Feasibility study of a randomised controlled trial to investigate the treatment of sarcoidosis-associated fatigue with methylphenidate (FaST-MP): a study protocol

Introduction Fatigue is a frequent and troublesome manifestation of chronic sarcoidosis. This symptom can be debilitating and difficult to treat, with poor response to the treatment. Symptomatic management with neurostimulants, such as methylphenidate, is a possible treatment option. The use of such treatment strategies is not without precedent and has been trialled in cancer-related fatigue. Their use in sarcoidosis requires further evaluation before it can be recommended for clinical practice. Methods and analysis The Fatigue and Sarcoidosis—Treatment with Methylphenidate study is a randomised, controlled, parallel-arm and feasibility trial of methylphenidate for the treatment of sarcoidosis-associated fatigue. Patients are eligible if they have a diagnosis of sarcoidosis, significant fatigue (measured using the Fatigue Assessment Scale) and have stable disease. Up to 30 participants will be randomly assigned to either methylphenidate (20 mg two times per day) or identical placebo in a 3:2 ratio for 24 weeks. The primary objective is to collect data determining the feasibility of a future study powered to determine the clinical efficacy of methylphenidate for sarcoidosis-associated fatigue. The trial is presently open and will continue until July 2018. Ethics and dissemination Ethical approval for the study was granted by the Cambridge Central Research Ethics Committee on 21 June 2016 (reference 16/EE/0087) and was approved and sponsored by the Norfolk and Norwich University Hospital (reference 190280). Clinical Trial Authorisation (EudraCT number 2016-000342-60) from the Medicines and Healthcare products Regulatory Agency (MHRA) was granted on 19 April 2016. Results will be presented at relevant conferences and submitted to appropriate journals following trial closure and analysis. Trial registration number NCT02643732; Pre-results.

Regarding the inclusion criteria, I agree with including patients with "treatment unchanged for 6 weeks". This will probably exclude some patients in the very acute and inflammatory phase of the disease, where the fatigue can improve with immunosuppression or time alone (SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2016;33: 124-129). However, I have two criticisms. First, the inclusion criteria "without anticipation of change in the treatment during the trial period" is very subjective and difficult to predict. Not sure if it will be beneficial to keep it.
And second, it may be better to define a time period from the diagnosis to the inclusion in the study (e.g. 3 months, 6 months), to exclude patients that would improve spontaneously or with immunosuppression alone. Minor comment: Page 7, line 50: there is a misplaced parenthesis after the number 21 Overall, I applaud the authors for this work. It will bring important information to the Sarcoidosis literature. And it will hopefully improve our ability to help patients with Sarcoidosis-related fatigue. 2. The inclusion criteria of "stable" disease as defined as unchanged treatment for 6 weeks appears subjective and arbitrary. Significant fatigue can still be present in those with subclinical disease. I think it would be of interest to include biomarkers such as circulating TNFalpha and CRP (Drent M, et al. ERJ 1999) and PET scans to evaluate their potential utility as an exploratory outcome measure in a larger prospective study.

REVIEWER
3. Careful documentation of specific treatments for sarcoidosis is essential as prednisone use has been associated with increased fatigue in these patients.
4. Why the complex 3:2 randomization scheme? If unequal arm size is desired, why not 2:1 (20 on study drug, 10 placebo) to simplify things a bit?
5. If this trial was approved by the local ethics board in June 2016 and is still presently open for enrollment, how many patients have already been recruited? It is important to clarify why recruitment for this study has been slow since fatigue is felt to be present in nearly 80% of sarcoidosis patients.
6. I would like to know the authors' opinion on why there has been little progress made using methylphenidate (or similar) for sarcoidosis-associated fatigue when a pilot RCT with a favorable safety profile and promising results was published in 2008, or nearly a decade ago? 7. Although methylphenidate has not been studied prospectively in sarcoidosis-associated fatigue for longer than 8 weeks, is there any actual published data that prolonged use of methylphenidate can cause significant harm? In the setting of a past positive pilot study, is there a real need for another pilot study? Why not propose this study to be a multicenter, phase 2 RCT? If positive, then this would be steps closer to being an approved treatment.

VERSION 1 -AUTHOR RESPONSE
Reviewer 1 comments (Professor Violeta Vucinic) Many thanks for the positive comments regarding our study. We hope to have the final study results at the end of next year.
Reviewer 2 comments (Manuel L. Ribiero Neto) Thank you for your positive comments on the study design. We note the comments made about the difficulty of anticipating change in treatment for sarcoidosis during the trial and agree with this; this wording has been used so that we are not including patients where they are not on stable treatment for their sarcoidosis. We do accept that it may not be beneficial to keep this statement, but we were keen to exclude patients where fatigue stemmed from high dose steroid use which would be decreasing during the study. As this is part of the current inclusion and exclusion criteria we have kept this for now, but it will be reviewed when considering future studies. The second comment, regarding a minimum duration of time since the diagnosis of sarcoidosis, was also considered. The reason that this has not been included is to allow inclusion of patients where diagnosis has been delayed but the disease has likely been present for a much longer period of time (for example, due to delay in seeking medical help or slow referral to secondary care for the diagnosis). We accept that specifying a minimum duration would help to minimise the risk of including patients where the fatigue will spontaneously improve and will review this for future studies.

Reviewer 3 comments (Dr Anoop M Nambiar MD MS)
We thank Dr Nambiar for his positive comments on the protocol, and for his questions regarding the study. I have tried to address the specific questions below -1. Since fatigue may affect those with extrapulmonary more than pulmonary disease, I would recommend that each patient's manifestations be carefully documented.
Response: This is an important point and one that we have now clarified within the text (page 7)we have been collecting this data from all patients being screened for the study, and for all participants entering the study.
2. The inclusion criteria of "stable" disease as defined as unchanged treatment for 6 weeks appears subjective and arbitraryit would be of interest to include biomarkers and PET scans to evaluate their potential utility as an exploratory outcome measure in a larger prospective study.
Response: We agree that the criteria is subjective, but has been chosen as a pragmatic marker of patients for whom fatigue is an issue but no other evidence of active disease that would necessitate the use of immunosuppression is present, hopefully emulating the clinical situation that clinicians would find themselves in when considering the use of neurostimulants. We do not believe biomarkers would provide additional information within this feasibility study as there would not be enough participants to determine if these biomarkers could have a role in a larger study.