Stone, Patrick Charles, Minton, Ollie, Richardson, Alison, Buckle, Peter, Enayat, Zinat E., Marston, Louise and Freemantle, Nick (2025) Methyphenidate verus placebo for fatigue in patients with advanced cancer: randomized, double-blind, multicenter, placebo-controlled trial. Journal of Clinical Oncology, 42 (20), 2382-2392. (doi:10.1200/JCO.23.02639).
Abstract
Purpose: to compare effects and side effects of 6 weeks of individually dose-titrated methylphenidate or placebo on fatigue in palliative care patients with advanced cancer.
Methods: this is a randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients had advanced incurable cancer and fatigue >3/10. Principal exclusions were hypertension; psychiatric, cardiovascular, cerebrovascular, renal, liver, or blood disorders; substance dependency; and epilepsy. Patients were randomly assigned 1:1 methylphenidate or placebo starting at 5 mg twice daily. Dose of methylphenidate/placebo was titrated once per week, over 6 weeks, up to a maximum of 20 mg three times daily. Trial ended at 10 weeks. Primary outcome was the difference in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scores between groups at 6 ± 2 weeks. Secondary outcomes included adverse effects, quality of life, and mood.
Results: one hundred sixty-two patients (73 men; mean, 65.8; standard deviation [SD], 10.3 years) were randomly assigned, and three were excluded from analysis. Seventy-seven were allocated placebo (baseline FACIT-F = 22 [SD, 10]); 82 were allocated methylphenidate (FACIT-F = 20 [SD, 9]). After 6 ± 2 weeks, FACIT-F scores were 1.97 points (95% CI, –0.95 to 4.90; P = .186) higher (better) on methylphenidate than placebo. Across 10 weeks of the study, FACIT-F was nominally higher in the methylphenidate group versus placebo (Diff, 2.20 [95% CI, 0.39 to 4.01]), but this did not reach the minimally clinically important difference (5-points). At 6 weeks, there were no differences between groups in quality-of-life or symptom domains except for depression scores (nominally reduced in the methylphenidate group: Diff, –1.35 [95% CI, –2.41 to –0.30]). There were no differences in mortality or serious adverse events.
Conclusion: after 6 ± 2 weeks of treatment, methylphenidate was not superior to placebo for treating fatigue in advanced cancer. Methylphenidate was safe and well-tolerated.
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