PRECISE trial (Pain RElief Combination Intervention StratEgies): protocol for the clinical trial of a pregabalin-melatonin combination for fibromyalgia.

INTRODUCTION:Fibromyalgia is associated with chronic widespread pain and disturbed sleep. Multidisciplinary, multimodal management often includes pharmacotherapy; however, current drugs used to treat fibromyalgia provide meaningful benefit to only 30-60% of treated individuals. Combining two or more different drugs is common in clinical practice with the expectation of better efficacy, tolerability or both; however, further research is needed to identify which combinations actually provide added benefit. Thus, we are planning a clinical trial to evaluate melatonin (MLT)-pregabalin (PGB) combination in participants with fibromyalgia. METHODS AND ANALYSIS:This will be a single-centre, double-blind, randomised, double-dummy, three-period, crossover trial comparing a MLT-PGB combination to each monotherapy in 54 adult participants satisfying the 2016 American College of Rheumatology criteria for fibromyalgia. Participants will receive maximally tolerated doses of MLT, PGB and MLT-PGB combination for 6 weeks. The primary outcome will be daily pain intensity (0-10); secondary outcomes will include the Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events and other measures. Analysis of the primary and secondary outcomes will involve a linear mixed model with sequence, period, treatment, the first-order carryover and baseline pain score as fixed effects and participant as a random effect to test whether there are any treatment differences among three treatments and to estimate the least square mean of the mean daily pain intensity for each treatment, adjusting for carryover as well as period effects (ie, stability of pain levels). ETHICS AND DISSEMINATION:This trial has been registered with the International Standard Randomised Controlled Trial Number Registry, ISRCTN #18278231, has been granted ethical approval by the Queen's University Health Sciences Research Ethics Board (Queen's HSREB Protocol #6040998) and is currently under review for a Clinical Trial Application to Health Canada Natural and Non-prescription Health Products Directorate. All participants will provide written informed consent prior to trial participation. Following trial completion, results will be disseminated in one or more biomedical journal publications and presented at one or more scientific meetings. TRIAL REGISTRATION NUMBER:This trial has been registered with the International Standard Randomised Controlled Trial Number Registry, ISRCTN18278231.