classification criteria ≥ 20 out of 50 on WOMAC pain subscale Stable analgesic regime for 2 months before study entry Exclusion criteria Prior joint replacement on study knee Sensitivity to nortriptyline or other TCAs Cardiovascular conditions Bipolar disorder Total participants randomised: 205 Age in years (mean): 64.5 Gender: 87/205 were female Pain duration in years (mean): 7.6
Interventions	Placebo n = 103 Inert Identical appearance and matched dosing schedule Nortriptyline ≤ 100 mg n = 102 TCA Flexible dosing dependent upon efficacy and tolerability Mean dose: 55.8 mg/day
Outcomes	Pain intensity Physical function Mood AEs SAE Withdrawal
Missing data methods	Imputation using multivariate normal multiple imputation
Funding source	Non‐pharmaceutical: project grant from the Health Research Council of New Zealand (reference number: 14/152).
Conflicts of interest	The authors have declared no competing interests
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised with a 1:1 allocation, computer‐generated randomisation list with blocks of varying size (1‐4) was prepared by the study statistician (https://cran.r‐project. org/web/packages/blockrand/index.html).
Allocation concealment (selection bias)	Low risk	The contracted pharmacist will determine which group of participants, A or B, will be allocated to receive nortriptyline. The study medication (nortriptyline or identical placebo) will be packaged in identical containers. Each container will be pre‐labelled (by the study pharmacist contracted to provide the study medication) with a study identifier according to randomisation schedule.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, identically appearing study drugs, matched dosing schedules
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Self‐reported outcomes from blinded participants
Incomplete outcome data (attrition bias) All outcomes	Low risk	Very low dropout with no data collection at follow‐ up (4/205). Multiple imputation for missing data Attrition Total: 4/205 (2.0%) Placebo: 1/103 (1.0%) Nortriptyline 25‐100 mg: 3/102 (2.9%)
Selective reporting (reporting bias)	Low risk	Published trial protocol: https://trialsjournal.biomedcentral.com/track/pdf/10.1186/s13063‐015‐0961‐1.pdf. All outcomes reported or reasons for no further analysis given. Although there was an error collecting data at baseline for the first 24 participants, this was reported and accounted for in the analysis.
Other bias	Low risk	No other sources of bias were identified.