Title: Methylphenidate versus placebo for fatigue in advanced cancer (MePFAC)
Funder: Department of Health and Social Care

Abstract: Design: Prospective randomised double-blind placebo-controlled trial with internal pilot Aim: Estimate clinical effectiveness of methylphenidate (MPH) vs placebo for cancer-related fatigue (CRF) in patients receiving specialist palliative care (SPC) Setting: Multi-centre study with community, day-care & outpatients Population: Patients with advanced cancer with CRF & receiving SPC Inclusions: 18+ years; advanced cancer; moderate to severe fatigue; informed consent; prognosis 2-12 months; under care of SPC Exclusions: Known contraindication to MPH; anaemia; liver failure; concomitant psycho-stimulant use Health technologies being assessed: MPH tablets 5mgs/day increasing up to maximum 60mgs/day in divided doses Outcomes: Primary outcome is fatigue at 6 weeks measured by Functional Assessment of Chronic Illness Therapy (FACIT-F). Secondary outcomes (measured at 3 & 9 weeks) are other measures of quality of life (using European Organisation for Research & Treatment of Cancer core Quality of Life Palliative Care questionnaire & the EuroQol EQ-5D 5 level [EQ-5D-5L]), adverse events, activities of daily living; appetite; satisfaction of patients & carers; survival & need for other medication. Missing data: Data are more likely to be missing when fatigue severity is greater, & may not reasonably be considered missing at random. Principal analysis will be on complete data, & we will explore the effects of missing data using developed deviance based likelihood ratio approaches Procedures: Patients will be identified by clinical teams & provided with study information. At screening, informed consent will be obtained & a specimen taken (full blood count, liver & renal function). After randomisation, face-to-face assessments will occur at weeks 3, 6 & 9 & will include; completion of outcome measures & blood pressure. Patients will be contacted by telephone weekly so that study medication can be titrated. The comparator group will receive individually titrated placebo tablets. Both groups will receive usual care Follow-up: Once participants have completed the nine week follow up they will be given the option to continue (or start) methylphenidate according to local clinical practice and circumstances. Pilot: Feasibility of recruitment strategy, randomisation & follow-up will be evaluated during a pilot at four centres during first 9 months of the study. During pilot phase (months 10-18) recruitment should exceed 70% of rate expected once trial is fully established. Sample size: With 230 randomised & 172 evaluable patients (25% attrition), this study has 90% power to detect a difference of 5-points on FACIT-F (effect size 0.5) between groups at 5% significance (two sided). Randomization will be computer generated & stratified by centre, by receipt of palliative cancer treatment, by baseline HADS depression score & by initial fatigue score >7 Timetable: Months 1–9 set-up; 10-18 internal pilot; 19–36 recruitment; 36-42 analysis, writing & dissemination Expertise: Our team includes expertise in palliative care, mental health, clinical trials, statistics & nursing

Lay abstract: Patients with cancer often experience severe fatigue which can cause problems with their ability to look after themselves and which can result in a decreased quality of life. Previous studies have suggested that the drug methylphenidate [MPH] (also known as Ritalin®) may have some benefits, but the evidence is not clear. MPH is a controlled drug (like morphine). It is most commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children. MPH can cause side-effects such as agitation, anxiety, difficulty sleeping & high blood pressure (BP). At the moment it is unclear whether or not MPH would be helpful in patients with cancer. Some studies have shown that MPH is effective for treating cancer-related fatigue and others have shown no benefit. To answer this question we will undertake a clinical trial. Patients with secondary cancer & fatigue will be invited to take part. If they agree they will receive nine weeks’ treatment with either MPH or a placebo tablet (an inactive “dummy” pill). Which treatment people receive will be determined randomly by a computer to ensure that our study is a “fair test”. The tablets will be made to appear identical so that neither the patient nor the staff knows which treatment is being used. During the study patients will be contacted by telephone by a research nurse every week to advise them about which dose of study medication to take. At the start of the study and after three, six and nine weeks, patients will be seen face-to-face by one of our medical team at an outpatient appointment, reassessed and asked to complete some questionnaires about their fatigue, their quality of life, a blood pressure check and to be re-supplied with medication. This will allow us to identify whether MPH is better at treating fatigue than a placebo. The dose of the drugs may need to be adjusted during the study. Everyone will start on the lowest dose. The dose will be adjusted by the research nurse over the telephone or by one of the medical team at the outpatient appointments, depending on response & side effects. All participants will be seen at the end of the study (9 weeks) to ask how fatigued they feel, about their quality of life & about any side-effects. This will allow us to quantify the longer term benefits and side-effects of treatment. At the end of the nine week study patients will be able to discuss with their doctors whether to start (or re-start) the medication. Patients will be given the opportunity to try the study medication should they wish to do so (& provided it is judged to be medically appropriate). Patients’ identities will be kept anonymous. Results of the study will be published in scientific journals & presented at scientific meetings. We will also announce our results to the media & through professional & patient interest group websites & social media.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS