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Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy

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Abstract

Purpose

Modafinil has been reported to benefit a subgroup of patients suffering severe fatigue while undergoing chemotherapy. Docetaxel is associated with fatigue that may lead to premature therapy withdrawal. We investigated whether modafinil could reduce fatigue during docetaxel chemotherapy.

Methods

This multicenter, randomized, double-blind, placebo-controlled study evaluated the efficacy of modafinil in patients with metastatic prostate or breast cancer undergoing docetaxel chemotherapy (every 21 days; minimum dose 50 mg/m2). At the start of their third or subsequent chemotherapy cycle, patients with significant docetaxel-associated fatigue were randomized to receive concurrent modafinil 200 mg/day or placebo for 15 days (“treatment periods” (TP)). Docetaxel was continued for up to four further cycles. Fatigue was evaluated with the fatigue component of the MD Anderson Symptom Inventory (MDASI). The primary endpoint was cumulative MDASI area under the curve (AUC) during the first 7 days of study medication during TP1 and TP2.

Results

Evaluable data were available from 83 patients (65 with prostate cancer). There was no statistically significant difference between the two treatment arms for the primary endpoint (MSADI AUC3–10 35.9 vs 39.6; 95 % confidence interval −8.9, 1.4; P = 0.15). Overall toxicity was comparable between treatment groups; however, the incidence of grade ≤2 nausea and vomiting was higher in the modafinil arm (45.4 vs 25 %).

Conclusions

Assessing and managing chemotherapy-related fatigue remains a major challenge. There was a lack of difference between the two arms in the planned primary endpoint. However, there was a modest but consistent trend towards improvement of docetaxel-related fatigue in those treated with modafinil. Based on the study findings, modafinil for the treatment of fatigue associated with docetaxel chemotherapy elicits modest improvements. Larger, longer term, randomized, controlled studies are required to clarify the exact role of modafinil in the treatment of docetaxel-related fatigue.

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Acknowledgments

We thank the patients and their families who took part in this study. We greatly appreciate the contributions of the clinicians and their staff from the hospitals from around Australia that were involved in this study, although not all were able to recruit patients. NSW: Prince of Wales Hospital, Bankstown - Lidcombe Hospital, Southern Medical Day Care, Sydney Haematology & Oncology Clinical Trials Unit, St George Hospital, St Vincent's Hospital, Coffs Harbour Base Hospital, Armidale Hospital, Tamworth Hospital, Lingard Private Hospital, The Tweed Hospital, Southern Highlands Cancer Centre, Manning Rural Referral Hospital; ACT: The Canberra Hospital; VIC: Box Hill Hospital, Monash Medical Centre, Frankston Hospital, Frankston Private Hospital, John Fawkner Private Hospital, Ballarat Oncology & Haematology Services; TAS: Launceston General Hospital; SA: Royal Adelaide Hospital, The Queen Elizabeth Hospital, Calvary Hospital North Adelaide and QLD: Gold Coast Hospital.

Funding and financial disclosures

This work has been carried out with financial support from Sanofi Australia Pty Ltd. The sponsor was involved in the design and conduct of the study, provided logistical support during the trial, funded statistical and editorial assistance, and reviewed the final draft before submission. The study Steering Committee (EJH, PLDeS, GMM, and AL) designed the trial protocol and contributed to the design of the statistical analysis plan. This study is registered at ClinicalTrials.gov, NCT00917748. Statistical analyses were performed externally (Caro-Anne Badcock, Statistical Revelations Pty Ltd). The decision to submit the report for publication was made by the Steering Committee, who drafted then finalized the report with the help of a medical writer (Hazel Palmer, Scius Solutions Pty Ltd). The sponsor funded statistical and editorial assistance and reviewed the final draft before submission.

Conflict of interest

Phillip Parente is currently conducting research sponsored by Sanofi Australia. Tal Rapke is an employee of Sanofi Australia Pty Ltd. Elizabeth Hovey, Gavin Marx, Paul deSouza, and Phillip Parente have each sat on an advisory board for Sanofi oncology products. All remaining authors have declared no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Oncology, Prince of Wales Hospital, High Street, Randwick, New South Wales, 2031, Australia

    Elizabeth Hovey

  2. University of New South Wales, Sydney, New South Wales, Australia

    Elizabeth Hovey & Andrew Lloyd

  3. University of Western Sydney, Penrith, New South Wales, Australia

    Paul de Souza

  4. Sydney Haematology Oncology Clinics, Sydney, New South Wales, Australia

    Gavin Marx

  5. Box Hill Hospital, Box Hill, Victoria, Australia

    Phillip Parente

  6. Sanofi Australia Pty Ltd, Macquarie Park, New South Wales, Australia

    Tal Rapke

  7. Gold Coast Hospital, Southport, Queensland, Australia

    Andrew Hill

  8. ANZGOG, Newcastle, New South Wales, Australia

    Antonino Bonaventura

  9. Calvary Hospital, North Adelaide, South Australia, Australia

    Antony Michele

  10. The Canberra Hospital, Garran, Canberra, ACT, Australia

    Paul Craft

  11. The Tweed Hospital, Tweed Heads, New South Wales, Australia

    Ehtesham Abdi

  12. Griffith University, Gold Coast, Queensland, Australia

    Ehtesham Abdi

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  1. Elizabeth Hovey
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Correspondence to Elizabeth Hovey.

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Hovey, E., de Souza, P., Marx, G. et al. Phase III, randomized, double-blind, placebo-controlled study of modafinil for fatigue in patients treated with docetaxel-based chemotherapy. Support Care Cancer 22, 1233–1242 (2014). https://doi.org/10.1007/s00520-013-2076-0

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  • DOI: https://doi.org/10.1007/s00520-013-2076-0

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