Methylphenidate versus placebo for fatigue in patients with advanced cancer: the MePFAC randomised controlled trial.

Abstract

Background: Previous meta-analyses suggested methylphenidate may be effective for cancer-related fatigue.

Trial design: Phase III, parallel-group, randomised, double-blind, placebo-controlled trial.

Methods: Participants were adults with advanced cancer with cancer-related fatigue receiving palliative care at 17 palliative care services in England between June 2018 and April 2023.

Principal exclusions: Pregnancy; glaucoma; pheochromocytoma; planned general anaesthesia; hyperthyroidism; severe psychiatric disorders; hypertension; severe cardiovascular disorders; cerebrovascular disorders; anaemia; thrombocytopenia; leucopenia; infection; renal or liver impairment; concomitant clonidine, warfarin, monoamine oxidase inhibitors or modafinil; alcohol or drug dependency; epilepsy.

Interventions: Methylphenidate 5 mg tablets or matching placebo. Starting at 1 tablet twice daily, titrated over 6 weeks to a maximum of 12 tablets/day.

Objective: To estimate clinical effectiveness of methylphenidate versus placebo for cancer-related fatigue in patients receiving palliative care.

Primary outcome: Fatigue at 6 (± 2) weeks measured using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale score. Secondary outcomes were fatigue at other time points; quality of life, adverse events, activities of daily living; appetite; anxiety; depression; patient satisfaction; survival and need for other medication.

Randomisation: Computer-generated 1 : 1 randomisation, stratified by centre, concomitant treatment, depression and initial fatigue score.

Blinding: Participants and outcome assessors were blinded to group assignment.

Results: Eighty-four were allocated to methylphenidate and 78 to placebo.

Recruitment: : Study completed.

Numbers analysed: Seventy-five in methylphenidate group and 72 in placebo group were included in analysis of primary outcome.

Outcome: There was no statistically or clinically significant difference in primary outcome between groups. Functional Assessment of Chronic Illness Therapy - Fatigue Scale scores were 1.97 points (95% confidence interval -0.95 to 4.90; p = 0.186) higher (better) on methylphenidate than placebo. Functional Assessment of Chronic Illness Therapy - Fatigue Scale score was nominally statistically significantly higher (better) in methylphenidate group across duration of study [Diff 2.20 (95% confidence interval 0.39 to 4.01)] but did not reach the minimal clinically important difference (5 points). At 6 weeks, there were no statistically significant differences in quality-of-life or symptom domains except for depression scores [nominally statistically significantly reduced in methylphenidate group: Diff -1.35 (95% confidence interval -2.41 to -0.30)].

Harms: There were 25 serious adverse events in 20 participants receiving methylphenidate and 25 serious adverse events among 16 participants receiving placebo. There were no suspected unexpected serious adverse reactions. There were no statistically significant differences in deaths occurring within 75 days of randomisation (2 participants in placebo group and 6 participants in the methylphenidate group; Fisher's exact p-value 0.278). Adverse events were similar in the two groups, with no pattern to suggest increased harm with methylphenidate.

Limitations: Participants were highly selected due to multiple exclusion criteria. The choice of 5-point difference in Functional Assessment of Chronic Illness Therapy - Fatigue Scale score as clinically significant primary outcome may be debated.

Conclusions: Methylphenidate did not reduce fatigue severity in patients with advanced cancer at 6 (± 2) weeks but was safe and well tolerated.

Future work: Further trials of methylphenidate for fatigue in patients with advanced cancer receiving palliative care are not recommended. There may be scope for further studies in different populations or for different indications.

Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 15/46/02.