Modafinil in the treatment of idiopathic hypersomnia without long sleep time a randomized, double-blind, placebo-controlled study

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1 J Sleep Res. (2015) 24, Modafinil and hypersomnia Modafinil in the treatment of idiopathic hypersomnia without long sleep time a randomized, double-blind, placebo-controlled study GEERT MAYER 1,2, HEIKE BENES 3, PETER YOUNG 4, MARION BITTERLICH 1 and ANDREA RODENBECK 5 1 Hephata Klinik, Schwalmstadt-Treysa, Germany, 2 Department of Neurology, Philipps-Universit at Marburg, Marburg, Germany, 3 Department of Neurology, University of Rostock, Rostock, Germany, 4 Department for Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany, 5 Charite-Universit atsmedizin Berlin, Berlin, Germany Keywords adverse events, clinical global impression, Epworth Sleepiness Scale, idiopathic hypersomnia without long sleep, maintenance of wakefulness tests, modafinil, sleep diaries, sleep latency Correspondence Geert Mayer, Hephata Klinik, D Schwalmstadt-Treysa, Schimmelpfengstr. 6, Germany. Tel.: ; fax: ; geert.mayer@hephata.com Accepted in revised form 18 June 2014; received 14 October 2013 DOI: /jsr SUMMARY In 2010 the European Medicines Agency withdrew the indication of modafinil for the treatment of obstructive sleep apnea, shift work sleep disorder and for idiopathic hypersomnia (IH). In uncontrolled studies, modafinil has been reported to be efficacious in the treatment of sleep disorders. We therefore performed a randomized, placebo-controlled study with the aim of proving the efficacy of modafinil treatment in these patients. Drug-free IH patients without long sleep according to ICSD2 criteria, age >18 years and disease duration >2 years were included. After a washout phase, patients at baseline received placebo or 100 mg modafinil in the morning and at noon over 3 weeks, followed by 1 week without medication. At each visit the Epworth Sleepiness Scale () and Clinical Global Impression () rating scale were performed. At baseline and on days 8 and 21 four Maintenance of Wakefulness Tests (MWTs)/day or per day were performed. Patients kept a sleep wake diary throughout the study. Between 2009 and 2011 three sleep centres recruited 33 participants. Compared to placebo, modafinil decreased sleepiness significantly and improved mean sleep latency in the MWT non-significantly. The improved significantly from baseline to the last visit on treatment. The most frequent adverse events were headaches and gastrointestinal disorders; skin and psychiatric reactions were not reported. The number of reported naps and duration of daytime sleepiness decreased significantly. Total sleep time of nocturnal sleep was slightly reduced. The sleep diaries showed increases in feeling refreshed in the morning; the diurnal diaries showed significant improvement of performance and of exhaustion. Modafinil is an effective and safe medication in the treatment of IH. Adverse events are mild to moderate. INTRODUCTION Idiopathic hypersomnia (IH) is a lifelong sleep disorder characterized by persistent daytime sleepiness that cannot be compensated by sleep. IH patients suffer from the same impaired quality of life and psychosocial consequences as narcolepsy patients (Ozaki et al., 2008). The International Classification of Sleep Disorders (ICSD2) distinguishes two types of IH (ICSD 2005): patients with IH with long sleep time have a major sleep episode > 10 h at least once a week; patients with IH without long sleep suffer from excessive 74 daytime sleep only. In both IH types, sleep latencies in the Multiple Sleep Latency Test (MSLT) are <8 min with fewer than two sleep onset rapid eye movement (REM) (SOREM) phases. Daytime sleep episodes are not refreshing. Sleep drunkenness is common in a quarter of these patients. IH is a rare disorder. The prevalence is estimated at between 0.5 per individuals (Bassetti and Aldrich, 1997). However, insufficient classification and lack of clear hallmark symptoms cause difficulties in discriminating it from other types of hypersomnia, and thus the prevalence remains vague. Most of the studies in IH patients used criteria that did

2 Modafinil versus placebo in idiopathic hypersomnia 75 not include MSLT tests, as required for the diagnosis (ICSD2). To date, only one prospective study for the treatment of patients with IH has been published (Bastuji and Jouvet, 1988). The effect of modafinil has been evaluated in 18 patients with IH without long sleep (mean age: years). Daytime sleepiness and sleep attacks were assessed using sleep diary data. Improvements were observed at the initiation of treatment, and peaked during the second month. During month 2 of treatment, results from 15 patients showed significant reductions from baseline in daytime drowsiness (60%) and number of sleep episodes (80%). In retrospective studies, approximately 75% of all IH patients with excessive daytime sleepiness and non-refreshing sleep episodes benefit from a stimulant treatment (Bassetti and Aldrich, 1997). The clearest improvements in daytime sleepiness could be achieved by treatment with methylphenidate (40 60 mg day 1 ), dextroamphetamine (10 15 mg day 1 ) and pemoline (112.5 mg day 1 ). Amphetamines are the only stimulants available in many European countries. Amphetamines have been labelled in none of the European countries for use in IH. Modafinil is the only drug that had a marketing authorization for the treatment of patients with IH in some European countries (France, Poland, Sweden, Norway and Turkey). However, the European Medicines Agency (EMA) ( ines/human/referrals/modafinil/human_referral_ jsp &mid=wc0b01ac05805c516f) withdrew the indication of modafinil for the treatment of IH due to the following reasons: On the basis of the available data the Committee concluded that the benefits of these medicines only outweighed their risks in the therapeutic indication narcolepsy, a chronic sleep disorder characterized by excessive daytime sleepiness. For all other indications the Committee found that the risk for development of skin or hypersensitivity reactions and neuropsychiatric disorders outweighed the evidence for clinically important efficacy. So far, most of the studies have been retrospective (Ali et al., 2009; Lavault et al., 2011; Sonka and Susta, 2012), and based on definitions that did not necessarily meet the ICSD2 criteria. Nevertheless, the American Academy of Sleep recommended modafinil as a reasonable option for the treatment of hypersomnias of central origin (Morgenthaler et al., 2007). Recently a group of paediatricians has shown that modafinil can be a successful and safe treatment in children and young people with narcolepsy (Lecendreux et al., 2012). AIM OF THE STUDY Due to the lack of studies meeting evidence-based criteria and internationally accepted classification, we began this investigator-initiated proof-of-concept study. The primary aims of this randomized, double-blind, placebo-controlled study on the efficacy of modafinil treatment versus placebo in patients with idiopathic hypersomnia without long sleep were to assess changes of sleepiness after 3 weeks of doubleblind treatment subjectively, using the Epworth Sleepiness Scale () and objectively, by sleep latencies in the Maintenance of Wakefulness Test (MWT). The secondary aims included changes in the Clinical Global Impression () rating scale (item: severity of illness), laboratory tests and vital signs, number and type of adverse events, number of unintended daytime naps and responder rates defined as scores 10 at final visit on medication. With the exception of the assessment of adverse events, the change between baseline and after 3 weeks of treatment of all listed parameters was compared. In order to reach an effect size of 0.9, we calculated that 40 IH patients had to be recruited. Study protocol Inclusion criteria comprised patients with idiopathic hypersomnia without long sleep time according to ICSD2, age: >18 years, disease duration >2 years with reported onset between age 10 and 30 years, Beck Depression Inventory (BDI) <16 points, hypocretin-1 in cerebrospinal fluid (if performed) >110 pg ml 1 and the patient s consent to the study protocol. Exclusion criteria included hypersomnia caused by psychiatric, neurological or internal disease or another sleep disorder (restless legs syndrome, sleep apnea with an apnea/hypopnea index >15/h or per h), unstable or nonaccepted (i.e. stimulants, prazosin) co-medication, pathological electroencephalograph (ECG), laboratory test or vital signs that could cause hypersomnia, skin, multi-organ hypersensitivity reaction or exacerbation of psychiatric disorder after exposure to modafinil and inability to refrain from stimulants or activating antidepressants after the washout period. All included patients complained about excessive daytime sleepiness for at least 3 months. The total sleep time in the polysomno-graphies lasted 6 9 h, the mean sleep latency was min and one patient had sleep-onset REM (Table 1). Four patients had one sleep-onset REM in one of five MSLTs. After a wash-out phase (93 half-life of co-medication, at least 1 week) patients received placebo or 100 mg modafinil at visit (V)2 (baseline) in the morning and at noon over 3 weeks up to V5, followed by 1 week without medication in both the placebo and modafinil groups (Fig. 1). Ali et al. (2009) reported that only 25 of 85 patients on a daily modafinil monotherapy dose of mg stayed with modafinil despite complete symptomatic relief in 72%. Because we expected that recruitment would be difficult and wanted to keep the dropout rate low, we decided not to titrate patients up to 400 mg daily, but to have them on a low dose of 100 mg twice a day. At each visit and were performed. At baseline (V2) and on days 8 (V3) and 21 (V5) four MWTs/day or per day were performed (Littner et al., 2005). Sleep latencies >

3 76 G. Mayer et al. Table 1 Demographic data Placebo Modafinil P-value No Gender 10 m/4 f 9 male/8 female NS Age (years) (31.01, 45.70) (27.83, 41.70) NS Age at onset (years) (13.24, 27.04) (17.53, 30.24) NS Duration of symptoms (years) (9.63, 26.80) 8.00 (6.92, 14.84) 0.09 BMI (24.62, 31.24) (23.81, 29.13) NS Premedicated patients 4 (28.6%) Modafinil: 4 patients 4 (23.5%) Modafinil: 2 patients, methyphenidate: 2 patients Habitual bedtime (min) (454.32, ) (470.71, ) NS Diagnostic PSG and MSLT Performed (years before study starts) 0.00 (0.06, 1.37) 0.00 ( 0.07, 3.36) NS Mean SL in MSLTs 5.80 (4.78, 6.59) 5.90 (5.34, 6.99) NS No. of pts. with 1 SOREMs in MSLTs 2 (14.2%) 3 (17.6%) or nocturnal PSG TST (min) (370.34, ) (376.77, ) NS SE (%) (84.22, 95.31) (87,22, 93,15) NS SL (min) (12.07, 24.37) (14.29, 31.71) NS N3 (%) (17.44, 33.26) (12.07, 28.11) NS REM (%) (16.00, 23.51) (16.92, 23.53) NS AHI 1.10 (0.61, 3.98) 1.30 (0.45, 3.10) NS Comorbidities (number of patients, %) Hypertension 4 (28.6) 2 (11.8) NS Hyperthyreosis 1 (7.1) 3 (17.6) NS Headache/migraine 1 (7.1) 2 (11.8) NS Allergy/asthma 7 (50.0) 6 (35.3) NS Reflux 2 (14.3) 1 (5.9) NS Coronary heart disease 1 (7.1) NS Herniatic vertebral disc/back pain 3 (21.4) 2 (11.8) NS NS, not significant; PSG, polysomnography; MSLT, multiple sleep latency test; TST, total sleep time; SE, sleep efficiency; SL, sleep latency; N3, sleep stage non-rapid eye movement (NREM) 3 (slow wave sleep); REM, rapid eye movement sleep; AHI, apnea hypopnea index. Data given as medians and 95% confidence interval (CI). Days 7 to 28: sleep-wake diary twice daily Days 1 to 1: wash-out Days 2 to 21: 2 x 100 mg modafinil or placebo in a double-blind, randomised setting Days 22-28: withdrawal V1 day 7 V2 day 1 baseline V3 day 8 V4 day 15 V5 day 21 V6 day 28 Study inclusion MWT MWT MWT Figure 1. Study protocol. V = visit; MWT = Maintenance of Wakefulness test; = Epworth Sleepiness Scale; = Clinical Global Impression scale min were considered to be normal (Doghramji et al., 1997). Patients kept a sleep wake diary throughout the study (Liendl et al., 2004). The medication was blinded and assigned randomly in blocks of four by the Pharmacy of the Asklepios Kliniken Schwalmstadt, Germany. The study was approved by the EMA (EudraCt number ), the ethical committee (EC) of the Chamber of Physicians, federal state Hessen, Frankfurt, Germany, the EC of the Chamber of Physicians Mecklenburg-Pommerania, Germany, Schwerin and the EC of the University of Münster, Germany. All patients signed a written informed consent as required by the EC. Patients Between 2009 and 2011 three sleep centres (Schwalmstadt, Münster and Schwerin) recruited 33 patients. As many of the patients were working and were not willing to accept 3 days

4 mean value Modafinil versus placebo in idiopathic hypersomnia 77 Table 2 Changes in, sleep latency in MWT and from V2 to V5 V2 (baseline) V5 (end of treatment) Delta (=diff) P (diff) t-value Effect size Placebo (13.55, 15.45) (10.15, 15.14) 1.50 ( 3.80, 0.089) Modafinil (12.57, 16.13) 8.00 (6.42,11.58) 6.00 ( 7.67, 2,92) MWT Placebo (8.85, 18.89) (9.42, 21.33) 0.19 ( 2.94, 5.96). NS Modafinil (n = 15) (8.70, 18.47) (10.88, 26.01) 3.00 (0.11, 9.61) Placebo 6.00 (5.45, 6.12) 5.50 (4.94, 5.92) 0.00 ( 0.84, 0.13) Modafinil (n = 16) 6.00 (5.46, 6.16) 5.00 (3.64, 5.24) 1.00 ( 2.26, 0.31) Delta (=diff): differences between baseline [visit (V)2] and V5. Data given as medians and 95% confidence interval (CI)., Epworth Sleepiness Scale; MWT, Maintenance of Wakefulness test;, Clinical Global Impression scale; NS, not significant. off work for the MWT, we were not able to reach the goal of including 40 patients. Patients followed their daily sleep wake schedule, partially including short sleep times. After 2.5 years an interim analysis revealed significant results of the primary parameters, allowing study closure. Thirty-one of 33 patients entered the statistical evaluation. One patient dropped out at baseline and one patient was a screen failure. There was no difference in age, age of symptoms onset, gender, body mass index (BMI) or number of premedicated patients (Table 1). However, there was a trend towards a longer disease duration in the placebo group. Data calculation and statistical analysis Statistics were performed with Statistica version 10. Data are presented as medians and 95% confidence intervals (95% CI). P < 0.05 was considered significant, P < 0.1 as a trend. As we performed a proof-of-concept study, no prior or posthoc power calculation was performed. MWTs were performed four times per day following international conventions, therefore the mean sleep latency per day was used for further statistical analysis. Diary data were pooled per week for each patient, except for the information on alcohol consumption and the number and duration of daytime sleep episodes, which were summarized per week and subject. Concerning MWT, and, the difference between baseline and end of treatment was calculated for each subject. Group comparisons based on these differences were assessed by using two-tailed t-tests for MWT, and diary data and Wilcoxon s non-parametric test for the. Additionally, values for each visit were analysed by multivariate analyses of variance (MANOVAs) with repeated measurements followed by post-hoc t-tests, respectively, and a Duncan test for sores with Friedman analyses of variance (ANOVAs). In order to assess effects of gender, age or centre, further covariance analyses were performed. The responder rate and adverse events were analysed by v 2 tests, while the effect sizes were calculated by Cohen s procedure of variance. RESULTS Overall, modafinil decreased sleepiness significantly compared to placebo, and improved clearly but not significantly the mean sleep latency in the MWT. Effects of age, gender *** # *** *** *** * # * * 0 Baseline V3 V4 V5 Figure 2. Epworth Sleepiness Scale () scores for modafinil and placebo. The solid line represents scores for the placebo groups (n = 14) over time, the dashed line modafinil (n = 17). #P < 0.1; *P < 0.05; ***P < Signs between the lines indicate group differences, signs above or below a line indicate the comparison with baseline. V = visit. V Baseline 1 week (V3) 3 weeks (V5) Figure 3. Mean Maintenance of Wakefulness test (MWT) sleep latency. V = visit. *P < 0.05 compared to baseline; solid line = placebo; dashed line = modafinil.

5 78 G. Mayer et al. 35 Baseline (V2) One week (V3) Three weeks (V5) 30 MWT sleep latency (min.) MWT MWT MWT Figure 4. Maintenance of Wakefulness test (MWT) sleep latencies given for each single MWT per group. V = visit; dotted line = placebo; dashed line = modafinil. or sleep centre could be ruled out (data not shown in detail). Epworth Sleepiness Scale () Modafinil reduced daytime sleepiness significantly as measured by the by more than five points compared to a reduction of 1.8 points in the placebo group (P = 0.023) (Table 2, Fig. 2). One patient in the placebo group and two patients in the modafinil group showed normal scores at baseline. The responder rate was significantly higher under modafinil compared to placebo. In detail, 12 of 17 treated patients reached normal value 10 points under modafinil medication and only three patients after placebo (P = ). Within the modafinil group, responders did not differ from non-responders concerning age, sex, age of onset, disease duration, premedication, BMI, baseline score or MWT sleep latency at baseline. Although gender did not influence the treatment effect on, it is of note that the difference between V2 and V5 was smaller in men than in women in both treatment groups. The day-to-day MANOVA (F = ; df = 4, P = ) revealed significant group 9 visit interaction (Fig. 2), thereby indicating a decreased sleepiness after 1, 2 and 3 weeks of treatment in the modafinil group only. Maintenance of wakefulness tests (MWT) Sleep latency in the MWT did not improve significantly in the modafinil or placebo groups by comparing the calculated difference between V2 and V5 (Table 2). Also, over all three time-points MANOVA showed no significant group effect, but indicated that sleep latency became generally longer from one visit to the next (F = 4.258; df = 2; P = 0.019). Post-hoc analysis revealed an increased sleep latency at V5 in the modafinil group only (P < 0.05) (Fig. 3). The additional analysis of the sleep latencies of each single MWT showed that sleep occurred later in the first morning MWTs at V3 and V5 in the modafinil group, with P < 0.05 compared to both baseline modafinil and placebo values of the same day and time-point (Fig. 4). Severity of illness () The severity of illness changed significantly in the modafinil group compared to baseline, resulting in a significantly larger V2 V5 difference (Table 2). While groups did not differ at Table 3 Adverse events (AEs) Placebo Modafinil v 2 P No. of patients 9 (64.3%) 9 (52.9%) NS with AEs Sum of AEs all 10 (33.3%) 20 (66.6%) patients Headache 1 (3.3%) 8 (26.4%) Gastrointestinal, 2 (6.6%) 6 (19.8%) total Cold, flu-like 4 (13.2%) 2 (6.6%) infection Dizziness 1 (3.3%) Palpitation 1 (3.3%) Dry mouth 1 (3.3%) Panic attack 1 (3.3%) Back pain 1 (3.3%) Tachycardia 1 (3.3%) Numbness of hands 1 (3.3%) NS, not significant.

6 Modafinil versus placebo in idiopathic hypersomnia 79 baseline or after withdrawing medication (V6), MANOVA and post-hoc analysis revealed significant group differences, with an improvement in the modafinil group at V4 and V5 (data not shown in detail). Laboratory tests and vital signs did not change throughout the studies and did not differ between the modafinil and placebo groups. Modafinil caused significantly more headaches (P = 0.01) and gastrointestinal complaints (P = ) compared to placebo, which were also the most frequent adverse events (Table 3). However, the number of patients with/without adverse events did not differ between the groups. Sleep wake diaries The evening questionnaire (Table 4) revealed that bedtimes, relaxation and alcohol consumption were similar in both groups and did not change throughout the study. MANOVAs showed a significant interaction of week and group for the items effectiveness/performance, exhaustion and number of daytime naps per week as well as a trend for total daytime sleep per week. Performance and exhaustion improved significantly at weeks 2 and 3 of active treatment, while no changes could be found under placebo. The number of daytimes naps was halved from weeks 1 to 2 in both groups, but this effect was stable over treatment time in the modafinil group only, followed by an increase in the withdrawal week. A similar effect could be seen for total daytime sleep per week. Morning questionnaire In contrast to the evening questionnaires, the MANOVAs of the morning items showed no relevant significant effects or group differences, besides the feeling of being less refreshed in the modafinil group in the baseline week (F = , P = ). However, they felt more refreshed under active treatment, while there was no change under placebo. Sleep latency, number and duration of nocturnal awakenings, final Table 4 Evening diaries throughout the study period Evening diary, means, sums Week 0 baseline (V1 V2) Week 1 (V2 V3) Week 2 (V3 V4) Week 3 (V4 V5) Week +1 withdrawal (V5 V6) MANOVA group 9 week interaction 1. Tense relaxed (6 ranks, 1 6, inverse scale)* M NS Pl P 2. Effectiveness/performance (6 ranks, 1 6, inverse scale)* M F = Pl P = P NS NS 3. Exhaustion (4 ranks, 0 3)* M F = Pl P = P NS NS NS 4. No. of naps per week M F = Pl P = P NS NS Sum of total daytime sleep per week (min) M F = Pl P = P NS NS NS No. of days with alcohol consumption M NS Pl P 7. Sum alcohol units per week M NS Pl P 8. Bedtime (lights off)* M 23:20 1:20 23:44 1:07 23:49 1:21 23:30 1:05 23:19 1:24 NS Pl 22:56 1:01 23:12 1:12 23:07 1:14 23:02 0:53 23:19 1:18 P Pl, placebo group; M, modafinil group; NS, not significant; V, visit. Data are given as means standard deviation, post-hoc between-group comparisons were only performed if multivariate analysis of variance (MANOVA) was significant. * = mean per week, based on individual mean per week and patient.

7 80 G. Mayer et al. awakening and rising time did not differ between the groups or showed MANOVA effects (data not given in detail). MANOVA of sleep duration revealed a trend (F = 2.154, P = 0.081) due to a sleep reduction of 1 h in the modafinil group in the first treatment compared to baseline ( h at baseline, h in week 1). DISCUSSION Our study shows that 100 mg modafinil given twice daily in patients with IH is a highly effective treatment. This randomized, double-blind, placebo-controlled study is the first, to our knowledge, that provides evidence of the effectiveness of modafinil in this adult patient group on a high evidence-based level. The effectiveness is underlined by the fact that the primary goal of reducing subjective sleepiness as measured by the was highly significant, although we failed to recruit the estimated number of patients to reach an effect size of 0.9. The difference of gender effect of modafinil and placebo on in V2 and V5 may be caused by the pharmacogenetic difference described in patients with narcolepsy by Dauvilliers et al. (2002). The subjective ratings in confirmed the significant effect of modafinil already found in older controlled trials (Bastuji and Jouvet, 1988; Billiard, 1996). The effect on the objective measurement of improvement of sleepiness as measured by the MWT was not significant, although it showed a slight tendency for longer sleep latencies compared to placebo. Therefore, a stronger effect might be reached with higher doses. The MWT is thought to be able to measure changes in the ability to stay awake in pharmacological studies (Littner et al., 2005). However, in other double-blind, randomized, placebo-controlled studies in hypersomnias of central origin the MWT only showed significant changes when the highest dose was applied, as in a study in narcolepsy patients with 9 g of sodium oxybate (Black and Houghton, 2006), although normalization was not reached. A meta-analysis of modafinil in narcolepsy (Golicki et al., 2010) showed improvement of sleep latencies in the MWT that were not sufficient to reach normalization (mean >18.9 min). In our study, patients treated with modafinil had a higher frequency of headaches (19 versus 11%), and lower frequency in palpitation (1 versus 13%) than patients in a recently published French study (Lavault et al., 2011) and in the modafinil multi-centre study by Mitler et al. (2000). Patients did not indicate suffering from nervousness, but they had a somewhat high amount of gastrointestinal complaints, as has been reported in earlier studies. The frequency of adverse events is higher than in narcoleptic patients, but this difference is not remarkable. As intervening variables have not been tested, we do not think that the difference is due to a different pathomechanism, but rather to the intake of different amounts of modafinil and the controlled study conditions. Compared to the same study, our patients had a much better effect of modafinil on ( versus ) than in the French study. Rather, improvement of resembled that of a long-term study with mazindol (1 6 mg) in narcolepsy and IH patients that were refractory to stimulants (Nittur et al., 2013). Our data clearly indicate that there is in contrast to the evaluation of the EMA a positive benefit/risk ratio. Major psychiatric or skin reactions could not be documented. Because the study lasted only 4 weeks and these reactions may occur in the course of long-term treatment, they might still occur. The sleep diaries support the data found in the and. The number of reported naps and duration of daytime sleepiness decreased significantly. Minor reduction in total sleep time of nocturnal sleep may be considered as a side effect. With these sleep diaries we could also show for the first time that the feeling of being refreshed was increased in the morning. Significant changes in the estimation of performance and reduction of exhaustion are an indicator that modafinil has the capacity to improve the quality of life which do not seem to be due to over-estimation as the results are not exceedingly high. Study limitations The study period of 3 weeks was too short to observe longterm adverse events such as skin or cardiovascular reactions. Looking at the evening morning protocols, we saw highly different sleep wake times in individual patients. Three patients slept only 5 6 h during week nights, and slept much longer during weekends, which was due to their work schedules and family duties. One patient had a mean total sleep time at night of 11 h. This high variation of sleep times and sleep habits shows that patients with IH without long sleep time are not a homogeneous group and are not in favour of the operationalization by the ICSD2. Therefore, the new ICSD3 (2014) states for IH: that a division of the disorder based on the length of nocturnal sleep lacks validity and patients with IH tend to overestimate their sleep time by a mean of 0.99 h, thus making the fundamental criterion for distinguishing between patients with long and shorter sleep inaccurate. Most probably, some of these patients would have fitted into the group of hypersomnia due to insufficient sleep. Nevertheless, they met the ICSD2 criteria. Taking this problem into consideration, we have run the statistics again by excluding all the patients with uncommon sleep times (n = 11) and came up with exactly the same significant result (data not shown in detail). In our opinion, this shows the robustness of modafinil s efficacy as a stimulant. ACKNOWLEDGEMENT This investigator-initiated study was supported by Cephalon GmbH, Germany. AUTHOR CONTRIBUTIONS GM initiated the study and performed all the formal applications (EMA, BfArM, ethical committees), recruited all patients

8 Modafinil versus placebo in idiopathic hypersomnia 81 from the Schwalmstadt site and wrote the article. HB and PY recruited patients and contributed to the article. AR performed the statistics and revised the article. CONFLICT OF INTEREST GM has received honoraria for speaker bureaux from UCB Pharma/Brussels, Genzyme, Desitin, is a member of advisory boards for UCB Pharma/Brussels and Genzyme and is a managment director of the Study Center Kassel Wilhelmshoehe. HB is a member of advisory boards for UCB Pharma/Brussels and Mundipharma. PY has received honoraria for speaker bureaux from UCB Pharma, Genzyme, Heinen and L owenstein and Teva. AR is a management director of the Study Center Kassel Wilhelmshoehe. REFERENCES Ali, M., Auger, R. R., Slocumb, N. L. and Morgenthaler, T. I. Idiopathic hypersomnia: clinical features and response to treatment. J. Clin. Sleep Med., 2009, 15: American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic and Coding Manual, 2nd edn. American Academy of Sleep Medicine, Westchester, IL, American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, Bassetti, C. and Aldrich, M. S. Idiopathic hypersomnia. Brain, 1997, 120: Bastuji, H. and Jouvet, M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog. Neuropsychopharmacol. Biol. Psychiatry, 1988, 12: Billiard, M. Idiopathic hypersomnia. Neurol. Clin., 1996, 14: Black, J. and Houghton, W. C. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep, 2006, 29: Dauvilliers, Y., Neidhart, E., Billiard, M. and Tafti, M. Sexual dimorphism of the catechol-o-methyltransferase gene in narcolepsy is associated with response to modafinil. Pharmacogenom. J., 2002, 2: Doghramji, K., Mitler, M. M., Sangal, R. B. et al. A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr. Clin. Neurophysiol., 1997, 103: European Medicines Agency: http: // jsp?curl=pages/medicines/human/referrals/modafinil/human_referral_ jsp&mid=wc0b01ac05805c516f Golicki, D., Bala, M. M., Niewada, M. and Wierzbicka, A. Modafinil for narcolepsy: systematic review and meta-analysis. Med. Sci. Monit., 2010, 16: RA177 RA186. Lavault, S., Dauvilliers, Y., Drouot, X. et al. Benefit and risk of modafinil in idiopathic hypersomnia vs. narcolepsy with cataplexy. Sleep Med., 2011, 12: Lecendreux, M., Bruni, O., Franco, P. et al. Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J. Sleep Res., 2012, 21: Liendl, S., Lauer, C. J. and Hoffmann, R. M. Pre-screening via sleep logs in sleep-disordered patients adaptational effects, yes or no? Somnologie, 2004, 8: Littner, M. R., Kushida, C., Wise, M. et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep, 2005, 28: Mitler, M. M., Hirsh, J., Hirshkowitz, M., Guilleminault, C. and for the US Modafinil in Narcolepsy Multicenter Study Group. Long-term efficacy and safety of modafinil (PROVIGIL â ) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med., 2000, 1: Morgenthaler, T. I., Kapur, V. K., Brown, T. et al. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep, 2007, 30: Nittur, N., Konofal, E., Dauvilliers, Y. et al. Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review. Sleep Med., 2013, 14: Ozaki, A., Inoue, Y., Nakajima, T. et al. Health related quality of life among drug-naive patients with narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia without long sleep time. J. Clin. Sleep Med., 2008, 15: Sonka, K. and Susta, M. Diagnosis and management of central hypersomnias. Ther. Adv. Neurol. Disord., 2012, 5: