Background: Docetaxel is the standard of care for castrate-resistant prostate cancer, but is associated with a high level of fatigue, limiting dosage and leading to premature withdrawal from therapy. Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel group study in patients with metastatic prostate or breast cancer suffering significant chemotherapy-related fatigue whilst undergoing docetaxel-based chemotherapy. Patients were enrolled at the start of their 3^rdor subsequent cycles of docetaxel which was continued for up to four further cycles (defined here as ‘treatment periods’). Patients were randomized 2:1 to receive modafinil 200mg daily or placebo for 15 days during each treatment period. Fatigue was evaluated by the MD Anderson Symptom Inventory (MDASI). The primary endpoint was MDASI area under the curve (AUC) during the first 7 days of study medication for the first two treatment periods (possible range 0-70). Other validated tools were used to record disturbances in sleep, mood and functional status. Results: Eighty-three patients (65 with prostate cancer) were randomized and received at least one dose of study medication. The number of grade 3 or 4 adverse events (AEs) was 16/55 (29.1%) in the modafinil group and 5/28 (17.9%) in the placebo group. The toxicity profile was largely consistent with docetaxel-based chemotherapy and with previously reported AEs associated with modafinil use in the community; 11 AEs were possibly related to docetaxel; 1 to modafinil and 9 to neither treatment. Conclusions: Assessing and managing chemotherapy-related fatigue remains a major challenge. Despite not reaching the primary endpoint, there was a consistent trend towards improvement of chemotherapy-related fatigue in the modafinil arm. Further studies are needed to better address the significant symptom of docetaxel-related fatigue. Funding sanofi-aventis; Study ID NCT00917748.

MDASI AUC_3-10 scores for the first two treatment periods.

	Treatment period		Least squares mean
	Placebo (N=28)	Modafinil (N=55)	Difference	p
1 & 2*	39.6	35.9	-3.7 [-8.9,1.4]	0.15
1	39.4	38.0	-1.4 [-7.0,4.2]	0.62
2	40.1	33.7	-6.4 [-12.2,-0.6]	0.03

* Primary endpoint. 95% confidence intervals in brackets