Campbell 2012.

Study characteristics
Methods	Randomised, double‐blind, multicentre (USA), parallel‐group study, 12‐week treatment period Study consists of a screening phase (28 ± 7 days), baseline phase (7 days), treatment phase, and follow‐up period. During screening phase, nociceptor function was tested by determining pain response to 0.1% topical capsaicin applied to the pretibial area of each participant for 30 minutes.
Participants	Inclusion criteria: Age between 18 and 80 years Established diagnosis of diabetes (type 1 or 2) with pain attributable to a symmetrical stocking distribution neuropathy in lower extremities Average daily pain score ≥ 4 on an NRS scale in the area of PDN Neuropathic pain lasting 6 months to 5 years before screening Stable glycaemic control regimen ≥ 3 months Stable analgesic regimen ≥ 21 days before randomisation Willingness to maintain current medication at the same dose throughout the study Exclusion criteria: Other chronic pain with greater intensity than PDN Other chronic pain within the region of PDN Any serious or unstable medical or psychological condition Hypotension History of illicit drug or alcohol abuse within a year Pregnant or lactating females, planning to become pregnant, or using unreliable means of birth control Cognitive or language difficulties that would impair understanding/completion of assessment instruments Receipt of other experimental drugs within 2 months of randomisation Prior use of TC gel Open lesions or skin conditions in the area of gel application Known sensitivity or intolerance to clonidine Number of patients screened: 464 Number of randomly assigned patients (C/P): 182 (91/91) Number of participants who received allocated intervention (C/P): 180 (90/90) Mean age (C/P): 59.4/57.6 years Number of males (C/P): 44/42 Duration of foot pain (years ± SD; C/P): 3.0 ± 1.3/2.9 ± 1.3 Mean baseline pain (0‐to‐10 NRS ± SD; C/P): 6.4 ± 1.4/6.5 ± 1.5
Interventions	Intervention group: clonidine gel 650 µg per foot, 3 times daily, concentration 0.1% self administered on both feet (n = 91) Control group: matching placebo (n = 91) 464 participants were screened, 182 were randomly assigned (91/91), 90 participants in both groups received allocated intervention (1 participant in each group was found to be ineligible after randomisation), 1 participant in the clonidine group was excluded from analysis because no baseline NRS score was available. Intention‐to‐treat population: clonidine 89/placebo 90 Discontinuation: participants lost to follow‐up: C: 3/P: 4; withdrawal of participant consent: C: 1/P: 1; protocol violation: C: 2/P: 4; adverse events: C: 1/P: 3; lack of efficacy: C: 1/P: 1
Outcomes	Participants with > 30% pain reduction Participants with > 50% pain reduction Avarage pain severity Brief Pain Inventory: severity scale, average pain, functional interference scale Chronic Pain Sleep Inventory: overall seep quality Clinician and Patient Global Impressions of Change: overall change in pain status Hospital Anxiety and Depression Scale: anxiety scale, depression scale Adverse events
Notes	Conducted in the USA, tertiary care setting (university hospital) No information on how the patients were recruited Participants discontinued use of "as needed" pain medications other than paracetamol, daily pain medications were continued on stable daily dosing. 97 participants underwent a 3‐millimetre skin punch biopsy performed to quantify intraepidermal nerve fibre density. Duration of pain (years): TC 3.0/capsaicin 2.9 Funding: the study was supported by biotechnology company, Arcion Therapeutics Conflict of interest of study authors: CMC was awarded a travel grant from Arcion to present and attend the Neuropathic Pain Conference in 2008. BS, MK, and WKS consult for Arcion. KB and JNC are employed by Arcion. The other authors have no conflicts of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation in blocks with stratifications with regard to baseline pain severity
Allocation concealment (selection bias)	Unclear risk	There is no information about allocation concealment in the study, although there is also no information suggesting that allocation concealment was absent or done improperly.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo formulation was identical in appearance, consistency, packaging, and labelling.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No detailed information on method of blinding of outcome assessment provided in the study, although there is also no information suggesting that blinding of outcome assessment was done improperly or not performed
Incomplete outcome data (attrition bias) All outcomes	Low risk	Baseline observation carried forward in cases of missing results
Selective reporting (reporting bias)	Low risk	Study protocol available, results for all outcomes listed in the protocol presented in a clear way.
Study size	Unclear risk	Size of study: more than 50 and fewer than 199 participants per treatment arm
Funding bias	High risk	The study was supported by biotechnology company, Arcion Therapeutics.