title: The Effect of Methylphenidate on Fatigue in Advanced Cancer: An Aggregated N-of-1 Trial.
abstract: BACKGROUND
  Fatigue is common in life-limiting cancer. Methylphenidate (MPH), a psychostimulant, may be a useful therapy. Gathering evidence in patients with advanced cancer can be challenging.
  
  
  OBJECTIVE
  To determine if MPH improves cancer-related fatigue in people with advanced cancer.
  
  
  METHODS
  N-of-1 trials are multicycle, double-blind, randomized, controlled crossover trials using standardized measures of effect in individuals. They are normally used to assess treatment effects in individuals. Aggregated N-of-1 trials from participants with end-stage cancer suffering fatigue were used to assess the group effect of MPH, producing an estimate of equivalent power to a parallel-group randomized controlled trial (RCT) but requiring less than half of the sample size. Up to three cycles of MPH 5 mg twice daily (three days) vs. identical placebo (three days) capsules were offered to participants. Primary outcome was improvement in fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue Scale and the Wu Cancer Fatigue Scale. Analysis used Bayesian statistical methods using intention-to-treat principles.
  
  
  RESULTS
  Forty-three participants completed 84 cycles of MPH and placebo in random order, exceeding sample size estimates. Overall, MPH did not improve fatigue (mean difference 3.2; 95% credible interval -2.0, 9.0; posterior probability of favorable effect 0.890). Eight participants showed important improvement, and one participant showed important worsening of fatigue on MPH. There were no features that distinguished participants whose fatigue responded to MPH compared with those who did not.
  
  
  CONCLUSIONS
  MPH does not improve fatigue in the population of patients with end-stage cancer. Aggregated N-of-1 trial methodology is feasible and produces population-based sample estimates with less than half the sample size required for the equivalent parallel-group RCT. It also identified individuals who did and did not respond to MPH, which is a feature difficult to achieve in a standard RCT. The study was registered with the Australian Clinical Trials Registry (12609000794202).
authors.affiliation: School of Medicine, University of Queensland, Brisbane, Queensland, Australia. Electronic address: g.mitchell@uq.edu.au.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Mitchell
authors.affiliation: Department of Palliative and Supportive Care, Mater Health Services, South Brisbane, Queensland, Australia; Mater Research, University of Queensland, South Brisbane, Queensland, Australia.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Hardy
authors.affiliation: School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Nikles
authors.affiliation: School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Sue-Ann S
authors.initials: SA
authors.lastname: Carmont
authors.affiliation: School of Medicine, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Hugh E
authors.initials: HE
authors.lastname: Senior
authors.affiliation: School of Health Sciences, University of Canterbury, Christchurch, New Zealand.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Schluter
authors.affiliation: Department of Palliative and Supportive Care, Mater Health Services, South Brisbane, Queensland, Australia; Mater Research, University of Queensland, South Brisbane, Queensland, Australia; St. Vincent's Private Hospital, Brisbane, Queensland, Australia.
authors.forename: Phillip
authors.initials: P
authors.lastname: Good
authors.affiliation: Cancer Institute of New South Wales, Sydney, New South Wales, Australia; Department of Palliative and Supportive Care, Flinders University, Adelaide, South Australia, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Currow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005221:Fatigue / Q000188:drug therapy* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D010166:Palliative Care / Q000379:methods*; D012720:Severity of Illness Index; D013727:Terminal Care / Q000379:methods; D016896:Treatment Outcome
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate
keywords: Methylphenidate; N-of-1 trial; advanced cancer; fatigue; palliative care