Clinical trial NCT02643732: Fatigue in Sarcoidosis - Treatment With Methylphenidate
Official title: Fatigue in Sarcoidosis - A Feasibility Study Investigating the Treatment of Fatigue in Stable Sarcoidosis Patients Using Methylphenidate
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Sarcoidosis
Fatigue
Keywords: Activity
Lead sponsor: University of East Anglia
Sponsor class: OTHER
Collaborators: name: Clinical Research and Trials Unit (Norfolk & Norwich University Hospital, UK)
First posted: 2015-12-31
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a small randomised-controlled trial (RCT) using methylphenidate as a treatment for clinically-significant fatigue in sarcoidosis patients with stable disease. The primary outcomes are feasibility, aimed at determining factors that will influence the design a future, larger RCT, which will be powered to look at clinical efficacy of the intervention.

Detailed description: Sarcoidosis and fatigue

Sarcoidosis is a systemic granulomatous disease that affects all ethnic groups and ages. In the United Kingdom the incidence of the disease is 5.0 cases per 100,000 patient years, with a mean age at diagnosis of 47 years, frequently affecting patients of working age(Gribbin et al). The cause is unknown and there is no cure(Iannuzzi et al). Many patients suffer from debilitating fatigue for which there is presently no treatment.

Fatigue has been described as a "core symptom" of sarcoidosis, and is present in up to 80% of patients(Marcellis et al). A "post-sarcoidosis chronic-fatigue syndrome" has been described(James), denoting the presence of fatigue where there is no evidence of active disease. The presence of this symptom has been shown to adversely affect quality of life(Michielsen et al). Although there increased risk of obstructive sleep apnoea and sleep-disordered breathing occurring in sarcoidosis patients(Michielsen et al; Drent et al) the majority of patients have no identifiable cause for fatigue other than their sarcoidosis.

Both the British Thoracic Society(Bradley et al) and American Thoracic Society(Costabel et al) produce guidelines for physicians treating people with sarcoidosis. Neither guideline gives any advice on treatment of fatigue. Fatigue is a common problem in sarcoidosis. In a study of 76 patients with sarcoidosis, 50.7% reported pathological levels of fatigue, defined as a Fatigue Assessment Scale (FAS) score of greater than 21 units, compared with 8.6% of controls. People reporting fatigue scores above 21, had poorer EuroQoL Visual Analogue Scale (EQVAS) scores compared with people reporting fatigue scores of 21 or below (mean scores 0.561 vs 0.792 , p\<0.001) (Unpublished data, Norfolk and Norwich University Hospital). This shows that fatigue impacts upon quality of life in sarcoidosis.

Methylphenidate - a treatment for fatigue

Methylphenidate (and its isomer dexmethylphenidate), which is used to treat attention deficit hyperactivity disorder(Keating et al), is an amphetamine-derivative which works by amplifying dopamine signals through inhibition of dopamine reuptake and enhancement of extracellular dopamine in the basal ganglia(Volkow et al). It has been used to treat fatigue in other settings with good effect. In a placebo-controlled, double-blind trial in post-chemotherapy participants with fatigue, methylphenidate exhibited a clinically significant reduction in fatigue(Lower et al). Prior to the results from this trial, a Cochrane review of treatments for cancer-related fatigue from 5 RCTs had shown an improvement in fatigue through methylphenidate treatment, leading them to conclude "the current evidence supports the use of psychostimulants in cancer-related fatigue"(Minton et al). Another trial investigated methylphenidate for the treatment of fatigue in 109 HIV-positive patients over a 6-week period. Methylphenidate improved fatigue on a visual analogue scale, with a 26.2 point increase (maximum of 100) from baseline, with 41% of participants receiving the drug demonstrating a greater than 50% improvement in visual analogue scale score(Breitbart et al). In contrast, no difference between methylphenidate and placebo was seen in a cohort of 68 fatigued patients who had received radiotherapy for brain tumours followed over a 12 week period(Butler et al).

In the case of sarcoidosis, so far only one small study has investigated the use of dexmethylphenidate for fatigue(Lower et al). Ten patients were included in this double blind crossover trial. Participants reported clinically and statistically significant improvements in fatigue measured by both the FAS and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score after 8 weeks of treatment, although no statistically significant improvement was seen in six minute walk distance (6MWD) compared with placebo. The drug was well tolerated; all participants completed the study and no significant increase in side effects was noted between the patients receiving placebo and dexmethylphenidate.

Rationale for current study

Prior to designing a definitive study, issues about the feasibility of undertaking a sufficiently large trial require to be resolved. Completed trials have only used methylphenidate for 8-12 weeks, so sustainability of effect, tolerability of medications over a long period and retention of participants within the trial are unknown. Whilst the use of medications such as methylphenidate may not be used on a continuous basis in the clinical setting, their use on a 6-12 month basis may not be unreasonable, hence the need to review the effect of the medication over a longer period. Furthermore, it is unclear how many people would be willing to participate in a longer trial , and how many potential participants would be suitable for enrolment using our present inclusion and exclusion criteria. For this reason, a feasibility trial is necessary before committing to a larger trial.

In addition, this trial will evaluate exercise and activity through both a modified shuttle walk test (MSWT) and accelerometer-measured change in activity levels. Although methylphenidate has not been shown to significantly improve 6MWD(Lower et al), a larger study using a more responsive test may be required to evaluate exercise capacity in this setting. This could be because as a self-paced test it is a sub-maximal exercise test - this has been shown to be the case in a study of interstitial lung disease (ILD) patients (including sarcoidosis) where peak oxygen uptake, carbon dioxide uptake and ventilation were all lower during 6MWD than on cardiopulmonary exercise testing(Holland et al). By not reaching their maximum exercise level this may make the test less responsive to change. This is particularly relevant given that the ILD cohort who did not reach maximal exercise or oxygen uptake during their 6MWD were likely to be much more limited in cardiopulmonary function than the cohort anticipated to be enrolled in a study of treatment of fatigue and therefore much more likely to get closer to their peak oxygen uptake during a 6MWD. Given that activity levels measured by accelerometers in people with sarcoidosis is related to fatigue (Korenromp et al), this trial will evaluate the feasibility of using them as an outcome measure in a clinical trial, including whether participants will wear the devices for long enough (i.e. 4 days out of 7, at least 10 hours per day) to get valid data for estimating daily activity levels.

Study Design

This is a parallel-arm RCT including 30 participants, randomised on a 1.5:1 basis in favour of the active treatment arm (18 participants will receive methylphenidate, 12 will receive placebo). The rationale of this trial is to determine the feasibility of designing and performing a sufficiently large RCT in the future looking for proof of clinical effect of methylphenidate in the treatment of sarcoidosis-associated fatigue. As a result, this study is not powered to detect a clinical difference in a clinical outcome, although these will be measured and analysed (the estimate of effect size will be used for future power calculations). Therefore the primary outcomes regard feasibility and safety, not treatment effect (see Outcome Measures section).

Participants will receive either methylphenidate or placebo for 24 weeks, with a further assessment performed 6 weeks after completion of the trial. They will be carefully monitored over the initial 6 weeks to ensure that they are stable on the drug - during this time they will be seen every 2 weeks (at 0,2,4 and 6 weeks). Following this period they will be seen less frequently (at 12 and 24 weeks, with postal questionnaires performed at 18 weeks) to detect sustainability of effect. Determining if treatment effect is sustained over the second half of the trial period will help to establish how long any future trial will need to be. Although each participant is required to attend frequent visits to the hospital, this trial has been designed in conjunction with sarcoidosis patients and ensures that participant safety is paramount.

Eligibility criteria: Inclusion Criteria:

1. Biopsy-proven diagnosis of sarcoidosis or diagnosis of sarcoidosis from interstitial lung disease multidisciplinary team meeting after review of radiological and clinical information
2. Stable disease (treatment unchanged for 6 weeks, without anticipation of treatment change during trial period)
3. FAS score greater than 21 units
4. Able to give informed consent
5. In patients on warfarin therapy - Willing to consent to increased frequency of monitoring

Exclusion Criteria:

1. Evidence of co-existing obstructive sleep apnoea. Patients screened with a "STOP-Bang" questionnaire (acronym taken from individual questions within the questionnaire itself) score of greater than 4 must undertake overnight oximetry; they are excluded if this shows a desaturation index of more than 15 events per hour on overnight oximetry.
2. Documented history of significant cardiac disease (including cardiac sarcoid) OR associated disease which would increase risk of underlying coronary artery disease (cerebrovascular disease, previous stroke or peripheral vascular disease). Definitively treated cardiac disease e.g. previous myocardial infarction treated with stents or coronary artery bypass grafting with no ongoing symptoms is permitted.
3. Hyperthyroidism evidenced by abnormal screening thyroid function tests (Thyroid stimulating hormone level outside normal range of 0.35 - 3.50 milliunits/litre (mU/L) or thyroxine (T4) outside normal range of 8 - 21 picomoles per litre (pmol/L)).
4. History of seizures, excluding febrile convulsions whilst an infant.
5. Abnormal electrocardiogram (ECG) with evidence of arrhythmia (except first degree heart block which has been stable for 3 months).
6. Concomitant therapy with the following drugs:

   * Tricyclic antidepressants
   * Monoamine oxidase inhibitors
   * Tramadol or buprenorphine
   * Levodopa
   * Haloperidol and atypical antipsychotics
7. Glaucoma or raised intra-ocular pressure for any reason.
8. Patients with established liver disease defined as Child-Pugh class B or C.
9. Documented medical history of psychiatric disorders (excluding depression)
10. History of drug-dependence or addiction at any time
11. Female participant who is pregnant, lactating or planning pregnancy during the course of the trial
12. Female patient of childbearing potential unable or unwilling to take two acceptable forms of contraception (see exclusions section)
13. Receiving an investigational drug or biological agent within 6 weeks (or 5 times the half-life if this is longer) prior to study entry.

Primary outcomes:
measure: Recruitment rate (Feasibility outcome)
timeFrame: Up to 18 months (recruitment period duration)
measure: Number of potential participants excluded (Feasibility outcome)
timeFrame: Up to 18 months (recruitment period duration)
measure: Number of participants dropping out/Participant retention rate (Feasibility outcome)
timeFrame: 24 weeks (trial duration)
measure: Side-effect rate (Feasibility and Safety outcome)
timeFrame: 24 weeks (trial duration)
measure: Number of missed or unfilled assessments (Feasibility outcome)
timeFrame: 24 weeks (trial duration)
measure: Number of accelerometers returned with valid data (Feasibility outcome)
timeFrame: 24 weeks (trial duration)
Secondary outcomes:
measure: Fatigue Assessment Scale (FAS) (Clinical outcome)
timeFrame: 0,2,4,6,12,18,14 and 30 weeks
measure: Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)
timeFrame: 0,2,4,6,12,18,14 and 30 weeks
measure: Kings Sarcoidosis Questionnaire (KSQ)
timeFrame: 0,6,12,18,14 and 30 weeks
measure: EuroQoL-5D (EQ5D) Questionnaire
timeFrame: 0,6,12,18,14 and 30 weeks
measure: Short-form 36 (SF-36) Questionnaire
timeFrame: 0,6,12,18,14 and 30 weeks
measure: Hospital Anxiety and Depressions Score (HADS)
timeFrame: 0,6,12,18,14 and 30 weeks
measure: Accelerometer Use (wrist-worn accelerometer)
timeFrame: 0, 12, 24 weeks
measure: Modified Shuttle Walk Test (MSWT)
timeFrame: 0, 12, 24 weeks
Other outcomes:
measure: Health Economic/Utility Use
timeFrame: 0, 12, 24 weeks
Locations:
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: Norfolk
Study officials:
affiliation: University of East Anglia
name: Andrew M Wilson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J, Tata LJ. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax. 2006 Nov;61(11):980-5. doi: 10.1136/thx.2006.062836. Epub 2006 Jul 14.
citation: Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007 Nov 22;357(21):2153-65. doi: 10.1056/NEJMra071714. No abstract available.
citation: Marcellis RG, Lenssen AF, Elfferich MD, De Vries J, Kassim S, Foerster K, Drent M. Exercise capacity, muscle strength and fatigue in sarcoidosis. Eur Respir J. 2011 Sep;38(3):628-34. doi: 10.1183/09031936.00117710. Epub 2011 Mar 24.
citation: James DG. Complications of sarcoidosis. Chronic fatigue syndrome. Sarcoidosis. 1993 Mar;10(1):1-3.
citation: Michielsen HJ, Drent M, Peros-Golubicic T, De Vries J. Fatigue is associated with quality of life in sarcoidosis patients. Chest. 2006 Oct;130(4):989-94. doi: 10.1378/chest.130.4.989.
citation: Turner GA, Lower EE, Corser BC, Gunther KL, Baughman RP. Sleep apnea in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 1997 Mar;14(1):61-4.
citation: Drent M, Verbraecken J, van der Grinten C, Wouters E. Fatigue associated with obstructive sleep apnea in a patient with sarcoidosis. Respiration. 2000;67(3):337-40. doi: 10.1159/000029523.
citation: Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, Hirani N, Hubbard R, Lake F, Millar AB, Wallace WA, Wells AU, Whyte MK, Wilsher ML; British Thoracic Society Interstitial Lung Disease Guideline Group, British Thoracic Society Standards of Care Committee; Thoracic Society of Australia; New Zealand Thoracic Society; Irish Thoracic Society. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008 Sep;63 Suppl 5:v1-58. doi: 10.1136/thx.2008.101691. No abstract available.
citation: Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur Respir J. 1999 Oct;14(4):735-7. doi: 10.1034/j.1399-3003.1999.14d02.x. No abstract available.
citation: Keating GM, Figgitt DP. Dexmethylphenidate. Drugs. 2002;62(13):1899-904; discussion 1905-8. doi: 10.2165/00003495-200262130-00009.
citation: Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ. Mechanism of action of methylphenidate: insights from PET imaging studies. J Atten Disord. 2002;6 Suppl 1:S31-43. doi: 10.1177/070674370200601s05.
citation: Lower EE, Fleishman S, Cooper A, Zeldis J, Faleck H, Yu Z, Manning D. Efficacy of dexmethylphenidate for the treatment of fatigue after cancer chemotherapy: a randomized clinical trial. J Pain Symptom Manage. 2009 Nov;38(5):650-62. doi: 10.1016/j.jpainsymman.2009.03.011.
citation: Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. Drug therapy for the management of cancer-related fatigue. Cochrane Database Syst Rev. 2010 Jul 7;2010(7):CD006704. doi: 10.1002/14651858.CD006704.pub3.
citation: Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J. A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med. 2001 Feb 12;161(3):411-20. doi: 10.1001/archinte.161.3.411.
citation: Butler JM Jr, Case LD, Atkins J, Frizzell B, Sanders G, Griffin P, Lesser G, McMullen K, McQuellon R, Naughton M, Rapp S, Stieber V, Shaw EG. A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy. Int J Radiat Oncol Biol Phys. 2007 Dec 1;69(5):1496-501. doi: 10.1016/j.ijrobp.2007.05.076. Epub 2007 Sep 14.
citation: Lower EE, Harman S, Baughman RP. Double-blind, randomized trial of dexmethylphenidate hydrochloride for the treatment of sarcoidosis-associated fatigue. Chest. 2008 May;133(5):1189-95. doi: 10.1378/chest.07-2952. Epub 2008 Feb 8.
citation: Holland AE, Dowman L, Fiore J Jr, Brazzale D, Hill CJ, McDonald CF. Cardiorespiratory responses to 6-minute walk test in interstitial lung disease: not always a submaximal test. BMC Pulm Med. 2014 Aug 11;14:136. doi: 10.1186/1471-2466-14-136.
citation: Korenromp IHE, Heijnen CJ, Vogels OJM, van den Bosch JMM, Grutters JC. Characterization of chronic fatigue in patients with sarcoidosis in clinical remission. Chest. 2011 Aug;140(2):441-447. doi: 10.1378/chest.10-2629. Epub 2011 Feb 17.
citation: Atkins C, Jones A, Clark AB, Stockl A, Fordham R, Wilson AM. Feasibility of investigating methylphenidate for the treatment of sarcoidosis-associated fatigue (the FaST-MP study): a double-blind, parallel-arm randomised feasibility trial. BMJ Open Respir Res. 2021 May;8(1):e000814. doi: 10.1136/bmjresp-2020-000814.
citation: Atkins C, Fordham R, Clark AB, Stockl A, Jones AP, Wilson AM. Feasibility study of a randomised controlled trial to investigate the treatment of sarcoidosis-associated fatigue with methylphenidate (FaST-MP): a study protocol. BMJ Open. 2017 Dec 4;7(12):e018532. doi: 10.1136/bmjopen-2017-018532.