Modafinil Not Better Than Placebo for Fatigue in Lung Cancer Patients


Key Points

  • Modafinil was not better than placebo in treatment of fatigue.
  • Both treatment groups exhibited a clinically meaningful improvement in fatigue.

In a trial reported in the Journal of Clinical Oncology, Spathis et al found that that the central nervous system (CNS) stimulant modafinil had no effect on fatigue compared with placebo in patients with advanced non–small cell lung cancer (NSCLC). Fatigue improved in both groups during the 28-day study.

Study Details

In the trial, 207 adults with advanced NSCLC who had not received chemotherapy or radiotherapy within the previous 4 weeks were randomly assigned at 24 UK hospitals to receive modafinil 100 mg on days 1 to 14 and 200 mg on days 15 to 28 (n = 104) or placebo (n = 103). Patients had to have WHO performance status of 0 to 2 and a screening numeric rating scale (0-10, 0 = no fatigue) fatigue score ≥ 5. The primary outcome measure was change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to 28 days adjusted for baseline fatigue and performance status. The minimal clinically important difference for the FACIT-Fatigue scale has been defined as a change of 3 points.

The modafinil and placebo groups were generally balanced for age (mean 69 years in both), sex (51% and 50% female), WHO performance status (0 in 10% in both, 1 in 54% and 55%, and 2 in 37% and 36%), disease stage (IIIa in 8% and 12%, IIIb in 23% and 21%, IV in 65% and 60%), screening fatigue score (5-6 in 45% and 50%, 7-10 in 55% and 51%), and hemoglobin level (mean 12.4 vs 12.6 g/dL).

No Difference in Improvement

Of the randomized population, 160 patients, consisting of 75 in the modafinil group and 85 in the placebo group, completed FACIT-Fatigue questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. Reasons for discontinuation from the study intervention included adverse events in 16 and 10 patients, respectively. FACIT-Fatigue scores improved by a mean of 5.29 points in the modafinil group and 5.09 points in the placebo group, with the difference in change between the groups not being significant (difference = 0.20, 95% confidence interval = −3.56 to 3.97). No significant differences were found after additional adjustment for disease stage and age. There were also no differences between groups in the secondary outcomes of daytime sleepiness (measured by the Epworth Sleepiness Scale), depression (Hospital Anxiety and Depression Scale), and quality of life (quality of life linear analog scale). Overall, 47% of modafinil patients and 23% of placebo patients stated that the intervention was not helpful.

Adverse events were of similar frequency and severity in the modafinil and placebo groups. Serious adverse events occurred in 14 vs 10 patients and were considered possibly related to study treatment in 4 vs 2. Overall, 30 vs 16 patients withdrew from study treatment (P = .02).

Placebo Effect

The authors noted that clinically meaningful improvement in fatigue was observed in both groups and that similar significant effects of placebo on fatigue have been observed in other trials of modafinil and the CNS stimulant methylphenidate in various settings. They thought it likely that the improvements in their trial were “the consequence of a placebo effect from receiving an intervention or another aspect of taking part in a clinical trial….”

The authors concluded, “Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect.”

Anna Spathis, MSc, of Addenbrookes Hospital, Cambridge, UK, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by grants from the National Cancer Research Institute and Sobell House Hospice Charity, Oxford. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.