Multicentre, double-blind, crossover trial to identify the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM): study protocol for a randomised controlled trial

Abstract

Background: The number of people with diabetes is growing rapidly. Diabetes can cause nerve damage leading to severe pain in the feet, legs and hands, which is known as diabetic peripheral neuropathic pain (DPNP). In the UK, the National Institute for Health and Care Excellence (NICE) recommends amitriptyline, duloxetine, pregabalin or gabapentin as initial treatment for DPNP. If this is not effective, adding one of the other drugs in combination with the first is recommended. NICE points out that these recommendations are not based on robust evidence. The OPTION-DM randomised controlled trial has been designed to address this evidence deficit, with the aims of determining the most clinically beneficial, cost-effective and tolerated treatment pathway for patients with DPNP.

Methods/design: A multicentre, double-blind, centre-stratified, multi-period crossover study with equal allocation to sequences (1:1:1:1:1:1) of treatment pathways. Three hundred and ninety-two participants will be recruited from secondary care DPNP centres in the UK. There are three treatment pathways: amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline and duloxetine supplemented with pregabalin. All participants will receive all three pathways and randomisation will determine the order in which they are received. The primary outcome is the difference between 7-day average 24-h pain scores on an 11-point NRS scale measured during the final follow-up week of the treatment pathway. Secondary outcomes for efficacy, cost-effectiveness, safety, patient-perceived tolerability and subgroup analysis will be measured at week 6 and week 16 of each pathway.

Discussion: The study includes direct comparisons of the mainstay treatment for DPNP. This novel study is designed to examine treatment pathways and capture clinically relevant outcomes which will make the results generalisable to current clinical practice. The study will also provide information on health economic outcomes and will include a subgroup study to provide information on whether patient phenotypes predict response to treatment.

Trial registration: ISRCTN17545443 . Registered on 12 September 2016.

Keywords: Amitriptyline; Crossover trial; Diabetes; Duloxetine; Painful diabetic neuropathy; Pregabalin.

Fig. 1

Participant flow

Fig. 2

a Dosing and titration schedule for each treatment pathway (standard pregabalin dosing, estimated glomerular filtration rate (eGFR) ≥ 60 ml/min). *Participants continue on the maintenance dose of drug from the first treatment phase for the duration of the second treatment phase. b Dosing and titration schedule for each treatment pathway (reduced pregabalin dosing, eGFR 30–59 ml/min). *Participants continue on the maintenance dose of drug from the first treatment phase for the duration of the second treatment phase

Fig. 3

Study assessment schedule (Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure). ^aThis visit is only required prior to randomisation, i.e. before starting the first treatment pathway. ^b Between scheduled study visits, the research nurse will contact the participant by telephone each week (a minimum of once per week). The nurse will confirm compliance with medication and remind the participant to complete study diaries/questionnaires. ^c Visits must normally be within ± 2 days of the scheduled visit date. Scheduled visit dates relate to the date of the previous visit. Where this is impossible, e.g. due to bank holidays or patient availability. ^d Week-8 visit only required for participants on combination treatment. ^e At the week-16 visit, participants will be given instructions to tape-off the current study treatment. Visits from week 0 to week 16 will be repeated until all 3 pathways have been completed. ^f Week 17 is only applicable following the final pathway. ^g FBC, urea and electrolytes, liver function tests, glycosylated haemoglobin A1c and serum creatinine. ^h hole blood sample to be collected and stored for future research. The sample can be obtained at the same time as any scheduled blood test for the study. Please refer to the OPTION-DM Sample Collection Manual for details. ⁱ Height (at week − 2 only), weight, heart rate and blood pressure (lying and standing). ^j To be completed by participants daily during the study, starting during the washout period. Pain scores may also be collected via daily text messages where participants have given additional consent for this. ^k Only required at week 0 of pathway 1, i.e. randomisation visit. ^l.Not required at week 0 of pathway 1, i.e. randomisation visit