|Methods||A multicentre, double-blind, placebo-controlled, randomised, parallel-group, dose-ranging study to evaluate the efficacy and safety of three daily doses of oral oxcarbazepine (600, 1200, and 1800 mg) as monotherapy for painful diabetic neuropathy. It consisted of a 2-week pre-randomisation screening phase and a 16-week double-blind phase (including a 4-week titration period and a 12-week maintenance period).|
|Participants||A total of 347 participants with painful diabetic neuropathy were included and randomised in a 1:1:1:1 ratio to oxcarbazepine 600 mg/day (300 mg bid; n = 83), 1200 mg/day (600 mg bid; n = 87), 1800 mg/day (900 mg bid; n = 88), or placebo (n = 89).|
Gender (% male) 600 mg, 900 mg, 1200 mg oxcarbazepine and placebo: 60%; 52%; 53%; 56%. Mean age, years (SD) 600 mg, 900 mg, 1200 mg oxcarbazepine and placebo: 61.1 (10.7); 60.3 (10.3); 59.3 (9.3); 62.1 (10.3).
Inclusion criteria: men and non-pregnant women; 18 years of age or older; with a diagnosis of diabetes mellitus (type 1 or 2) and pain attributed to diabetic neuropathy for 6 months to 5 years; with a pain rating score of at least 50 units on a 100-unit VAS at the screening visit, stable glycaemic control (as evidenced by a HbA1c level of ≤11% at baseline), and baseline serum sodium levels of 35 mmol/L or higher; the VAS must have averaged at least 40 units during the pre-randomisation phase, with < 25% variability in the last 7 days prior to randomisation.
Exclusion criteria included: people with other types of pain; clinically significant medical or psychiatric illnesses; a prior history of hyponatraemia or non-compliance; drug or alcohol abuse in the preceding year; amputations other than the toes; treatment with lithium or monoamine oxidase inhibitors; previous treatment with oxcarbazepine; a history of sensitivity to carbamazepine or its metabolites.
|Interventions||Participants received the initiated dose of 300 mg oxcarbazepine (one tablet) or matching placebo daily for three days, then one tablet bid from the fourth day. Thereafter, the dose was increased by one tablet every 5 days until the target dose of 600 mg/day, 1200 mg/day or 1800 mg/day for each group was reached. Dose reductions due to tolerability problems were allowed at any time during the study.|
|Outcomes||The primary outcome was change in mean VAS score from baseline to the end of the study (16 weeks).|
Secondary outcomes included participants' Global Assessment of the Therapeutic Effect, onset of therapeutic effect, durability of treatment effect, sleep disturbances, and quality of life.
Safety was also assessed during the screening and double-blind treatment phases, consisting of monitoring vital signs, neurological and physical examinations, laboratory parameters, spontaneous reports of adverse events, and serious adverse events.
|Notes||Trial conducted between November 2001 and September 2003 at 37 centres across the United States. This study was funded by Novartis Pharmaceuticals Inc.|
|Risk of bias|
|Bias||Authors' judgement||Support for judgement|
|Random sequence generation (selection bias)||Low risk||The study is similar to the Dogra study so it is likely that randomisation was adequate.|
|Allocation concealment (selection bias)||Low risk||The study is similar to the Dogra study so it is likely allocation concealment have been performed.|
|Blinding (performance bias and detection bias) |
|Low risk||It was stated that there was a double-blind phase, and matching placebos were used.|
|Incomplete outcome data (attrition bias) |
|High risk||Missing data of both groups were clearly described and an ITT analysis was performed. The number of withdrawals was not balanced across different doses of oxcarbazepine and placebo groups (respectively 16/83 at 600 mg/day oxcarbazepine, 34/87 at 1200 mg/day, 48/88 at 1800 mg/day, and 17/89 of participants on placebo), especially those due to adverse events (respectively 9/83, 20/87, 36/88, and 6/89 in each group).|
|Selective reporting (reporting bias)||Low risk||Outcomes listed in the methods section were all reported.|
|Other bias||Low risk||No other potential bias was found.|