Title: Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM) trial
Funder: Department of Health and Social Care

Abstract: DESIGN: Multicentre, double-blind, crossover RCT of Treatment Pathways (TP) for diabetic peripheral neuropathic pain (DPNP). Each TP has 2 periods (6-week monotherapy followed by 10-week combination therapy: amitriptyline followed by pregabalin; pregabalin followed by amitriptyline and duloxetine followed by amitriptyline). Eligible patients will be randomised to 1 of 6 treatment sequences. Each sequence will examine all 3 TPs in stratified order. An internal pilot will be incorporated assessing recruitment and retention feasibility, with stop/go criteria at 6 and 12 months into recruitment. SETTING: 8 DPNP hospital centres aligned with 80 primary care practices in the UK. TARGET POPULATION: Primary/secondary care DPNP patients >/=18 yrs old. INCLUSION: Daily pain for > 3 months, neuropathy confirmed by Michigan Neuropathy Screening Instrument (MNSI) score >/= 3, Douleur Neuropathique 4 (DN4), numeric rating scale (NRS) 24-hour average pain of >/=4, stable diabetes control (A1c<108mmol/mol). EXCLUSION: Significant cardiovascular/liver disease, non-diabetic neuropathies, alcohol/substance abuse, major psychiatric disorders, contraindications to study medications, pregnancy/breast feeding. HEALTH TECHNOLOGIES TO BE ASSESSED: Patients will be randomised 1:1:1:1:1:1 to 6 parallel sequences stratified by site and titrated to maximum tolerated dose. Treatment response will be assessed by 7-day average 24-hr NRS score at the end of monotherapy. Patients with scores </=3 will be considered "responders" and will remain on monotherapy during follow-up (10 weeks). "Non-responders" (NRS>3) will receive the second agent in combination. Patients intolerant of monotherapy (or with no change in pain score) will be switched to the 2nd agent. Before starting the next TP, the study drug will be tapered down (3 days) and washed out (4 days). Blinding will be maintained with over-encapsulated drugs, matching placebo and identical dosing regimen for all groups. PRIMARY OUTCOME MEASURE: 7-day average 24-hour pain on NRS (0=no pain; 10=worse pain imaginable) during the final follow-up week. SECONDARY OUTCOME MEASURES: Head- to-head comparison of monotherapy, BPI-MSF measure of pain interference with function, mood assessed by BDI and HADS, health status assessed by SF-36, sleep duration and quality examined using diaries, responder rates analysis (30% and 50% pain relief), EuroQoL-5D-5L, Patient Global Impression of Improvement (PGI-I) modified health resource questionnaire based on Client Service Receipt Inventory (CSRI) to capture health resources used. Adverse events and serious adverse events will be assessed. The relationship of pain phenotype to treatment response will be assessed using Neuropathic Pain Symptom Inventory (NPSI). SAMPLE SIZE: A 0.5 mean change between groups represents an 8% increase in the proportion of subjects improving by at least 1 point (the MCID in an individual). Using 0.5 change, within subject SD of 1.65, two sided significance level of 0.0167, and 90% power, assuming 25% attrition, we require 392 subjects. ANALYSIS: The primary outcome and other continuous outcomes will be analysed using a mixed model with patient, treatment, sequence and period entered into the model. Patient will be entered as a random term. Contrasts will be used to evaluate the difference in means. HEALTH ECONOMICS: A cost-utility analysis will be conducted. QALYs will be calculated using the EQ-5D-5L. An NHS and PSS perspective for costs will be taken, with personal and societal costs included within a sensitivity analysis. The analysis will be reported to the NICE reference case standard. The main outcome will be incremental cost per QALY gained.

Lay abstract: The number of people with diabetes is growing rapidly in the UK and is predicted to increase from 3.2 million in 2013 to 5 million by 2025. Unfortunately diabetes causes nerve damage that causes severe painful symptoms in the feet, legs and hands. One quarter of all people with diabetes experience these symptoms, known as “painful diabetic neuropathy”. Patients may present with burning, aching or “electric-shock” type pains. In some patients normal touch by day time or bed cloths can cause severe pain as the skin becomes extremely sensitive to touch. As the pain is felt every day, patients may have difficulty doing simple daily activities such as walking to the shop or socializing with friends. This results in a poor quality of life and depression. Unfortunately current individual medications provide only partial benefit in around of half of all patients, with many enduring inadequate pain relief and unwanted reactions. Not surprisingly therefore, many patients are frustrated with not being able to work and too many visits to see the doctor. The negative impact on them, their families and the NHS is considerable. The National Institute for Heath and Care Excellence (NICE) recommends a choice of four drugs; amitriptyline, duloxetine, pregabalin or gabapentin, as initial treatment for painful diabetic neuropathy. If the initial treatment is not fully effective NICE recommends adding one of the other drugs in combination with the first drug. However, the NICE highlighted that: 1) these individual drugs haven’t been compared against each other to see which one is the best and 2) the different combinations of these drugs have also not been compared against each other. In the proposed study we aim to find out the most effective initial treatment and then the best additional treatment for patients with painful diabetic neuropathy. This will improve patient care and quality of life. This will also benefit doctors treating patients with painful diabetic neuropathy and the NHS, as improved pain management reduces GP and hospital visits. This study will compare 3 treatment pathways using amitriptyline, duloxetine and pregabalin and their combinations. Gabapentin was excluded as: the evidence for gabapentin is only derived from one reasonable quality trial compared to 8 in pregabalin; gabapentin is a trice daily drug; and gabapentin, unlike pregabalin requires a long titration period to avoid toxicity. 392 patients from 8 hospitals clinics and 80 GP practices will be recruited. The investigators at each centre are specialists in diabetes and the treatment of painful diabetic neuropathy, and have experience in recruiting suitable patients for the study. Patients will be allocated to one of three treatment pathways starting with either amitriptyline, duloxetine or pregabalin for 6 weeks and for people still in pain, another drug added for a further 10 weeks. Each patient will go through all three treatment pathways. The total length of the study for each patient will be one year. During this period patients will be contacted by telephone or seen in hospital on 26 occasions. Study medications will be started at a low dose and increased gradually to the right dose for the patient. Throughout the study, response to treatment will be measured using pain diaries which patients will be asked to complete. We will also use measures of quality of life, mood, sleep and reactions to the drug, using special questionnaires. The value for money of each treatment pathway will also be measured. In summary, we hope this trial will tell us what the most effective treatment is for nerve damage causing pain in people with diabetes.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE