Abstract
BACKGROUND: Fatigue is highly prevalent in adults with multiple sclerosis (MS) and current treatments offer limited benefit. It has been speculated that placebos only have an effect when they are administered with deception and concealment, which is unethical in clinical practice. Recent studies suggest that ethically informed, open-label placebos (OLP) can produce symptomatic benefits. As such, we primarily sought to investigate the feasibility and secondarily assess the preliminary effects of OLP to treat MS fatigue. METHODS: Feasibility outcomes including accrual, retention, and OLP adherence estimates were assessed in this 21-day assessor blinded, RCT. We compared results of assignment to three conditions: (1) OLP with a positive expectancy for beneficial effects along with the prescription to take 2 placebo pills twice a day (OLP), (2) positive expectancy (EXP) for beneficial placebo effects, or (3) a usual care only (UCO). We considered the study to be feasible if progression criteria, including the enrollment target of 48 participants, retention target of > 80% participants, and OLP adherence target of > 90%, were met. As secondary analyses, we provide descriptive statistics and crude linear mixed models (LMM) based estimates to assess the change in fatigue (assessed via Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)) at days 21, 28, and 35 versus baseline with corresponding 95%, 85%, and 75% confidence intervals. RESULTS: One-hundred and eight adults with MS were screened of which 48 were randomized (16 per group). Retention rate was 98% with one participant being lost to follow-up. Placebo adherence was over 90%. At day 21, 7 of 9 (78%) randomized to OLP considered prescribing placebos to treat fatigue as "moderately-to-completely" acceptable. Next, the LMM based change in FSS mean score at day 21 with respect to baseline in the OLP and EXP group versus UCO group was about 0.6 units lower (95% CI: - 1.206, - 0.003; - 1.301, - 0.065, respectively). CONCLUSIONS: OLP was deemed feasible and acceptable by most participants and there was mild evidence that, compared to UCO, it may reduce fatigue severity in adults with MS. Larger trials of OLP are required to determine whether OLP might be a viable treatment for MS fatigue. TRIAL REGISTRATION NUMBER: NCT04002102 ( https://clinicaltrials.gov/show/NCT04002102 , 2019); registered 30 September 2019.