Title: Sarcoidosis and Fatigue: A feasibility study of the treatment of fatigue in sarcoidosis with methyphenidate
Funder: Department of Health and Social Care

Abstract: Background Fatigue in sarcoidosis is a common and important problem for patients, and a difficult symptom to treat. It occurs independently of disease activity. Fatigue significantly impairs the quality of life of patients, many of whom are of working age. I have conducted a cross-sectional questionnaire study of 76 patients with sarcoidosis in Norwich, which showed that 50.7% had clinically relevant fatigue compared to 8.6% of 76 age-matched controls using the Fatigue Assessment Scale (FAS), and that higher levels of fatigue leads to impaired quality of life. Methylphenidate, a neurostimulant, has been shown to be effective at treating fatigue in HIV and, as evidenced in a Cochrane review, post-chemotherapy for various cancers. Case histories and one small cross-over study have suggested that methylphenidate can improve fatigue in sarcoidosis and is well-tolerated, but data is limited. In order to design a viable RCT investigating methylphenidate in treating sarcoidosis-associated fatigue a feasibility study is required. Objectives I will determine the feasibility of a large-scale trial to evaluate the effectiveness and cost effectiveness of methylphenidate for the treatment of sarcoidosis-associated fatigue. I will explore the acceptability of undertaking the definitive study from patient and healthcare professional viewpoints using both quantitative and qualitative measures, and the suitability of the chosen end-points for a larger trial. Design This double-blind, randomised feasibility trial, with health economic and qualitative assessment, will randomize 30 patients on a 1.5:1 ratio to receive methylphenidate or placebo for a 6 month period. Patients diagnosed with sarcoidosis, following multidisciplinary team discussion and fatigue assessment scale showing scores greater than 21 units without evidence of sleep apnoea, will be randomized into the study. Dose escalation will occur every 2 weeks (1 tablet twice daily, 2 tablets morning and 1 evening, 2 tablets twice daily) over 6 weeks. Patients will receive tablets containing 10mg of methylphenidate or identical placebo and continue on the maximal tolerated dose. Measurements will be taken after 0, 6 weeks, 3 months and 6 months for the following: fatigue (FAS), health related quality of life (King's Sarcoidosis Questionnaire), generic quality of life (EuroQoL-5D) anxiety and depression (Hospital Anxiety and Depression Score), costs and medical resource usage (cost questionnaires) and electrocardiograph (ECG). Patients will wear an accelerometer for 1 week at baseline, 3 months and 6 months to determine activity levels, and undertake a six-minute walk test (6MWT) to measure exercise capacity. Safety (likert) scales for insomnia, jitteriness, palpitations and chest pain, plus blood tests, will be assessed at dose escalation (2, 4 and 6 weeks) and assessment visits. Assessments will be made of recruitment strategies and rates, acceptability of the intervention and placebo arms, and questionnaire burden and use of tolerability of accelerometer device. Focus groups will explore the opinions of patients regarding the study design and feasibility of a definitive trial as well as their views of intervention, both in terms of impact upon symptoms and quality of life, and the acceptability of ongoing treatment. An analysis of potential health-economic benefits from treatment of fatigue will also be undertaken. Expected outcomes We expect that this study will determine the feasibility of performing a large-scale RCT designed to answer whether methylphenidate is effective, both clinically and economically, at improving sarcoidosis-related fatigue and quality of life. Anticipated benefit The results of the subsequent, definitive trial following this feasibility study would lead to the clinical use of methylphenidate as a safe and effective treatment for fatigue in sarcoidosis. This could significantly enhance the lives of patients blighted by fatigue as well as their carers. Patients may be enabled to return to work and benefit society as a whole.

Lay abstract: Many patients with sarcoidosis suffer from extreme tiredness for which there is no treatment. This trial investigates whether it will be possible to undertake a large-scale study to tell whether a drug called methylphenidate (Ritalin) is helpful for patients with sarcoidosis suffering from tiredness. Methylphenidate is used to help exhausted patients in other conditions. Patients will receive treatment with methylphenidate or an identical dummy tablets for 6 months. Tiredness and quality of life will be measured using questionnaires, with activitymeasured using a motion sensor and a walking distance test. We will measure how many patients agree to help, whether they finish the study, and whether they are able to complete the assessments. Assessment of increases in activity levels with any improvements in tired ness will also be recorded, and participants will be asked to describe how they have perceived improvements in fatigue through discussionhs held in focus groups at the end of the trial.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM