Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

Abstract

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

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Open
The orexin system has been implicated in the regulation of
functions such as reward seeking,1 feeding behavior,2 locomo-
tion and physical activity,3–5 and arousal from sleep and the
sleep–wake cycle.6,7 Orexin-A and orexin-B (also known as
hypocretin-1 and hypocretin-2, respectively) are neuropep-
tides that bind to the G protein–coupled receptors orexin-1 and
orexin-2.8–10 In rats as well as in humans, orexin levels in cer-
ebrospinal fluid have been shown to fluctuate with the circadian
cycle.11–13 The levels are highest at the end of the wake-active
period and lowest at the end of the sleep period.11–13 Orexin
deficiency has been linked to narcoleptic symptoms such as
sudden sleep attacks and cataplexy, in animals14–16 as well as
in humans.17,18
Experiments in mice and rats have shown that orexin recep-
tor antagonists have sleep-enabling effects.3,19 The dual orexin
receptor antagonist almorexant elicits somnolence without
cataplexy in healthy rats, dogs, and humans when given dur-
ing the active phase of the circadian cycle.20 A phase I study
investigating single-dose daytime administration of almorex-
ant in healthy human subjects showed dose-dependent phar-
macodynamic effects, with reductions in vigilance, alertness,
visuomotor, and motor coordination observed for the 400- and
1,000-mg doses.21 In the same study, pharmacoelectroencepha-
lography profiles showed that almorexant decreases alpha Pz–Oz
and increases beta Fz–Cz activities, as well as delta and theta
power.21 The increase in delta and theta power may potentially
1Actelion Pharmaceuticals Ltd., Allschwil, Switzerland; 2Medical University of Vienna, Vienna, Austria; 3Siesta Group Schlafanalyse GmbH, Vienna, Austria; 4Somni Bene
Institute for Medical Research and Sleep Medicine, Schwerin, Germany; 5Center for Sleep Medicine, Charité Campus Mitte, Berlin, Germany; 6Competence Center
Sleep Medicine, University Medicine Berlin, Charité Campus Benjamin Franklin, Berlin, Germany; 7Centre d’Investigacio de Medicaments, Hospital de la Santa Creu i
Sant Pau, Barcelona, Spain; 8Technion Sleep Medicine Center, Rambam Medical Center, Haifa, Israel; 9Medical University of Vienna, Vienna, Austria; 10Sleep Research
Unit, Department of Physiology, University of Turku, Turku, Finland; 11Tampere University Hospital, University of Tampere, Tampere, Finland; 12Institute of Physiology,
Charité University Medicine and the German Heart Institute Berlin, Berlin, Germany; 13University Hospital for Neurology, Medical University of Vienna, Vienna,
Austria; 14ScanSleep, Copenhagen, Denmark; 15Helsinki Sleep Clinic, Vitalmed Research Centre and Department of Neurology, University of Helsinki, Helsinki,
Finland; 16University Hospital Zurich, Zurich, Switzerland; 17Current address: Neurology Department, Neurocenter of Southern Switzerland, Lugano, Switzerland;
18Innsbruck Medical University, Innsbruck, Austria; 19The London Sleep Centre, London, UK; 20Psychiatric University Clinics (UPK) Basel, Basel, Switzerland;
2189B Uppsala Akademiska Hospital, Uppsala, Sweden; 22Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 23University Hospital Giessen and
Marburg, Marburg, Germany; 24Actelion Pharmaceuticals Italia, s.r.l., Imperia, Italy; 25University of Regensburg, Regensburg, Germany; 26Current address: Department
of Psychiatry, Psychotherapy and Psychosomatic Medicine, Social Foundation Bamberg, Teaching Hospital of the University of Erlangen, Bamberg, Germany.
*Deceased. Correspondence: J Dingemanse (jasper.dingemanse@actelion.com)
Received 7 November 2011; accepted 27 December 2011; advance online publication 2 May 2012. doi:10.1038/clpt.2011.370
Orexin Receptor Antagonism, a New
Sleep-Enabling Paradigm: A Proof-of-Concept
Clinical Trial
P Hoever1, G Dorffner2, H Beneš3,4, T Penzel5, H Danker-Hopfe6, MJ Barbanoj7*, G Pillar8, B Saletu9,
O Polo10,11, D Kunz12, J Zeitlhofer13, S Berg14, M Partinen15, CL Bassetti16,17, B Högl18, IO Ebrahim19,
E Holsboer-Trachsler20, H Bengtsson21, Y Peker22, U-M Hemmeter23, E Chiossi24, G Hajak25,26 and
J Dingemanse1
The orexin system is a key regulator of sleep and wakefulness. in a multicenter, double-blind, randomized, placebo-
controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist
almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The
primary end point was sleep efficiency (se) measured by polysomnography; secondary end points were objective latency
to persistent sleep (lps), wake after sleep onset (Waso), safety, and tolerability. Dose-dependent almorexant effects
were observed on se, lps, and Waso. se improved significantly after almorexant 400 mg vs. placebo (mean treatment
effect 14.4%; P < 0.001). lps (–18 min (P = 0.02)) and Waso (–54 min (P < 0.001)) decreased significantly at 400 mg vs.
placebo. adverse-event incidence was dose-related. almorexant consistently and dose-dependently improved sleep
variables. The orexin system may offer a new treatment approach for primary insomnia.

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indicate slow-wave sleep. Hence, inhibiting the orexin system
with almorexant could represent a novel approach to the treat-
ment of insomnia.
Insomnia is a persistent problem in ~10% of adults,22–24
with primary insomnia estimated to be present in ~25% of
patients with chronic insomnia.25 Sleep-maintenance prob-
lems and nocturnal awakenings are more prevalent than
sleep-onset difficulties.26,27 Nonpharmacologic treatments
are often preferred;28 however, eventually, most patients
either seek pharmacologic treatment or remain untreated.29
Current standard pharmacologic treatments for insomnia
include the benzodiazepine receptor agonists, (which poten-
tiate the activity of γ-aminobutyric acid at the ionotropic
γ-aminobutyric acid-A receptor), and the melatonin receptor
agonist ramelteon. Benzodiazepine receptor agonists include
benzodiazepines that decrease sleep latency and increase
sleep time,30–32 with some agents also improving sleep
maintenance.30,32 However, benzodiazepines have been asso-
ciated with daytime drowsiness, tolerance, dependency, and
withdrawal symptoms.33–35 Newer benzodiazepine receptor
agonists (nonbenzodiazepines) and ramelteon decrease sleep
latency,33,36,37 whereas some agents, such as eszopiclone and
modified-release zolpidem, increase sleep time and improve
sleep maintenance.38,39 The side-effect profiles of nonbenzodi-
azepines and ramelteon appear to be better than those of ben-
zodiazepines, with fewer next-day effects observed.33,35–37,40
New insomnia therapies with different mechanisms of action
are currently under investigation with the aim of further
improving tolerability and sleep maintenance and specifically
targeting sleep–wake architecture.41,42
We performed a two-part clinical study to evaluate the effect
of almorexant on sleep in patients with primary insomnia. The
primary objective was to determine the minimum dose of almo-
rexant that would have a significant effect on sleep efficiency
(SE). In the first part of the study, the effect of almorexant on SE
was evaluated at a high dose of 400 mg; thereafter, we conducted
the dose-ranging part of the study, which aimed to identify the
minimum effective dose. The safety and tolerability of almorex-
ant and its effect on objective and subjective sleep variables were
also evaluated.
Results
Between May 2006 and August 2007, 368 patients were screened
and 161 were enrolled. Supplementary Figure S1 online shows
a summary of study enrollment and the patients treated at each
dose level. The main reasons for screening failure were total
sleep time (TST) >6 h and/or latency to persistent sleep (LPS)
<20 min. Overall, eight patients were excluded from the per-
protocol analysis: two of these did not complete the second
treatment night because of adverse events (AEs) and six were
excluded because of technical difficulties during polysomnog-
raphy. The per-protocol analysis set therefore consisted of 153
patients. The mean age of all the patients treated was 45.2 years
(60% in the age group 41–60 years); 66.5% were women; 98.8%
were Caucasian, 0.6% were Hispanic, and 0.6% were Asian. The
mean body mass index was 24.2 kg/m2.
efficacy
Objective polysomnographic assessments. The mean values for
objective sleep variables on the screening/adaptation night
and the almorexant and placebo treatment nights for almo-
rexant 400, 200, 100, and 50 mg are reported in Table 1. SE
significantly improved after a single 400-mg dose of almo-
rexant, relative to placebo (mean treatment effect 14.4%; P <
0.001), thereby demonstrating the efficacy of almorexant at
this dose level (Figure 1a). A dose-related increase in SE was
observed with almorexant 100, 200, and 400 mg relative to pla-
cebo (Figure 1a). The lowest effective dose was 100 mg (mean
treatment effect 4.6%; P = 0.02). No significant treatment effect
was observed for a dose of 50 mg (mean treatment effect 3.3%;
P = 0.23), and enrollment was stopped in accordance with the
study protocol. As a result, only six patients were recruited to
the 25-mg dose group, and consequently the efficacy data for
this dose group are not reported; however, the data for these
patients were included in the safety analysis. The robustness
of the main analysis was confirmed by similar findings for the
all-treated analysis, which persisted even after adjustment for
period and carryover effects (see Supplementary Table S1
online). LPS was significantly reduced after the 400-mg dose of
almorexant relative to placebo (mean treatment effect –18 min;
P = 0.02; Figure 1b). Wake after sleep onset (WASO) declined
significantly in response to the 400-mg dose relative to placebo
(mean treatment effect –54 min; P < 0.001), and dose-related,
clinically relevant, and nominally significant improvements
were observed after almorexant doses of 200 (P < 0.001) and
100 mg (P = 0.004) (Figure 1c).
Exploratory polysomnography measurements showed dose-
related increases in mean TST for almorexant 400, 200, and
100 mg as compared with placebo (Figure 1d). Almorexant
400 mg was associated with a mean of 411.8 min sleep vs.
342.1 min with placebo. Higher almorexant doses reduced
latencies to S1 (400 mg), S2, S3, and S4 sleep stages (200 mg)
(data not shown). Latency to rapid eye movement (REM) sleep
decreased dose-dependently (Figure 1e). Almorexant 400 mg
decreased the time spent in S1 and increased the time spent
in S2, S3, S4, and REM sleep stages, as compared with placebo
(Table 2). Similar but less pronounced effects were observed
after the 200- and 100-mg doses. The percentage of TST spent
in S1 decreased dose-dependently and the percentage of TST
spent in REM increased dose-dependently after 400 and 200 mg
as compared with placebo. The percentages of TST spent in S2,
S3, and S4 were similar after placebo and after almorexant, irre-
spective of the almorexant dose.
Subjective assessments. The mean values for subjective assess-
ments on the night of the screening/adaptation and on the
nights of almorexant (400-, 200-, 100-, and 50-mg doses) and
placebo treatments are given in Table 3. Self-reported patient
assessments showed dose-related increases in subjective SE
(Figure 2a) and decreases in subjective sleep latency after
almorexant 400 and 200 mg relative to placebo (Figure 2b).
No treatment differences were observed for mean subjective
WASO at any almorexant dose relative to placebo (Figure 2c).

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Subjective TST increased dose-dependently (Figure 2d).
Subjective sleep quality improved after almorexant 400 and
200 mg relative to placebo (Figure 2e). Awakening quality and
somatic complaint subscores were similar among treatments
(data not shown).
Next-day performance. Overall, no relevant negative residual
effects of the previous night’s treatment were observed after
any of the almorexant doses relative to placebo with respect to
subjective alertness levels (Bond and Lader visual analog scale;
Figure 3a). With respect to mean reaction time (Figure 3b),
there was a small increase after almorexant 400 mg only
(mean treatment effect 34.7 ms (95% confidence interval 4.9–
64.5 ms)). Almorexant had no effect on the scores in the fine-
motor test (data not shown); in the digit span test, a lower for-
ward score was observed for almorexant 200 mg as compared
with placebo (mean treatment effect –0.41 (95% confidence
interval –0.80 to –0.01)) (data not shown).
safety
Overall, a larger proportion of patients reported at least one AE
after almorexant administration than after placebo (21.9% vs.
13.8%). Dizziness, nausea, fatigue, headache, and dry mouth
were the most common AEs reported after almorexant treat-
ment (Table 4). The proportion of patients with one or more AE
was highest after almorexant 400 mg (40.0%) but was markedly
lower after doses of 200, 100, and 50 mg (12.8, 17.9, and 13.9%,
respectively). There was one serious AE (vasovagal syncope after
placebo treatment) and no deaths. Other than the serious event,
all AEs were of mild or moderate severity. One patient discontin-
ued the study because of a febrile upper respiratory tract infection
after receiving almorexant 400 mg (unrelated to study treatment);
another discontinued because of the aforementioned serious AE.
No treatment-related changes in laboratory parameters, vital signs,
or quantitative electrocardiogram variables were observed, nor
did any electrocardiogram abnormalities develop. No narcolepsy
or cataplexy events were reported, and no trend or dose relation-
ship was detected by the narcoleptic effects questionnaire.
Discussion
This is the first study to suggest that the orexin system may play
a role in nocturnal sleep regulation in humans and that orexin
receptor antagonism results in sleep-enabling effects in patients
with primary insomnia. It extends and confirms previous pre-
clinical and clinical observations.20,21 In this two-part clini-
cal study in patients with primary insomnia, a significant and
clinically relevant increase in SE was observed after almorexant
400 mg, and the lowest effective dose was 100 mg. Almorexant
400 mg significantly improved sleep initiation as assessed by
LPS, and at doses ≥100 mg almorexant dose-dependently and
significantly decreased WASO, a measure of sleep maintenance.
Almorexant decreased latency to REM sleep in a dose-depend-
ent manner and decreased latencies to S1–S4 sleep stages at
the higher doses, while increasing TST. The drug reduced the
time spent in S1 and increased the time spent in REM sleep.
At all doses ≥100 mg, it had similar effects on the percentages
table 1 Mean values of objective sleep variables for the screening/adaptation night and the treatment nights
almorexant dose level
screening/
adaptation
placebo
almorexant
400 mg
screening/
adaptation
placebo
almorexant
200 mg
screening/
adaptation
placebo
almorexant
100 mg
screening/
adaptation
placebo
almorexant
50 mg
Variable
n = 39
n = 38
n = 38
n = 32
SE
% (SD)
63.4 (14.1)
71.0(14.9)
85.4(8.7)a
64.2(15.2)
75.6(15.2)
83.8(11.8)a
60.7(14.3)
78.1(12.8)
82.7(10.1)a
62.7(10.1)
75.4(16.7)
78.7(9.1)
LPS
min (SD)
74.3(53.1)
54.2(43.7)
36.2(31.6)a
73.5(55.1)
38.7(35.5)
28.2(24.1)
78.5(41.1)
46.9(49.5)
36.5(29.3)
97.8(59.8)b
49.6 (35.6)b
43.9(33.4)b
WASO
min (SD)
119.0(46.0)
94.0(56.5)
40.0(29.0)a
124.1(57.5)
86.9(59.6)
52.7(54.1)a
127.6(50.0)
68.5(46.7)
48.4(40.3)a
115.2(46.2)
69.6(47.3)
62.9(37.9)
TST
min (SD)
306.8(68.6)
342.1(71.3)
411.8(42.2)a
308.1(71.8)
363.1 (73.6)
402.3(56.9)a
291.7(68.9)
375.8 (61.4)
397.2(48.7)a
301.2(48.5)
362.0 (80.1)
377.9(43.5)
Latency to REM
min (SD)
134.3(60.7)c
121.9(66.3)
76.6(38.8)a
154.5(74.6)d
127.6 (63.1)
96.9(54.6)a
135.5(59.9)e
105.7 (45.7)
93.6(40.4)
151.7(81.0)b
122.7 (50.4)b
108.2(51.7)b
LPS, latency to persistent sleep; REM, rapid eye movement; SE, sleep efficiency; TST, total sleep time; WASO, wake after sleep onset.
aSignificant difference in treatment effect observed between the almorexant and placebo treatment nights (P < 0.05). P value determined by paired t-test. bn = 31 patients with evaluable data. cn = 38 patients with evaluable data.
dn = 36 patients with evaluable data. en = 37 patients with evaluable data.

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of TST spent in the S1 and REM sleep stages. The increase in
time spent in REM sleep brought the percentage of TST spent
in REM to approximately within the normal range, generally
20–25% in normal young adults43 and decreasing with age to
18% in men and 19% in women (age range 61–70 years).44 These
results indicate that the administration of an almorexant dose as
low as 100 mg caused an increase in the TST during the night,
mainly by improving sleep maintenance. This dose level admin-
istered in the daytime did not result in detectable impairment
of vigilance, alertness, or visuomotor and motor coordination
in healthy subjects.21
Consistent effects were generally observed between objective
and subjective assessments of sleep variables, particularly with
respect to SE, TST, and LPS, although differences were apparent
at the lower almorexant doses. The drug had no effect on sub-
jective WASO at any dose, although objective WASO decreased
dose-dependently and patients reported improved sleep qual-
ity. This absence of an effect on subjective WASO warrants
0
400 mg
(n = 39)
14.4
8.2
4.6
3.3
P < 0.001
P < 0.001
P = 0.02
P = 0.23
200 mg
(n = 38)
100 mg
(n = 38)
50 mg
(n = 32)
Almorexant dose
Improvement Improvement
Improvement
Improvement
Improvement
Primary end point: sleep efficiency
Placebo–corrected mean treatment
effect +95% CI (%)
2
4
6
8
20
18
16
14
12
10
a
P < 0.001
P = 0.39
–70
–80
50 mg
(n = 32)
c
P < 0.001
P = 0.004
400 mg
(n = 39)
0
–10
–20
–30
–40
–50
–60
200 mg
(n = 38)
100 mg
(n = 38)
Almorexant dose
Secondary end point: wake after sleep onset
Secondary end point: latency to persistent sleep
Almorexant dose
Placebo–corrected mean treatment
effect –95% CI (min)
–54.0
–34.3
–20.1
–6.7
400 mg
(n = 39)
200 mg
(n = 38)
100 mg
(n = 38)
50 mg
(n = 31)
0
–5
–10
–15
–20
–25
–30
–35
P = 0.02
P = 0.10
P = 0.16
P = 0.44
b
Placebo–corrected mean treatment
effect –95% CI (min)
–18.0
–10.4–10.4
–5.7
400 mg
(n = 39)
200 mg
(n = 38)
100 mg
(n = 38)
50 mg
(n = 32)
Almorexant dose
Placebo–corrected mean treatment
effect +95% CI (min)
d
P < 0.001
P < 0.001
P = 0.02
P = 0.22
10
0
20
30
40
50
60
70
80
90
Total sleep time
21.4
15.8
69.7
39.3
e
P < 0.001
P = 0.02
P = 0.17
P = 0.12
400 mg
(n = 39)
0
–10
–20
–30
–50
–40
–60
–70
–80
200 mg
(n = 38)
100 mg
(n = 38)
50 mg
(n = 31)
Almorexant dose
Latency to rapid-eye-movement sleep
Placebo–corrected mean treatment
effect –95% CI (min)
–45.2
–30.7
–12.1
–14.5
Figure 1 Treatment effects of almorexant on objective sleep variables. Mean changes relative to placebo with 95% CIs. CI, confidence interval.

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further investigation in future studies using other sleep-diary
assessments. With respect to all the objective sleep variables,
improvements were observed in the mean values from the night
of screening/adaptation to that after placebo treatment. This
may be due to an improvement in the patients’ comfort with
the equipment and sleep laboratory procedures.
Two residual effects on next-day performance, namely,
increased mean reaction time and a lower forward score on
the digit span test, were detected in association with the higher
almorexant doses (400 and 200 mg, respectively). Given that
the major goal for insomnia therapies is to improve sleep
maintenance without affecting next-day performance, further
investigation of any potential next-day effects after almorexant
treatment at the therapeutic dose would be valuable. Of the cur-
rent standard pharmacologic treatments used for sleep mainte-
nance indications, benzodiazepines are associated with next-day
effects; however, nonbenzodiazepine agents such as eszopiclone
and controlled-release zolpidem cause minimal or no residual
daytime effects.35,39,40,45
The safety profile of almorexant was similar to that of placebo
for the lower doses, and an increase in the incidence of AEs
was evident only for the 400-mg dose. There was no evidence
of narcolepsy or cataplexy as seen from AE reporting and the
narcoleptic effects questionnaire. The decrease in latencies to
REM after almorexant administration deserves further attention
and should be studied in larger trials at the therapeutic doses.
Shortened REM latency could potentially point to narcolepsy-
like changes in sleep architecture or potential direct effects of
dual orexin receptor antagonists on sleep; alternatively, it could
indicate REM rebound in individuals susceptible to chronic par-
tial REM deprivation.
The strengths of this study include the trial design, which
involved the initial administration of a high dose of almorex-
ant followed by decreasing doses in subsequent stages. This
design allowed the efficacy of almorexant at a high dose to be
established first before determining the lowest effective dose.
Limitations of the study include the shortness of the treatment
duration from which to assess the efficacy, safety, and tolerability
of almorexant. The sleep-enabling and -maintaining effects and
long-term safety and tolerability of dual orexin receptor antago-
nist treatment need to be assessed in large, long-term, ran-
domized trials. This step is essential for new insomnia therapies
because long-term use of current pharmacologic treatments can
be associated with the development of tolerance and depend-
ence, and with rebound insomnia on their withdrawal.22,46,47
The clinical development of almorexant was discontinued in
January 2011 for reasons not related to any of the observations
in our study.48
In conclusion, in this study, a single dose of the dual orexin
receptor antagonist almorexant enabled initiation and mainte-
nance of sleep in patients with primary insomnia. Almorexant
treatment was associated with a dose-dependent improvement
in SE, strongly suggesting that the endogenous orexin system
plays an important role in the sleep–wake cycle. Consistent
improvements were observed in sleep time, initiation, and main-
tenance, and in the patients’ perception of sleep. Small effects
on next-day performance were observed only after the higher
almorexant doses. No safety concerns were revealed. Overall,
table 2 Mean values of time in sleep stages and percentage of each sleep stage of total sleep time for the treatment nights
almorexant dose level
placeboalmorexant 400 mg placeboalmorexant 200 mg placeboalmorexant 100 mg
sleep stage
n = 39
n = 38
n = 38
Stage 1
Time, min (SD)35.4 (18.0)29.2 (16.1)a
34.8 (17.1) 28.4 (12.4)a
28.0 (12.2) 24.2 (11.2)a
Percentage of TST, % (SD)10.6 (5.4)7.1 (4.0)a
10.1 (6.0)7.5 (4.6)a
7.8 (4.3)6.3 (3.2)a
Stage 2
Time, min (SD)194.3 (53.8) 231.8 (45.8)a
210.4 (57.4) 227.4 (49.3)209.9 (48.6)227.9 (49.3)a
Percentage of TST, % (SD)56.6 (9.0) 56.2 (9.2)57.9 (11.0)56.7 (10.6)55.9 (10.3) 57.7 (11.6)
Stage 3
Time, min (SD) 24.7 (14.3) 33.8 (22.1)a
28.3 (17.1)30.4 (16.7) 38.4 (25.9) 40.4 (25.2)
Percentage of TST, % (SD)7.3 (4.0) 8.2 (5.2)8.1 (6.4) 7.3 (3.7)9.9 (6.2) 10.0 (5.9)
Stage 4
Time, min (SD) 31.2 (30.4)37.4 (35.7)a
30.4 (31.2)36.6 (32.4)a
26.9 (30.1) 28.8 (28.7)
Percentage of TST, % (SD)9.3 (9.0)9.3 (9.0) 8.0 (7.3) 8.9 (7.6)7.1 (7.9)7.0 (6.7)
REM
Time, min (SD) 56.5 (23.5)79.6 (27.7)a
59.1 (24.8) 79.5 (26.6)a
72.7 (27.0)75.9 (24.9)
Percentage of TST, % (SD)16.2 (5.1) 19.2 (5.9)a
15.9 (5.6)19.7 (5.7)a
19.3 (6.4)19.0 (5.7)
Data for almorexant 400, 200, and 100 mg doses only shown; no significant differences were observed between the almorexant 50 mg and placebo treatment nights.
REM, rapid eye movement; TST, total sleep time.
aSignificant difference in treatment effect observed between the almorexant and placebo treatment nights (P < 0.05). P-value determined by paired t-test.

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table 3 Mean values of subjective sleep variables and next-day performance for the screening/adaptation night and the treatment nights
almorexant dose level
screening/
adaptation
placebo
almorexant
400 mg
screening/
adaptation
placebo
almorexant
200 mg
screening/
adaptation
placebo
almorexant
100 mg
screening/
adaptation
placebo
almorexant
50 mg
Variable
n = 39
n = 38
n = 38
n = 32
SE
Evaluable data, n
36
37
37
37
37
37
35
36
36
30
30
30
% (SD)
56.7 (17.8)
62.3 (16.1)
73.0 (14.8)a
52.3 (22.0)
61.7 (23.3)
68.5 (17.8)a
52.3 (20.1)
66.7 (18.4)
68.9 (19.1)
61.2 (24.3)
65.2 (25.6)
69.7 (18.4)
Sleep latency
Evaluable data, n
34
34
34
34
34
34
33
35
35
29
30
30
min (SD)
93.8 (63.2)
81.5 (65.8)
42.8 (31.8)a
101.2 (84.7)
76.3 (69.5)
45.7 (34.7)a
100.2 (90.8)
78.5 (73.7)
60.2 (45.1)
86.5 (59.8)
63.0 (55.8)
60.7 (50.0)
WASO
Evaluable data, n
34
34
34
34
34
34
33
34
34
28
29
29
min (SD)
115.9 (75.5)
93.0 (65.1)
91.1 (73.9)
118.7 (63.5)
98.3 (68.9)
94.7 (48.6)
127.2 (69.1)
85.3 (56.8)
92.2 (68.2)
80.5 (64.3)
95.0 (79.2)
78.8 (69.1)
TST
Evaluable data, n
36
37
37
37
37
37
36
37
37
30
30
30
min (SD)
276.4 (89.0)
300.9 (77.9)
356.0 (74.0)a
253.5 (106.6) 300.3 (115.2)
331.6 (83.6)a
255.6 (96.4)
322.3 (88.1)
333.1 (95.1)
278.2 (105.5) 303.7 (112.6) 328.8 (84.7)
Sleep quality
Evaluable data, n
39
39
39
38
38
38
37
37
37
32
32
32
SSA (SD)
19.2 (4.0)
18.6 (3.8)
14.8 (4.5)a
20.9 (3.4)
18.3 (4.9)
16.6 (4.8)a
19.1 (4.3)
16.3 (4.9)
15.1 (4.6)
18.1 (3.7)
17.0 (4.4)
16.3 (4.5)
Next-day performance alertness
Evaluable data, n
38
39
39
38
38
38
38
38
38
32
32
32
mm (SD)
57.5 (17.7)
60.4 (16.0)
56.7 (15.5)
58.9 (18.8)
60.1 (20.0)
62.5 (18.5)
61.9 (22.0)
62.7 (20.5)
67.3 (19.7)
64.0 (17.4)
64.3 (19.4)
64.7 (16.0)
Reaction time
Evaluable data, n
25
29
29
33
34
34
30
34
34
27
28
28
ms (SD)
845.0 (174.2) 844.8 (145.2) 879.5 (167.3)a797.9 (115.3) 830.9 (152.3) 811.2 (141.9) 899.9 (237.8) 900.1 (189.0) 898.9 (208.1) 826.1 (176.9) 830.1 (105.0) 840.1 (122.8)
SE, sleep efficiency; SSA, self-rating sleep and awakening quality questionnaire; TST, total sleep time; WASO, wake after sleep onset.
aSignificant difference in treatment effect observed between the almorexant and placebo treatment nights (P < 0.05). P value determined by paired t-test.

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dual orexin receptor antagonism may offer a potential new treat-
ment approach for primary insomnia.
MethoDs
study design. This was a prospective, multicenter, multistage, double-
blind, randomized, placebo-controlled, two-way crossover, single-
dose study involving almorexant in patients with primary insomnia.
The study was conducted at 20 centers across Europe and Israel (6 in
Germany; 3 in Austria; 2 each in Finland, Sweden, and Switzerland;
and 1 each in Denmark, Israel, the Netherlands, Spain, and the United
Kingdom). The study design incorporated two parts: a first part to
determine the efficacy of almorexant at a high dose followed by a sec-
ond part with dose-descending stages to establish the minimum effec-
tive dose. In the first part of the study, the patients received a single
dose of 400 mg oral almorexant and a placebo on different treatment
nights 1 week apart, in a crossover design. The patients were allocated
0
2
4
6
8
10
12
14
16
18
P < 0.001
P = 0.01
P = 0.46
P = 0.28
400 mg
(n = 37)
200 mg
(n = 37)
Almorexant dose
100 mg
(n = 36)
50 mg
(n = 30)
400 mg
(n = 37)
200 mg
(n = 37)
Almorexant dose
100 mg
(n = 36)
50 mg
(n = 30)
Improvement
Subjective sleep efficiency
Placebo–corrected mean treatment
effect +95% CI (%)
a
10.7
6.9
2.2
4.4
0
10
20
30
40
50
60
70
80
90
P < 0.001
P = 0.03
P = 0.44
P = 0.21
Improvement
Subjective total sleep time
Placebo–corrected mean treatment
effect +95% CI (min)
d
n=30
55.1
31.4
10.8
25.2
0
–10
–20
–30
–40
–50
–60
–70
P = 0.002
P = 0.002
P = 0.11
P = 0.84
400 mg
(n = 34)
200 mg
(n = 34)
100 mg
(n = 35)
50 mg
(n = 30)
Almorexant dose
Improvement
Subjective sleep latency
b
Placebo–corrected mean treatment
effect –95% CI (min)
–38.6
–30.6
–18.3
–2.4
–50
400 mg
(n = 34)
P = 0.87
–1.9
P = 0.75
P = 0.53
P = 0.30
50 mg
(n = 29)
200 mg
(n = 34)
Almorexant dose
100 mg
(n = 34)
Improvement
Subjective wake after sleep onset
Placebo–corrected mean treatment
effect ±95% CI (min)
–40
–30
–20
30
20
10
0
–10
c
6.9
–16.2
–3.6
0
–1
–2
–3
–4
–5
–6
P < 0.001
P < 0.05
P = 0.06
P = 0.39
400 mg
(n = 39)
200 mg
(n = 38)
100 mg
(n = 37)
50 mg
(n = 32)
Almorexant dose
Improvement
Subjective sleep quality
e
Placebo–corrected mean treatment
effect –95% CI (SSA subscore)
–3.7
–1.7
–1.2
–0.8
Figure 2 Treatment effects of almorexant on subjective sleep variables. Mean changes relative to placebo with 95% CIs. CI, confidence interval; SSA, self-rating
sleep and awakening quality questionnaire.

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in a 1:1 ratio to the two treatment sequences (placebo/almorexant and
almorexant/placebo) on the first treatment night, using a computer-
generated randomization list. The study treatments were indistinguish-
able with respect to packaging, appearance, and number of capsules
administered. The duration of the washout period and the timing of
study drug administration were based on pharmacodynamic and
pharmacokinetic data from a previous ascending single-dose study of
almorexant in healthy subjects. Almorexant was rapidly absorbed, with
a median time to maximum concentration ranging from 0.7 to 2.3 h
and rapid decreases to ~20% of peak plasma concentrations over the
course of 8 h after time to maximum concentration.21 The pharmaco-
dynamics of the drug correlated well with the concentration levels and,
in general, the onset of pharmacodynamic effects was observed within
1 h after the dose.21
If the primary end point treatment effect was found to be significant
(P < 0.05), the study continued with the next lower dose (200, 100, 50,
or 25 mg) in new patients sequentially until the treatment effect was no
longer statistically significant. When the number of patients success-
fully screened reached the target sample size for a dose level, subsequent
patients were assigned to the next dose level. Therefore some patients
entered the next dose level before the outcome for the previous dose
was known. After study enrollment was completed, all the patients were
scheduled to complete all periods and assessments. If the primary end
point was not significant at 400 mg, 1,000 mg was to be tested against
placebo in new patients. For each dose level, patients underwent a screen-
ing period (up to 4 weeks), first treatment night, 1-week washout period,
second treatment night, and 28-day post-treatment follow-up. Patients
were required to complete a daily sleep log for at least 1 week before the
screening/adaptation night, 1 week before the first treatment night, and
during the 1-week washout period before the second treatment night.
The sleep log consisted of a “day questionnaire” and the self-rating sleep
and awakening quality questionnaire (SSA).49 The “day questionnaire”
assessed the patient’s daily habits regarding meals, caffeine-containing
beverages, alcoholic drinks, smoking, nonstudy medication, and naps.
In addition, information on the patient’s well-being, physical and emo-
tional stress, and expected stressful events was collected. The investigator
reviewed the sleep log and assessed the patient’s well-being and compli-
ance before each polysomnography recording. Polysomnography was
performed for 8 h overnight during the screening/adaptation night and
each treatment night. The purpose of the screening/adaptation night
was to objectively confirm the subjectively patient-reported pattern of
sleep disturbances relating to TST and sleep onset latency. The screening/
adaptation night also served to accustom the patient to the sleep labora-
tory, the polysomnography equipment, and the psychometric tests. All
polysomnography results were analyzed in accordance with the rules of
Rechtschaffen and Kales, using the validated Somnolyzer 24 × 7 scoring
tool50–52 and including a structured expert review. Sleep was scored in
30-s epochs. During treatment nights, a single dose of almorexant or pla-
cebo was administered 30 min before the start of the polysomnography.
The patients were required to remain at the center the morning following
the polysomnography until they were free of symptoms possibly related
to sleep-enabling medication, as judged by the physician responsible.
Patients. Male and female patients 18–65 years of age were eligible for
inclusion if they had primary insomnia (by the criteria of the Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition—Text
Revision) and a history (≥3 months) of subjectively reported usual TST
of 3–6 h, usual sleep disturbance with a subjective sleep onset latency
of >30 min, and daytime complaints associated with poor sleep. Other
inclusion criteria were polysomnographic confirmation of TST of <6 h
and LPS ≥20 min during the screening/adaptation night; a body mass
index of 18–30 kg/m2; no clinically relevant abnormalities as shown
by a 12-lead electrocardiogram and by hematology/biochemistry test
results; willingness to refrain from central nervous system-active drugs
for five half-lives of the drug (at least 1 week); and a negative urine test for
barbiturates, cannabinoids, amphetamines, and cocaine. Psychotropic
drugs were not permitted, except hypnotics with a short half-life of ≤10 h
taken ≥48 h before each treatment night; other stable medications were
allowed. Cytochrome P450 isoenzyme 3A4 inhibitors were not per-
mitted within 1 week before screening. Key exclusion criteria included
major depressive disorder, severe psychosis, or significant anxiety disor-
der; a score >2 on the symptom assessment questionnaire for diagnosis of
apnea,53 a raw score ≥50 on the Zung Self-Rating Depression or Anxiety
Scale;54,55 and restless legs syndrome or insomnia associated with or
caused by sleep apnea or periodic limb movement disorder, as assessed
by polysomnography during the screening night (defined as apnea/
hypopnea index >10/h or periodic limb movement arousal index >10/h,
respectively). Caffeine consumption of >7 U/ day was not permitted on
a regular basis (one unit of caffeine was defined as one cup of coffee or
two cups of tea). Pregnancy and lactation were also exclusion criteria.
Women with childbearing potential were administered urine pregnancy
tests at predefined time points during the study and were required to use
a reliable method of contraception during the entire study duration and
for at least 3 months after intake of the study drug.
study end points. The primary end point was SE as determined by
polysomnography, where SE (%) = (TST in minutes/total time in bed in
minutes (fixed to 480 min)) × 100. Secondary end points, determined
by polysomnography, were LPS (the time in minutes from the start of
recording to the beginning of the first 20 nonwake epochs) and WASO
(the time in minutes spent awake after sleep onset until the end of the
recording, where sleep onset is the time of the first occurrence of three
400 mg
(n = 39)
P = 0.19
–3.7
2.4
P = 0.40
P = 0.05
P = 0.88
200 mg
(n = 38)
100 mg
(n = 38)
50 mg
(n = 32)
Almorexant dose
VAS alertness
Placebo–corrected mean treatment
effect ±95% CI (mm)
–15
–10
–5
0
15
10
5
a
4.6
0.3
400 mg
(n = 29)
200 mg
(n = 34)
100 mg
(n = 34)
50 mg
(n = 28)
P = 0.02
P = 0.08
P = 0.94
P = 0.50
Almorexant dose
Mean reaction time
Placebo–corrected mean treatment
effect ±95% CI (ms)
–60
–40
–20
0
80
60
20
40
b
–1.2
–19.6
34.7
10.0
Improvement
Improvement
Figure 3 Treatment effects of almorexant on next-day alertness and
performance (reaction time test). Mean changes relative to placebo with 95%
CIs. CI, confidence interval; VAS, visual analog scale.

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consecutive epochs in S1 or first occurrence of S2). Exploratory end
points measured by polysomnography included TST (the amount of
actual sleep time in minutes in the total sleep period), latency to sleep
stages (the time in minutes from the start of the polysomnography
recording to the first occurrence of the respective sleep stage) including
REM sleep (the time in minutes from sleep onset to the first occurrence
of REM), and time spent (in minutes) and percentage of TST for each
of the sleep stages; and subjective measures of SE, sleep latency, WASO,
TST, and sleep quality, assessed using the SSA. Next-day performance
and alertness after treatment nights were assessed using the Bond and
Lader visual analog scale, which assesses 16 subjective feelings;56 fine-
motor testing, reaction time testing;57,58 and both forward and back-
ward digit span testing.59
safety assessments. AEs and serious AEs occurring within 36 h of
administration of study treatment were recorded, irrespective of
whether they were considered to be related to the study treatment. Any
AE that continued for 24 h after the last drug intake was monitored for
up to 28 days. Clinical laboratory tests, vital signs, 12-lead electrocardi-
ogram, and a subjective narcoleptic effects questionnaire were assessed
the morning after study drug administration. The narcoleptic effects
questionnaire was specifically designed for this study; it evaluated
symptoms of cataplexy and sleep paralysis seen in narcolepsy with a
series of yes/no questions on muscle relaxation/weakness and dreams.
statistical analysis. This dose-ranging study was powered to detect a
placebo-corrected mean difference in SE of 6.5%. SE was assumed to
be normally distributed, with a standard deviation of 9.8%; no period
or carryover effects were expected. The desired power for each dose
level (1,000, 400, 200, 100, 50, and 25 mg) was 98%, 98%, 96%, 94%,
94%, and 94%, requiring 39, 39, 34, 31, 31, and 31 patients, respectively.
This approach was used to maximize the power for the first dose tested
(400 mg) and to have ≥80% actual power at the 50 mg dose level. By this
calculation, a minimum of 78 patients (400 and 1,000 mg dose levels)
and a maximum of 166 patients (400, 200, 100, 50, and 25 mg dose lev-
els) were required for the study. The null hypothesis of no difference
between each dose and placebo was tested using a two-sided paired
t-test on the per-protocol analysis set, and rejected when P < 0.05. If
the null hypothesis was rejected, secondary end points were to be
sequentially tested (i.e., first LPS, then WASO) using a two-sided paired
t-test. Robustness analyses of the primary and secondary end points
included the Wilcoxon signed-rank test, and analysis of the all-treated
set using all available data. For the primary end point, carryover and
period effects were investigated using mixed modeling. If the carryover
effect was significant (at the α = 0.10 level), statistical analysis of only
the first period was carried out. Exploratory end points were analyzed
in the same manner as the main analysis of the primary end point, but
any statistical inferences had no confirmatory value. Statistical analyses
were performed using SAS software version 8.2 (SAS Institute, Cary,
NC). Safety end points were analyzed descriptively.
study oversight. All materials were reviewed and approved by the
appropriate independent ethics committees before the study began. The
study was conducted in accordance with the Declaration of Helsinki,
followed the International Conference on Harmonization Guidelines
for Good Clinical Practice, and was registered at ClinicalTrials.gov
(NCT00640848). Written informed consent was obtained from each
patient before any study procedure and after adequate explanation of
the aims, methods, objectives, and potential hazards of the study. It was
made clear to each patient that he or she was completely free to refuse
to enter the study or to withdraw from it at any time for any reason.
Data were collected by the investigators and analyzed by the sponsor.
The authors had access to the data, and they vouch for the accuracy
and completeness of the data.
suPPleMentARY MAteRiAl is linked to the online version of the paper at
http://www.nature.com/cpt
AcknowleDgMents
This study was sponsored by Actelion Pharmaceuticals Ltd, Switzerland.
The sponsor supplied the study treatment capsules and analyzed the data.
Actelion Pharmaceuticals provided payments to investigators or their
institutions to perform the study and paid for travel and/or accommodation
expenses for investigators to attend meetings related to the study. The
authors received medical writing support from Gail Rickard (Medi Cine
International, UK), sponsored by Actelion Pharmaceuticals. Data from this
study were previously presented in poster and oral presentations at the 5th
World Sleep Congress in 2007.60
table 4 Adverse events (safety population) occurring at least once in the overall almorexant group or the placebo group (includes
related and unrelated events)
event
almorexant
placebo (n = 160)50 mg (n = 36) 100 mg (n = 39) 200 mg (n = 39) 400 mg (n = 40)overalla (n = 160)
Patients with at least
one event, n (%)
5 (13.9) 7 (17.9)5 (12.8)16 (40.0) 35 (21.9) 22 (13.8)
Total events, n
8 116 427330
Adverse events, n (%)
Dizziness1 (2.8)1 (2.6) 1 (2.6)2 (5.0)7 (4.4)0
Nausea1 (2.8) 1 (2.6)1 (2.6) 2 (5.0)7 (4.4)0
Fatigue 1 (2.8)00 5 (12.5)6 (3.8) 4 (2.5)
Headache2 (5.6)2 (5.1)0 2 (5.0) 6 (3.8) 4 (2.5)
Dry mouth0 1 (2.6)0 4 (10.0)5 (3.1)0
Somnolence00 1 (2.6)3 (7.5)4 (2.5) 1 (0.6)
Sleep apnea syndrome0 1 (2.6)1 (2.6) 1 (2.5) 3 (1.9)0
Abdominal pain000 2 (5.0) 2 (1.3)0
Abnormal dreams000 2 (5.0) 2 (1.3)0
Cardiac murmur000 2 (5.0) 2 (1.3)0
Diarrhea1 (2.8)00 1 (2.5) 2 (1.3)0
Includes patients who were randomized to receive at least one dose of study medication and had at least one postbaseline assessment.
aIncludes six patients who received almorexant 25 mg.

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AuthoR contRiButions
P.H. wrote the manuscript, designed research, and analyzed data. G.D.
wrote the manuscript, designed research, analyzed data, and contributed
new reagents/analytical tools. H. Beneš performed research. T.P. performed
research. H.D.-H. wrote the manuscript, performed research, and
contributed new reagents/analytical tools. M.J.B. wrote the manuscript
and performed research. G.P. performed research and analyzed data. B.S.
designed and performed research. O.P. performed research and analyzed
data. D.K. wrote the manuscript and performed research. J.Z. wrote the
manuscript and performed research. S.B. performed research. M.P. wrote
the manuscript and performed research. C.L.B. performed research.
B.H. wrote the manuscript and performed research. I.O.E. performed
research. E.H.-T. performed research. H. Bengtsson performed research.
Y.P. performed research . U.-M.H. performed research. E.C. designed and
performed research, and analyzed data. G.H. designed and performed
research, and analyzed data. J.D. wrote the manuscript, designed research,
and analyzed data.
conFlict oF inteRest
P.H., E.C., and J.D. were full-time employees of, and own stock options in,
Actelion Pharmaceuticals Ltd. All the other authors were investigators of the
study, and payments were received either by them or by their institutions
from Actelion Pharmaceuticals for performing the study and for travel
and/or accommodation expenses for investigator meetings related to
the study. The Siesta Group Schlafanalyse, Vienna, Austria, was paid by
Actelion Pharmaceuticals for data analysis. The following authors report
disclosures for activities unrelated to the submitted work: G.D. is the chief
executive officer of the Siesta Group Schlafanalyse and is also employed
by Philips Respironics; he owns stock options in the Siesta Group and has
been paid for his expert testimony by the Gerson Lehrmann Group. G.D.’s
institution has received grants from Philips Respironics, and the Siesta Group
provides analysis services to several pharmaceutical companies. H. Beneš
has received honoraria from GSK, Boehringer Ingelheim, Cephalon, and
UCB for educational lectures and advisory board meetings. T.P. has received
financial support from several pharmaceutical companies for attending
conferences and advisory board meetings, and his institution has received
grants from the European Union and German National Funds. H.D.-H. has
received consultancy fees from PAREXEL International and refund of travel
expenses incurred for activities supported by GSK, MSD, Sanofi-Synthelabo,
and UCB; her institution has received grants from Actelion Pharmaceuticals,
GSK, MSD, Bioprojet, and PAREXEL International. G.P. has received payments
from Actelion Pharmaceuticals for expenses relating to his position as a
steering committee member of a separate study. B.S. has received research
support from Abiogen Pharma, Actelion Pharmaceuticals, AstraZeneca,
Cephalon, GlaxoSmithKline, Sanofi-Aventis, Schwarz Pharma, Servier, and
Takeda. He has received honoraria (not exceeding US$10,000/year) for
serving on scientific advisory boards of Nycomed, Servier, Takeda, UCB, and
Sanofi-Aventis; for being a consultant for Merck and Xenoport; and for being
a speaker for AstraZeneca, Cephalon, Ixico, Janssen, and Lundbeck. He is a
shareholder of the Siesta Group Schlafanalyse. O.P. has received consultancy
fees from Orion Pharma, MSD, Pfizer, and Actelion Pharmaceuticals, and
payment from Boehringer Ingelheim, Pfizer, GSK, AstraZeneca, and Maribo
Medical for lectures; he owns stocks in Unesta, which provides services for
several pharmaceutical companies. M.P. has received consultancy fees from
Cephalon, Leiras-Nycomed, Sanofi-Aventis, Servier, and UCB, and payment
from Boehringer Ingelheim, GSK, Leiras, Servier, and UCB for lectures;
his institution has received grants from the Academy of Finland and the
Parkinson Foundation. C.L.B. has received payments from UCB, Pfizer,
Boehringer Ingelheim, Bioprojet, Lundbeck, and Actelion Pharmaceuticals
for advisory board membership, and from UCB, Pfizer, Lundbeck, Bioprojet,
Boehringer Ingelheim, and Novartis for lectures; his institution has
received grants from UCB, Pfizer, ResMed, and Respironics, and payment
from Pfizer for the development of educational presentations. B.H. has
received consultancy fees from UCB, Boehringer Ingelheim, GSK, Pfizer,
and Jazz Pharmaceuticals; payments from UCB, Boehringer Ingelheim, GSK,
Cephalon, and Sanofi for lectures; and royalties from CUP. Her institution
has received grants from UCB. Y.P. has received payments from ResMed,
Roche, and AstraZeneca for lectures, and his institution has received grants
from the Swedish Heart and Lung Foundation and other national and local
foundations as well as from ResMed, ResMed Foundation, Pfizer, Boehringer
Ingelheim, and Actelion Pharmaceuticals. U.-M.H. has received payment for
serving on advisory boards of Eli Lilly, Bristol-Myers Squibb, and Pfizer. G.H.
has received consultancy fees, payments for advisory board membership
and participation in speaker boards, and research funding from Actelion
Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim,
Cephalon, Daimler Benz, Eli Lilly, EuMeCom, Essex Pharma, Gerson Lerman
Group Council of Healthcare Advisors, GSK, Janssen-Cilag, Lundbeck,
McKinsey, MedaCorp, Merck, Network of Advisors, Novartis, Organon,
Pfizer, Sanofi-Aventis, Schering-Plough, Sepracor, Takeda, Transcept
Pharmaceuticals, UCB, Volkswagen, Weinmann, and Wyeth. D.K., J.Z., S.B.,
I.O.E., E.H.-T., and H. Bengtsson have no financial disclosures or potential
conflicts of interest to report. M.J.B. is deceased and therefore no disclosures
are reported for this author.
© 2012 American Society for Clinical Pharmacology and Therapeutics
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