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Abstract

Objective: To assess whether modafinil, a wakefulness-promoting agent, is useful for fatigue in patients with multiple sclerosis (MS).
Methods: Patients with MS with stable disability, and a baseline score of 45 or more on the Modified Fatigue Impact Scale (MFIS), were eligible for the 5-week randomized, double-blind, placebo-controlled, parallel group study. The initial daily dose of modafinil was 200 mg for 1 week. Depending on tolerance, the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35. The primary outcome variable was the change of MFIS score at day 35.
Results: A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis. The mean MFIS score at baseline was 63 ± 9 in the placebo group and 63 ± 10 in the modafinil group. MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups, but no significant difference was detected between the two groups. There was no major safety concern.
Conclusions: There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale.

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Letters to the Editor
13 June 2005
Modafinil for fatigue in MS: A randomized placebo-controlled double-blind study
George H. Kraft, University of Washington
James Bowen
We read with interest the study by Stankoff et al. [1] We have also examined the management of fatigue in MS [2] and have since had the opportunity to use multiple fatigue medications in our patients and observe their putative effects. Clinically, we note that modafinil works well to relieve fatigue in most MS patients and this has been supported by two pilot trials. [3,4]

Consequently, the result in the paper by Stankoff, et al that modafinil produces no improvement in fatigue was surprising. [1] The diagnosis of fatigue in MS patients is difficult. Depression, which is common in MS [5], as well as cognitive impairment, can produce symptoms in common with fatigue. Many of the questions on the Modified Fatigue Impact Scale (scores > 45 on the MFIS were used to define fatigue) are affected by depression, cognitive impairment, or both. Perhaps the interplay of these three symptoms dilutes the effect of modafinil on fatigue as measured by the MFIS.

In addition, it is possible that the unusual dosing regimen in the Stankoff trial may have been a factor in the negative results. Dosing recommendations listed in the PDR are for a daily a.m. dose. Modafinil has a half-life of greater than 15 hours, and it is conceivable that the dosing schedule of the study (a.m. and noon) might have impaired the quality of sleep and resulted in additional daytime fatigue. Although a mid-day dose may be necessary in an occasional patient, the Stankoff study routinely used a BID schedule.

Finally, this study includes patients who were treated with medications for fatigue if those medications were withdrawn at least 14 days prior to randomization. This potentially selects subjects who are refractory to treatment since those who are successful in treating their fatigue are unlikely to stop a beneficial treatment in order to enter a placebo-controlled study. The authors did find that modafinil tended to provide benefit in their subset of patients with excessive daytime sleepiness. It still may be that dosing modafinil in the recommended manner (i.e., a single dose) is effective in appropriately selected MS patients.

References

1. Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 2005;64:1139-1143.

2. Kraft GH, Freal JE, Coryell JK. Disability, disease duration, and rehabilitation service needs in multiple sclerosis: patient perspectives. Arch Phys Med Rehabil 1986;67:164-168.

3. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002;72:179-183.

4. Zifko UA, Rupp M, Schwarz S, Zipko HT, Maida EM. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002;249:983-987.

5. Chwastiak L, Ehde DM, Gibbons LE, Sullivan M, Bowen JD, Kraft GH. Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample. Am J Psychiatry 2002;159:1862-1868.

13 June 2005
Reply to Kraft et al
Bruno Stankoff, Centre d'Investigation Clinique
Emmanuelle Waubant, Catherine Lubetzki, Michel Clanet for the French Modafinil Study Group

We thank Kraft and Bowen for their comments about our recent study. [1] They were surprised by our results and note that modafinil worked well on fatigue in their current practice. In our study, patients treated with modafinil also felt better at the end of the study when compared to baseline, but the improvement was not greater than in patients treated by placebo. We are certain that if the same patients were not evaluated in a controlled study, it could be concluded that modafinil was indeed effective for fatigue, despite that improvement was mainly linked to a placebo effect.

We agree that fatigue may be influenced by depression or cognitive symptoms and that common scales for fatigue also account for those symptoms. However, our study should have allowed the identification of any specific pharmacologic effect of modafinil on fatigue, independent from depression or cognition, because we did not include patients with depression or dementia, and those symptoms (evaluated respectively by MADRS and Trail Making Test) did not differ between groups at baseline and were not significantly modified during the study. In addition, whereas FIS and MFIS contain items related to depression or cognition, we also measured a specific VAS for fatigue as a secondary endpoint. Interestingly this scale showed exactly the same evolution as MFIS.

We can not definitively rule out that the dosing schedule used in this study (am and noon) could have strengthened the influence of study drug on sleep, but this should not impact the final result as only 8/56 patients treated with modafinil had insomnia.

Regarding inclusion criteria, we have included patients who could be refractory to other existing treatment. However, this should not deeply modify the conclusion of the study, as we know that patients who respond well to these treatments are rare. In future studies, we should further restrict inclusion criteria, especially concerning the level of sleepiness, which should be high for all patients. This symptom is frequently associated or confounded with fatigue, and it might represent the real target and the best indication for modafinil.

7 June 2005
Modafinil for fatigue in MS: A randomized placebo-controlled double-blind study
Kottil W. Rammohan, Ohio State University
Deborah Joanne Lynn

Stankoff et al recently reported that modafinil failed to improve MS-related fatigue. [1] This study conflicts with our earlier study in which a strong favorable effect of modafinil over placebo was demonstrated in the treatment of MS related fatigue (p = <0.001). [2]

We have several concerns regarding the recent study, in particular the dosing regimen that was used. Stankoff et al confirmed our earlier observation that a dose of 400 mg of modafinil was not effective as compared to placebo. The more useful dose of 200 mg was not examined. By failing to examine patients during their dose titration, the study in effect failed to identify any beneficial effect of modafinil.

The authors indicate that over 90% of patients reached dosage levels of 300 mg or more. MFIS, the primary measure of efficacy, was only administered at screen, baseline and day 35. The authors rule out a dose effect on the basis of the only test administered during dose titration, the VAS. As to whether VAS data was captured in all patients at 200 mg is unclear because it is not shown. The 400 mg dose was probably not effective because unpleasant side effects overshadowed efficacy on fatigue. The high drop-out rate due to adverse events and intolerance indicate this.

In this study, modafinil lowered the scores on every tested fatigue scale, but the effect was dwarfed by an unprecedented treatment effect from the placebo group not seen in any previous study. Of concern is that this placebo effect also negated any beneficial effect of modafinil as a wake-promoting agent, since the placebo was as effective as modafinil group in promoting wakefulness (Fig. 2). This conflicts with the sleep scores recorded in our study as well as the many other studies that have examined modafinil as a wake-promoting agent.

It is unfortunate that this study failed to use the information from our earlier trial to study a dose that showed benefit, but instead chose to study a dose of modafinil that had previously been shown to be ineffective. Some patients with MS do not tolerate 400 mg of modafinil, but report that lower doses of modafinil have improved their quality of life standards.

This useful agent should not be disregarded on the basis of the present study which failed to examine the more useful lower dose.

References

1. Stankoff B, Waubant E, Confavreux C, et al and the French Modafinil Study Group Modafinil for fatigue in MS: A randomized placebo-controlled double-blind study. Neurology 2005; 64: 1139-1143.

2. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld A, Pollak CP, Nagaraja HN. Efficacy and Safety of Modafinil (Provigil) for the Treatment of Fatigue inmultiple sclerosis - a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002;72:179-183.

7 June 2005
Reply to Rammohan et al
Bruno Stankoff, Centre d'Investigation Clinique
Emmanuelle Waubant, Catherine Lubetzki, Michel Clanet for the French Modafinil Study Group

We thank Rammohan et al for their comments on our study [1] which is in contrast with their previous study. [2] They question whether this discrepancy could be explained by the different dose-regimen used (200 mg/day versus 200-400 mg/day). Although this is an important point, we think that this does not explain the lack of difference between modafinil and placebo for the following reasons:

i) Concerning side effects, we have performed a per-protocol analysis, in which patients who discontinued treatment for safety reasons were excluded: in this analysis there was no difference between groups. Moreover, during the titration period, the dosage of study drug was increased only in patients who tolerated well their current dosage.

ii) Concerning the dose regimen, in [2], fatigue was improved in the modafinil group compared to placebo at the end of the 200 mg treatment phase, but not at the end of the 400 mg phase. As this study was not randomized, with the same sequence of treatments for all patients, a placebo effect weaning off over time is possible. During our study, we have captured a VAS for fatigue during the titration period (see figure). All patients received 200 mg/day of modafinil or placebo during the first week of treatment and at day 7 (no missing data) both groups improved compared to baseline, with no difference between groups. Patients were subsequently offered each week to increase the dosage. At day 21, 93% and 72% of patients had reached the dosage of 300 mg and 400 mg respectively. Only 2 and 5 VAS were missing at day 14 and 21 respectively. There was no benefit of modafinil over placebo during titration.

iii) Concerning the placebo effect, which has already been described in previous study in MS [3], was not surprising considering that MS fatigue is a very subjective and fluctuant symptom. This emphasizes the crucial need for a rigorous methodology aimed at neutralizing confounders in all trials evaluating MS fatigue. In this respect double- blinding and randomization appear mandatory.

Rammohan comment on the lack of difference between treatment groups concerning sleepiness. Sleepiness was elevated in our cohort reinforcing the concept that it may contribute to the complaint of fatigue in MS. [4] Our study was not specifically designed to assess whether modafinil could improve sleepiness among patients complaining of sleepiness-related fatigue. To answer this question, specific scales assessing sleepiness or wakefulness should be used in addition to general fatigue scales, which probably lack specificity, and we agree that lower doses should be tested.

References

1. Stankoff B, Waubant E Confavreux C, et al. Modafinil for fatigue in MS. A randomized placebo-controlled double-blind study. Neurology 2005;64:1139-1143.

2. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002;72(2):179-183.

3. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. The Canadian MS Research Group. Can J Neurol Sci 1987; 14(3):273-278.

4. Attarian HP, Brown KM, Duntley SP, Carter JD, Cross AH. The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch Neurol.2004;61: 525-528.

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Neurology®
Volume 64Number 7April 12, 2005
Pages: 1139-1143
PubMed: 15824337

Publication History

Published online: April 11, 2005
Published in print: April 12, 2005

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Affiliations & Disclosures

B. Stankoff, MD, PhD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
E. Waubant, MD, PhD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
C. Confavreux, MD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
G. Edan, MD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
M. Debouverie, MD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
L. Rumbach, MD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
T. Moreau, MD, PhD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
J. Pelletier, MD, PhD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
C. Lubetzki, MD, PhD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
M. Clanet, MD, PhD
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.
French Modafinil Study Group
From the Fédération de Neurologie (Drs. Stankoff and Lubetzki), Centre d’Investigation Clinique (Drs. Stankoff and Waubant), Hôpital de la Salpêtrière, AP-HP, Paris, France; Services de Neurologie, CHU de Lyon (Dr. Confavreux), Rennes (Dr. Edan), Nancy (Dr. Debouverie), Besançon (Dr. Rumbach), Dijon (Dr. Moreau), and Marseille (Dr. Pelletier); Fédération de Neurologie (Dr. Clanet), CHU de Toulouse, France; and UCSF MS Center (Dr. Waubant), San Francisco, CA.

Notes

Address correspondence and reprint requests to Dr. Bruno Stankoff, Centre d’Investigation Clinique, Hôpital de la Salpêtrière, 47 boulevard de l’Hôpital, 75651 Paris cedex 13, France; e-mail: [email protected]

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