Tesfaye 2013.

Study characteristics
Methods	Design: parallel Duration: 8 weeks Assessment: baseline to post‐intervention Country: Australia, Canada, Croatia, France, Germany, Greece, Italy, South Korea, Mexico, Netherlands, Poland, Spain, Sweden, Switzerland, Turkey, UK
Participants	Pain condition: diabetic neuropathy Population: adults with diabetes type 1 or 2 and diabetic neuropathy Minimum pain intensity: ≥ 4 on 0‐10 scale Inclusion criteria Pain due to bilateral peripheral neuropathy caused by type 1 or type 2 diabetes mellitus, beginning in the feet in a relatively symmetrical fashion Daily pain should have been present for at least 3 months and the diagnosis had to be confirmed by a score of ≥ 3 on the MNSI at screening 24‐hour average pain severity of ≥ 4 on BPI Exclusion criteria Any suicidal risk as judged by the investigator or as defined by a score of ≤ 2 on item 9 of the BDI II Total participants randomised: 811 Age in years (mean): 61.7 Gender: 356/804 were female Pain duration in years (mean, SD): NR
Interventions	Duloxetine 60 mg n = 401 SNRI Fixed dose, forced titration Pregabalin 300 mg n = 403 Anticonvulsant Fixed dose, forced titration Identical capsules to duloxetine
Outcomes	Pain intensity Physical function Mood Moderate pain relief Substantial pain relief PGIC AEs SAEs Withdrawal
Missing data methods	ITT with LOCF
Funding source	Pharmaceutical: The sponsor, Eli Lilly & Company (Indianapolis, IN, USA), was involved in study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the paper for publication.
Conflicts of interest	The sponsor, Eli Lilly & Company (Indianapolis, IN, USA), was involved in study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the paper for publication. Stefan Wilhelm, Alexander Schacht, and Vladimir Skljarevski own stock in and are Lilly employees. Alberto Lledo, former Lilly employee, owns Lilly stocks. Solomon Tesfaye, Thomas T√∂lle, Didier Bouhassira, Giorgio Cruccu, and Rainer Freynhagen have received economic compensation for participation in the Lilly EU Pain Advisory Board. Solomon Tesfaye declares having received honoraria for invited lectures from Eli Lilly & Company and Pfizer Inc. Thomas Tolle reports consultancy and invited lectures for Grunenthal, Mundipharma, Biogen Idec, Hexal, Pfizer Inc., Janssen‐Cilag, Astellas, Pharmaleads, Boehringer‐Ingelheim, Eli Lilly & Company, and Esteve. Didier Bouhassira has served on the Speakers‚Äô Bureau for Eli Lilly & Company, Pfizer Inc., and Astellas, and has worked as a consultant to Eli Lilly & Company, Pfizer Inc., Sanofi‐Aventis, SanofiPasteur‐MSD, Astra Zeneca, and Astellas and has received research support from Pfizer Inc. Giorgio Cruccu has received fees for advisory boards and for lectures by Astellas, Eli Lilly & Company, and Pfizer Inc. Rainer Freynhagen has received consultancy and speaker fees in the past 12 months from Astellas, Epionics, Grunenthal, Forrest Research, HRA, Eli Lilly & Company, and Pfizer. All authors have made substantial contribution to conception and design of the COMBO‐DN study, or analysis or interpretation of the data or revising the manuscript critically for important intellectual content. Alberto Lledo was responsible for generating the primary hypothesis of the study and reviewed the manuscript critically. Solomon Tesfaye, Thomas Tolle, Didier Bouhassira, Giorgio Gruccu, and Rainer Freynhagen were involved in the early conception of the study, the selection of the primary and secondary objectives and the final review of the manuscript. Alexander Schacht was responsible for building the final statistical plan. Stefan Wilhelm and Alexander Schacht were responsible for data collection and extraction and completion of the final study report. Solomon Tesfaye and Stefan Wilhelm wrote the primary version of the manuscript and Vladimir Skljarevski reviewed the manuscript critically with regard to interpretation of the data.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"At the start of the initial therapy period, patients were randomised in a 1:1:1:1 ratio to 4 parallel groups stratified by site, based on a computer‐generated sequence"
Allocation concealment (selection bias)	Low risk	Participants were allocated using a centralised interactive voice response system.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind, identical study drugs, matched dosing
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Self‐reported outcomes from blinded participants
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT with LOCF Attrition Total: 138/811 (17.1%) Pregabalin 300 mg: 70/403 (17.4%) Duloxetine 60 mg: 68/401 (17.0%)
Selective reporting (reporting bias)	Low risk	Outcomes match trial registration
Other bias	Low risk	No other sources of bias identified