AASM	American Academy of Sleep medicine
AHI	apnea-hypopnea index
ANC	absolute neutrophil count
ANCOVA	analysis of covariance
ANOVA	analysis of variance
ASDA	American Sleep Disorders Association
BMI	body mass index
BP	blood pressure
BUN	blood urea nitrogen
CGI-C	Clinical Global Impression of Severity
CGI-S	Clinical Global Impression of Change
CMH	Cochran-Mantel-Haenszel
CNS	central nervous system
DBP	diastolic blood pressure
ECG	electrocardiography/electrocardiogram
EDS	excessive daytime sleepiness
ES	excessive sleepiness
ESS	Epworth Sleepiness Scale
FOSQ	Functional Outcomes of Sleep Questionnaire
GGT	gamma-glutamyl-transferase
GABA	gamma aminobutyric acid
HLA	human leukocyte antigen
ICSD	International Classification of Sleep Disorders
KSS	Karolinska Sleepiness Scale
MAO-B	monoamine oxidase type B
MSLT	Multiple Sleep Latency Test
MWT	Maintenance of Wakefulness Test
NA	Not applicable
nCPAP	nasal continuous positive airway pressure
NOS	not otherwise specified
NPSG	nocturnal polysomnography
OSAHS	sleep apnea/hypopnea syndrome
PLMD	periodic limb movement disorder
PSG	polysomnography
PVT	Psychomotor Vigilance Task
REM	rapid eye movement
RLS	restless leg syndrome
SAE	serious adverse event
SBP	systolic blood pressure
SCPT	the Steer-Clear Performance Test
SF‑36	Short Form Health Survey 36
SGOT	serum glutamic oxaloacetic transaminase
SGPT	serum glutamate pyruvate transaminase
SWSD	shift work sleep disorder
t_max	time of maximum observed drug concentration
ULN	upper limit of normal
WBC	white blood cell count
WHO	World Health Organisation

1 NEW INDICATION FOR PROVIGIL: EXCESSIVE SLEEPINESS ASSOCIATED WITH DISORDERS OF SLEEP AND WAKEFULNESS

Background Information

Modafinil was first marketed in France in 1994 for the treatment of narcolepsy, and is currently marketed in over 20 countries. PROVIGIL, the brand name of modafinil in the United States (US), was approved as an orphan drug by the FDA in 1998 to “improve wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.” The efficacy of PROVIGIL in reducing EDS associated with narcolepsy was established in two 9‑week, double‑blind, placebo-controlled, multicenter studies conducted in the US in patients with narcolepsy, which served as the basis of approval in the US.

In June 1999, Cephalon met with FDA’s Division of Neuropharmacological Drug Products (the Division) to discuss the clinical development program that would be required to expand the indication of PROVIGIL for the treatment of patients with excessive sleepiness associated with other clinical conditions. Specifically, Cephalon proposed that excessive sleepiness (ES) is a debilitating symptom common to many medical disorders, such as obstructive sleep apnea/hypopnea syndrome (OSAHS), Parkinson’s disease, and Alzheimer’s disease, and that PROVIGIL may be beneficial to any patient with ES. However, at that time, the FDA indicated there was a need for more efficacy data in a “normal” sleep-deprived population and that conditions such as Parkinson’s disease and Alzheimer’s disease would not be appropriate as the etiology of ES in these patients is not clear. The Division stated they would be interested in efficacy data in OSAHS and other models of sleep-deprived states.

In December 1999, an IND (IND 59,522 Serial 000) was submitted “for use of PROVIGIL in the treatment of excessive daytime sleepiness (EDS) associated with acute and chronic sleep deprivation,” and the initial proposed expanded indication for PROVIGIL was “for EDS secondary to sleep deprivation associated with OSAHS.” This indication had previously been discussed in the 24 June 1999 meeting with the Division. It was noted in this submission that a broader indication might be pursued for “improvement of wakefulness in patients with EDS associated with acute and chronic sleep deprivation.”

In reply to the IND submission, the Division noted that in its view Cephalon’s “proposed claim for treatment of EDS in patients with sleep apnea, could be considered a pseudo-specific claim, misleadingly implying that PROVIGIL was specifically effective against EDS in this setting.” The Division further noted that “since EDS occurs in multiple clinical settings, they would be willing to grant a general claim for the treatment of EDS if it could be shown that PROVIGIL had an effect on this symptom regardless of the clinical setting in which it occurred.”

At a meeting in July 2000, the Division made a new proposal, namely that the expanded indication should be narrowed to “[to improve wakefulness in patients with] ES in sleep disorders due to interference with night time sleep or disordered sleep.” In subsequent interactions, this potential indication was referred to as “to improve wakefulness in patients with ES associated with sleep loss in sleep disorders.” In the discussion following this proposal, the Division requested data from 3 models meeting these criteria to support this indication and suggested restless leg syndrome/periodic limb movement disorder (RLS/PLMD) as a potential model in addition to OSAHS. Cephalon discussed with the Division the potential to include ES associated with sleep loss in patients with shift work sleep disorder (SWSD) as the third model. The Division’s notes from this meeting stated that “the possibility of using sleep deprived patients due to shift work as a third disease model was discussed and FDA expressed a preference for this type of study in lieu of a study in sleep-deprived healthy subjects, if such a study were appropriately designed to separate out circadian misalignment effects.”

In a subsequent letter to the Agency, dated 20 December 2000, Cephalon clarified that patients with SWSD are indeed a highly select population of shift workers with a diagnosed sleep disorder, and that The American Sleep Disorders Association criteria for this disorder have been published since 1987. Cephalon explained in detail that the ES in patients with SWSD is due to both a circadian drive for sleep and chronic sleep disruption.

In that letter, Cephalon also detailed its effort to identify the appropriate third clinical model. Cephalon and its scientific and clinical advisors investigated all potential models and concluded that the 3 models, which represented the broadest group of patients with ES that was at least in part associated with sleep loss in sleep disorders, were residual ES in OSAHS, SWSD, and narcolepsy. At this time Cephalon also proposed the following alternative for the expanded indication for PROVIGIL “to improve wakefulness in patients with excessive sleepiness associated with sleep loss in sleep disorders.” In addition, Cephalon proposed the principal and supportive studies that would be sufficient to support the application for this expanded indication. These are the patient populations included in the studies that were submitted in the supplemental New Drug Application for PROVIGIL.

On 2 April 2001, Cephalon and its expert consultants met with the Division to discuss the details of the application to expand the indication for PROVIGIL “to improve wakefulness in patients with excessive sleepiness associated with sleep disorders.” This meeting initiated discussion on the appropriateness of SWSD as a model and the desire of the Division to distinguish patients with SWSD from shift workers who are “otherwise normal.” This issue was discussed further at a subsequent meeting on 9 August 2001. As a result of these discussions, it was agreed that patients enrolled in the SWSD trial would meet criteria for “substantial pathological sleepiness” and, as such, meet more than the minimal criteria for the SWSD. In addition, the daytime polysomnography (PSG) that would occur as part of screening assessments would confirm objectively that patients were having difficulty with daytime sleep and had no other disorder to account for their sleepiness. In addition, at the 2 April 2001 meeting, agreement was reached between the Division and Cephalon that the narcolepsy data that formed the basis of the approval of the current indication could be resubmitted, with longer-term data, as part of the data supporting the expanded indication.

At the 2 April 2001 meeting and, to a lesser extent, at the 9 August 2001 meeting, there was a good deal of discussion about the appropriateness of the models and what sleep disorders would and would not be included in the potential indication. The Division concluded that it was premature to discuss exact wording of the indication and that because of the precedent‑setting nature of the application it would consult with the Advisory Committee to:

a) determine whether the 3 proposed models are adequately representative of sleep disorders to justify a broader label

b) determine the likelihood that the drug effects seen in the models studied would be predictive of the drug effects seen in all sleep disorders

Proceeding under the understanding that an Advisory Committee meeting would be necessary, Cephalon completed the studies and prepared an application containing representative clinical models of ES associated with narcolepsy, residual ES associated with OSAHS, and ES associated with SWSD assuming that these models would be acceptable in pursuit of an expanded indication to improve wakefulness in patients with ES associated with disorders of sleep and wakefulness.

The following points are provided as an overall summary of rationale behind this effort:

· ES is a symptom that occurs in qualitatively similar ways in many clinical settings.

· ES is a consequence of some degree of sleep disruption and/or increased drive for sleep.

· Regardless of the underlying cause, ES can be measured objectively and subjectively using standardized, clinically relevant, well-validated tools.

· Patients with ES associated with disorders of sleep and wakefulness ES can be grouped into 3 diagnostic categories based of the nature of the primary underlying pathophysiology: disorders of sleep-wake dysregulation, disorders of sleep disruption, and disorders of circadian misalignment.

· These disorders can be operationally defined as disorders of sleep and wakefulness.

· Within the disorders of sleep and wakefulness, clinical studies have been conducted, or resubmitted with longer-term data, in clinical models that are representative of each of the 3 categories defined above: disorders of sleep‑wake dysregulation (ie, narcolepsy [resubmitted]), disorders of sleep disruption (ie, residual ES in OSAHS), and disorders of circadian misalignment (ie, SWSD).

· Together these 3 models represent the largest group of patients encountered in clinical practice in which pharmacologic management of ES may be necessary and appropriate.

2 review of excessive sleepiness and disorders of sleep and wakefulness

2.1 Introduction

Excessive sleepiness (ES) is a disabling symptom that is associated with many clinical conditions. This review of ES and disorders of sleep and wakefulness explains the physiology of normal and excessive sleepiness and delineates specific disorders of sleep and wakefulness with the symptom of ES.

Furthermore, the manifestations and consequences of ES are described, as is how these are assessed in clinical practice and in clinical trials using objective and subjective measures. Finally, the treatment of patients with ES associated with disorders of sleep and wakefulness is considered.

2.2 Normal and Excessive Sleepiness

2.2.1 Physiology of Normal sleepiness

Sleepiness is defined as a biologic drive state characterized by a decreased ability to maintain wakefulness or an increased propensity to fall asleep. Sleepiness is a physiologic indication of the need for sleep, analogous to hunger reflecting the need for food (Carskadon and Dement 1982, Thorpy 1992). Like hunger, it is normal for individuals to experience some degree of sleepiness.

The normal variation in sleepiness is primarily determined by an interaction between 2 processes: (1) the homeostatic sleep drive (ie, sleep load or sleep pressure), which is determined by the amount and continuity of sleep and the time since last sleep, and (2) the circadian drive for wakefulness or sleep, which is determined by the biological time of day (Borbély 1982).

Sleep load/pressure increases nearly linearly as a function of the amount and continuity of sleep as well as the amount of time awake since the last sleep episode. This accumulation of sleep pressure serves to increase sleep propensity and decrease ones ability to maintain wakefulness. In healthy people therefore, homeostatic sleep pressure builds up with increasing time awake and is relieved by sleep.

In humans, a circadian process controlled by the suprachiasmatic nucleus is responsible for generating an alerting signal during the day that opposes the homeostatic sleep pressure so that wakefulness can be sustained throughout the entire waking day. At night a circadian drive for sleep serves to increase sleep propensity and decrease one’s ability to maintain wakefulness.

The level of sleepiness or, inversely, wakefulness that a person experiences is therefore the result of a well-defined interaction between the homeostatic and circadian sleep-wake processes. The daily variation in wakefulness can be expressed as the wake propensity rhythm, which is depicted in Figure 1.

Figure 1: Physiologic Determinants of Sleepiness

2.2.2 Excessive Sleepiness

Excessive sleepiness is a symptom that is defined as difficulty in maintaining wakefulness and increased propensity to fall asleep, even in inappropriate circumstances and in situations that interfere with activities of daily living. Depending on the population sample and definition, the prevalence of ES is about 10%.

ES is the result of either sleep disruption or an increased drive for sleep during wakefulness. Sleep disruption can take multiple forms including inability to initiate or sustain consolidated sleep or sleep fragmentation. ES can also occur as a result of an inappropriate increased drive for sleep. This increased drive for sleep can be a result of dysregulation in the sleep‑wake mechanisms or as a result of misalignment between a person’s sleep-wake patterns and the internal circadian rhythms responsible for promoting sleep and wakefulness.

2.3 Sleep Disorders

The information presented in this section is an attempt to categorize sleep disorders according to (1) the international Classification of Sleep Disorders (ICSD), (2) the ICSD differential diagnosis of ES, and (3) the disorders of sleep and wakefulness.

2.3.1 International Classification of Sleep Disorders (ICSD)

Sleep disruption and/or increased drive for sleep during wakefulness and the subsequent ES can be seen in a variety of sleep disorders. These sleep disorders are classified as part of the International Classification of Sleep Disorders (ICSD). The ICSD was produced by the American Academy of Sleep medicine (AASM) in association with the European Sleep Research Society, the Japanese Society of Sleep Research, and the Latin American Sleep Society.

The ICSD classifies sleep disorders into 4 categories as outlined below.

1. Dyssomnias	A. Intrinsic Sleep Disorders
	B. Extrinsic Sleep Disorders
	C. Circadian Rhythm Sleep Disorders

2. Parasomnias	A. Arousal Disorders
	B. Sleep–Wake Transition Disorders
	C. Parasomnias Usually Associated with REM Sleep
	D. Other Parasomnias

3. Sleep Disorders Associated with Mental, Neurologic or Other Medical Disorders	A. Associated with Mental Disorders B. Associated with Neurologic Disorders
	C. Associated with Other Medical Disorders

4. Proposed Sleep Disorders

REM = rapid eye movement.

The first category comprises the dyssomnias (ie, the disorders of initiating and maintaining sleep and the disorders of excessive sleepiness, or both). The second category, the parasomnias, comprises the disorders of arousal, partial arousal, or sleep stage transition. These disorders do not cause a primary complaint of insomnia or excessive sleepiness. The third category, sleep disorders associated with mental, neurologic, or other medical disorders, comprises disorders with a prominent sleep complaint that is felt to be secondary to another condition. The fourth category, proposed sleep disorders, includes those disorders for which there is insufficient information available to confirm their acceptance as definitive sleep disorders.

The disorders that are considered primary sleep disorders are contained in the first 2 categories (dyssomnias and parasomnias). The dyssomnias are further subdivided in part into the intrinsic, extrinsic and circadian-rhythm sleep disorders. The distinction into intrinsic and extrinsic sleep disorders divides the major causes of insomnia and excessive sleepiness into those that are induced primarily by factors within the body (intrinsic) and those primarily by factors outside of the body (extrinsic). The full presentation of the ICSD outline can be found in Appendix 1.

2.3.2 ICSD Differential Diagnosis of Excessive Sleepiness

The classification outlined above classifies the sleep disorders mainly for coding purposes; it is not a differential-diagnostic tool. For the purpose of categorizing disorders with ES, it may be useful to classify those disorders based on the presence of this symptom. Outlined below is a differential‑diagnostic listing of sleep disorders that have ES as a primary symptom from the ICSD (pages 334-335). Using this organizational classification it is easier to define the primary sleep disorders with associated ES.

ICSD Differential Diagnosis of Excessive Sleepiness

Primary sleep disorders

Other*

Associated with Sleep Induced Respiratory Impairment

a. Obstructive Sleep Apnea Syndrome

b. Central Sleep Apnea Syndrome

c. Central Alveolar Hypoventilation Syndrome

d. Sleep‑Related Neurogenic Tachypnea^†

Associated with Behavioural/Pyschologic Disorders

a. Inadequate Sleep Hygiene

b. Insufficient Sleep Syndrome

c. Limit-Setting Sleep Disorder

d. Adjustment Sleep Disorder

Associated with Movement Disorders

a. Periodic Limb Movement Disorder

b. Restless Legs Syndrome

Associated with Mental Disorders

a. Mood Disorders

b. Psychoses

c. Alcoholism

Associated with Disorders of the Timing of the Sleep-Wake Pattern

a. Long Sleeper^†

b. Time Zone Change (Jet‑Lag) Syndrome

c. Shift Work Sleep Disorder

d. Delayed Sleep‑Phase Syndrome

e. Advanced Sleep‑Phase Syndrome

f. Non-24-Hour Sleep-Wake Syndrome

g. Irregular Sleep-Wake Pattern

Associated with Environmental Factors

a. Environmental Sleep Disorder

b. Toxin-Induced Sleep Disorder

Associated with Drug Dependency

a. Hypnotic-Dependent Sleep Disorder

b. Stimulant-Dependent Sleep Disorder

c. Alcohol-Dependent Sleep Disorder

Other Causes of Excessive Sleepiness

a. Menstrual-Associated Sleep Disorder

b. Pregnancy Associated Sleep Disorders

Associated with Neurologic Disorders (NOS)

a. Narcolepsy

b. Idiopathic Hypersomnia

c. Post‑Traumatic Hypersomnia

d. Recurrent Hypersomnia

e. Subwakefulness Syndrome^†

Associated with Neurologic Disorders (NOS)*

f. Fragmentory Myoclonus,

g. Parkinsonism,

h. Dementia

i. Sleeping Sickness

j. Sleep-Related Epilepsy

*Not considered primary sleep disorders (excluded).
^†Proposed sleep disorder (excluded).
ICSD = International Classification of Sleep Disorders (2001); NOS = not otherwise specified.

In summary, the categories of primary sleep disorders that are associated with ES are those associated with sleep-induced respiratory impairment, movement disorders, the timing of the sleep‑wake pattern, and neurologic disorders (items a through e only).

2.4 Excessive Sleepiness Associated With Disorders of Sleep and Wakefulness

2.4.1 Categorization of Disorders of Sleep and Wakefulness

As discussed earlier, the pathophysiology of ES is sleep disruption and increased drive for sleep during wakefulness. It is therefore possible to link the 4 categories of primary sleep disorders with ES to the main underlying pathophysiologic driver of the ES, resulting in 3 categories. These 3 categories are:

(a) sleep-wake dysregulation – disorders in which there is a central nervous system (CNS) pathology leading to an increased drive for sleep during the time one needs to be awake. These disorders would include those classified as associated with neurologic disorders (items a through e only) using the ICSD differential diagnosis outlined in section 2.3.2

(b) sleep disruption – disorders in which there is disturbed sleep resulting in increased sleep load during the time one needs to be awake. These disorders would include those classified as associated with sleep induced respiratory impairment and movement disorders using the ICSD differential diagnosis outlined in section 2.3.2.

(c) circadian misalignment – disorders in which there is a displacement or misalignment of situational appropriate sleep and wakefulness to times that are not in phase with the circadian rhythm leading to both an increased drive for sleep during the time of desired wakefulness, and disturbed sleep during the time of desired sleep. These disorders would include those associated with disorders of the timing of the sleep wake pattern using the ICSD differential diagnosis outlined in section 2.3.2.

It is important to note that, in respect to these disorders of sleep and wakefulness, regardless of which specific disorder is being considered the main driver of the ES, the disorders have evidence of both disturbed sleep and an increased drive for sleep during times of desired wakefulness. It is therefore possible to refer to these disorders collectively as Disorders of Sleep and Wakefulness.

Using the categories outlined above, the Disorders of Sleep and Wakefulness are definable in terms of those disorders which should be included in the indication being sought and are listed in Table 1.

Table 1: Pathologic Categories of Disorders of Sleep and Wakefulness With Associated Excessive Sleepiness

Disorders of sleep and wakefulness (ICSD)

Sleep–wake
dysregulation

Sleep
disruption

Circadian-rhythm
misalignment

Narcolepsy*

Idiopathic Hypersomnia

Recurrent Hypersomnia

Post-Traumatic Hypersomnia

OSAHS*

Central Sleep Apnea Syndrome

Central Alveolar Hypoventilation Syndrome

Periodic Limb Movement Syndrome

Restless Leg Syndrome

SWSD*

Advanced Sleep-Phase Syndrome

Delayed Sleep-Phase Syndrome

Non-24-hour Sleep-wake Syndrome

Time Zone Change Syndrome

Circadian Rhythm Sleep Disorder NOS

Irregular Sleep Wake Pattern

*Narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD) are the most commonly encountered disorders in the 3 categories and will be discussed in greater detail below.

ICSD = International Classification of Sleep Disorders.

CNS = central nervous system.

NOS = not otherwise specified.

In deciding the contents of this submission, Cephalon in conjunction with external advisors and after discussions with the Agency considered various representative disorders of sleep and wakefulness that would best suit a clinical program that would ultimately support the new indication. The efforts of this endeavor resulted in the belief that 3 models comprising narcolepsy, OSAHS, and SWSD were the best representation of primary sleep disorders with ES as the primary symptom. The rationale for this was that in clinical practice narcolepsy, OSAHS and SWSD are the most commonly encountered disorders of sleep‑wake dysregulation, disorders of sleep disruption, and disorders of circadian-rhythm misalignment, respectively.

Thus, ES, the same symptom but from 3 distinct underlying disorders, is at the center of this broadened indication. Cephalon’s clinical program did not focus on a single specific disease or disorder; rather, it focused on a single symptom, ie, ES associated with disorders of sleep and wakefulness. A more in-depth discussion on each category follows.

2.4.2 Excessive Sleepiness Associated With Disorders of Sleep‑Wake Dysregulation

In these disorders, ES is primarily caused by some CNS disruption in the internal processes responsible for promoting wakefulness and sleep. The disorders in this category are narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, and posttraumatic hypersomnia. All of these disorders involve some degree of CNS disturbance that leads to the dysregulation of the sleep‑wake processes.

Narcolepsy results from a hypocretin (orexin) deficiency in the brain that is characterized by excessive sleepiness that typically is associated with cataplexy and other rapid eye movement (REM) sleep phenomena, such as sleep paralysis and hypnagogic hallucinations. It is the most prevalent of the Disorders of Sleep-Wake Dysregulation and is estimated to occur in 0.03% to 0.16% of the general population (ICSD 2001). Narcolepsy most commonly begins in the second decade of life and excessive sleepiness is usually the first symptom to appear. Accidents due to sleepiness and cataplexy can occur in almost any situation and serious social consequences can result because of ES leading to marital disharmony and loss of employment.

The diagnostic criteria for narcolepsy are given in the International Classification of Sleep Disorders (ICSD 347) and are provided in Appendix 2.

2.4.3 Excessive Sleepiness Associated With Disorders of Sleep Disruption

In these disorders, ES is caused by insufficient duration of sleep or, most commonly, inadequate consolidation of sleep (ie, sleep disruption). Sleep in these patients is characterized by frequent, brief arousals of less than 15 seconds in duration. The disorders in this category are the sleep‑related breathing disorders such as obstructive sleep apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome; movement disorders such as periodic limb movement syndrome and restless legs syndrome.

The arousing stimulus differs among these disorders and can be identified in some (eg, apneas in OSAHS or leg movements in PLMD), but not in others. Regardless of the etiology, these arousals result in disturbed sleep. This results in a decrease in the more restorative “deep” sleep (ie, stages 3 to 4 non–rapid-eye-movement [NREM] and rapid‑eye‑movement [REM] sleep) and an increase in the less restorative “light” sleep (ie, stage 1 NREM sleep). Overall, regardless of the underlying etiology, disturbed sleep leads to patients starting each day with an elevated sleep load manifested by the symptom of ES.

Obstructive sleep apnea is the most commonly diagnosed and clinically managed disorder in this category. OSAHS is estimated to affect 2% to 4% of middle‑aged adults (Young et al 1993). Men are at greater risk for OSAHS than women; other risk factors include obesity and increasing age (American Sleep Disorders Association 2000). It is characterized by repeated episodes of complete or partial collapse of the upper airway during sleep, with a reduction in blood oxygen saturation (American Sleep Disorders Association 2000). This leads to frequent arousals during sleep and disrupted, inefficient, poor‑quality sleep (Guilleminault 1989). The sleep disruption seen in OSAHS (ie, sleep fragmentation/impaired sleep consolidation) is also typical of the other disorders in this category in which ES is a primary complaint.

The diagnostic criteria for OSAHS are given in the International Classification of Sleep Disorders (ICSD 780.53-0) and are provided in Appendix 2.

2.4.4 Excessive Sleepiness Associated With Disorders of Circadian Misalignment

In these disorders, ES is caused by a misalignment between the sleep-wake patterns and the internal processes responsible for promoting sleep and wakefulness. The disorders in this category are shift work sleep disorder, time zone change syndrome, irregular sleep‑wake pattern, delayed sleep-phase syndrome, advanced sleep-phase syndrome, and non-24-hour sleep-wake syndrome.

Due primarily to the large number of shift workers and its profound impact on productivity and safety, SWSD is the most commonly encountered disorder in this category. A shift worker is defined as someone who works outside the standard hours of 0700 to 1800 (Monk and Folkard 1992). Although the true prevalence of SWSD is unknown it is thought to affect 2% to 5% of shift workers (ICSD 2001).

Shift workers experience a major misalignment between the work‑rest schedule imposed by their occupation and the circadian rhythm. A proportion of shift workers are not able to adapt to this misalignment and experience ES in relation to work shifts. Although the specific predisposing factors are not known, there are individual differences both in the ability to adapt internal circadian rhythms to different work-rest/light-dark schedules and in the ability to tolerate working and sleeping out of alignment with the internal processes responsible for promoting sleep and wakefulness. Regardless of the predisposing factors, ES associated with SWSD is caused by increased drive for sleep because individuals are attempting to work when the internal sleep‑wake processes are promoting sleep and attempting to sleep when the internal sleep‑wake processes are promoting wakefulness causing disturbed sleep. In the other disorders within the category of circadian misalignment, the primary cause of ES is the same, ie, misalignment between external sleep-wake patterns and the internal sleep‑wake processes.

The diagnostic criteria for SWSD are given in the International Classification of Sleep Disorders (ICSD 307.45‑1) and are provided in Appendix 2.

2.4.5 Appropriateness of Models Used in the Clinical Program

The 3 models chosen in this clinical program (ie, narcolepsy, OSAHS, and SWSD) appropriately represent the individual disorders with associated ES within the Disorders of Sleep and Wakefulness on the basis of prevalence, severity of ES, and chronicity of ES.

(a) Prevalence of Excessive Sleepiness

As stated previously, the models chosen, narcolepsy, OSAHS, and SWSD, are the most commonly diagnosed and managed disorders within the categories of sleep‑wake dysregulation, sleep disruption, and circadian misalignment, respectively, for which the symptom of ES is a primary complaint. Although narcolepsy is by far the most commonly diagnosed disorder of sleep‑wake dysregulation, it remains an uncommon disorder with a prevalence of 0.03% to 0.16% of the general population. OSAHS is considerably more common with a prevalence of 2% to 4% of middle-aged adults, and although the true prevalence of SWSD is unknown, it is thought to affect approximately 2% to 5% of shift workers.

(b) Severity of Excessive Sleepiness

The symptom of ES can be rated as mild, moderate, or severe. Mild ES, which may not manifest itself every day, is present only during times of rest or when little attention is required, and produces a minor impairment of social or occupational function. Moderate ES that manifests itself every day is present in very mild physical activities requiring a mild to moderate degree of attention, and produces moderate impairment of social or occupational function. Severe ES, which manifests itself every day, is present during times of physical activity and when moderate levels of attention are required, and produces marked impairment of social or occupational function.

ES associated with Disorders of Sleep and Wakefulness can occur with different levels of severity and, as such, disorders with varying levels of severity of ES were included in Cephalon’s clinical program. For example, patients with OSAHS treated with nasal continuous positive airway pressure (nCPAP) therapy tend to experience less severe ES than patients with narcolepsy. Although patients with SWSD do not have ES upon awakening they experience moderate to severe ES during their night shift and commute home. It is well documented that patients with narcolepsy are clearly at the extreme with severe ES throughout the entire waking day.

The inclusion of disorders with differing degrees of severity of ES has allowed the assessment of efficacy and safety of PROVIGIL at the current approved dose of 200 mg administered once daily across a spectrum of patients with moderate to severe ES.

(c) Chronicity of Excessive Sleepiness

The chronicity of ES is another important factor. ES associated with the Disorders of Sleep and Wakefulness can have different levels of chronicity. The symptom of ES in some disorders, such as recurrent hypersomnia and non-24-hour sleep-wake syndrome, can be quite severe but may occur in relatively short episodes, from several days to several weeks at a time. In other disorders, such as idiopathic hypersomnia, the symptoms of ES can be life-long. The disorders studied, ie, narcolepsy, OSAHS and SWSD, reflect this diversity in chronicity. Although it can be a chronic disorder, SWSD is a disorder that by definition occurs temporally associated with night work and, therefore, requires intermittent drug administration. Narcolepsy, on the other extreme, is a chronic condition that requires life-long pharmacologic management. Therefore, Cephalon’s clinical program included disorders required daily and intermittent administration.

2.5 Manifestations and Consequences of Excessive Sleepiness Associated With Disorders of Sleep and Wakefulness

Regardless of the underlying pathophysiology of the ES, the manifestations and consequences of ES are similar and consistent across the disorders of sleep and wakefulness. The manifestations of ES vary with the degree of ES present and include changes in concentration, lapses of attention, and unintentional napping. The most disabling consequences of ES in these disorders are behavioral in nature and fall into 3 categories: undesired sleep episodes, effects on performance, and effects on mood (Greenberg et al 1987, Roth et al 1988, Aldrich 1989, Breslau et al 1996, Simon and Vonkorff 1997, Roth and Ancoli-Israel 1999, Mitler et al 2000, Richardson and Roth 2001). Behavioral consequences can include accidents, decreased work productivity, and depressed mood. These can all contribute to impaired quality of life, health perceptions, and functional status (Broughton et al 1981, Broughton and Broughton 1994, Weaver et al 1997, Marrone et al 1998).

2.6 Excessive Sleepiness, Sleep, and Quality-of-Life Measures

2.6.1 Excessive Sleepiness

Excessive sleepiness can be quantified using objective or subjective measures. The key methods of measuring ES include the following:

· Objective measures

—Physiologic measures of sleep tendency, eg, the Maintenance of Wakefulness Test (MWT), the Multiple Sleep Latency Test (MSLT)

—Neurobehavioral measures of the impact of ES, eg, the Psychomotor Vigilance Task (PVT), the Steer-Clear Performance Test (SCPT)

· Subjective measures

—Clinician-completed measures based on patient interview, eg, Clinical Global Impression of Severity or Change (CGI-S or CGI-C)

—Patient-completed measures, eg, Epworth Sleepiness Scale (ESS), Karolinska Sleepiness Scale (KSS), and patient diaries

2.6.1.1 Objective Measures

(a) MSLT/MWT

The standard objective measures of ES are the MSLT and MWT, both of which are measures of the physiologic tendency to fall asleep. Although, as described below, the testing procedures differ, they are considered to be largely interchangeable and measure the same variable, ie, sleep latency. An increased or faster tendency to fall asleep reflects a greater level of sleepiness. The methodology for the MSLT was first described more than 25 years ago. The procedure requires a subject to lie down in a quiet darkened room and not resist falling asleep (Carskadon et al 1986).

The methodology of the MWT resembles that of the MSLT except that the subject is instructed to attempt to stay awake, sitting in a darkened room without taking extraordinary measures such as vigorous mental or physical activity to remain awake (Hartse et al 1982, Mitler et al 1982, Doghramji et al 1997). In general, a mean MSLT latency of less than 10 minutes and a mean MWT latency of less than 15 minutes are considered indicative of ES.

The MSLT and MWT have been validated in a wide variety of clinical conditions known to cause ES. They have been shown to be sensitive to factors that increase sleepiness, such as sleep disruption, sleep loss, and sleep disorders, and have been shown to be responsive to manipulations that reduce ES (Dement et al 1978, Härmä et al 1998, US Modafinil in Narcolepsy Multicenter Study Group 1998). Using the MSLT and the MWT, pathologic levels of ES have been documented in patients with narcolepsy and OSAHS (Mitler et al 1982, George et al 1996, Roth and Roehrs 1996, US Modafinil in Narcolepsy Multicenter Study Group 1998, 2000). Studies have demonstrated that a subset of night shift workers demonstrates significant sleepiness during their usual work times as assessed by the MSLT and MWT (Åkerstedt 1998).

(b) PVT/SCPT

The impact of ES can be measured by objective neurobehavioral measures such as the PVT and SCPT (Dinges et al 1997, George et al 1997). The tendency to experience microsleeps, evidenced by lapses and increased reaction times during performance tasks such as these is considered relevant to real‑world situations.

One of the most frequently used neurobehavioral measures of the impact of sleepiness is the PVT, which measures behavioral alertness (Dinges et al 1997, Jewett et al 1999). During PVT testing, a visual stimulus appears and the subject responds. The ability to sustain attention and respond rapidly becomes unstable when ES is present. The PVT has been extensively validated to be sensitive to measure ES.

Although there are a number of performance parameters that can be extracted from the PVT, the key parameter is number of lapses. Lapses of attention are brief episodes of nonresponsivity, sometimes caused by microsleeps, and are associated with impairment of performance.

The SCPT is a personal computer-based test of performance that evaluates the operator’s ability to avoid obstacles. Individual results are reported on the basis of the number and percentage of obstacles that were avoided or hit, the time of each hit, and the frequency that the obstacles appeared (speed). The SCPT has been used in studies in patients with OSAHS and narcolepsy (Findley et al 1995, Cephalon data on file).

2.6.1.2 Subjective Measures

Subjective measures of ES can be divided into assessments completed by clinicians on the basis of patient interviews and those completed by the patients themselves.

(a) CGI

The most commonly used clinician-completed measure is the Clinical Global Impressions (CGI) scale. The CGI scale is a standardized assessment tool that allows the clinician to rate the severity of illness, change in clinical condition over time, and efficacy of treatment on the basis of an interview with a patient (Guy 1976). The CGI scale consists of the Clinical Global Impression of Severity (CGI-S) scale, a measure of the severity of the clinical condition and the CGI-C scale, a measure of the change in condition. The CGI-C scale consists of 7 categories from very much improved to very much worse. This instrument can be also anchored to a specific symptom, such as the patient’s report of their level of ES.

(b) ESS/KSS

The patient-completed measures of ES can be divided into 3 categories: (a) self‑reports of the level of sleepiness, (b) self-reports of sleep propensity in various daily-life situations, and (c) reports of sleep events (eg, unintentional naps). Measures of the level of sleepiness, such as the KSS are sensitive to both sleep deprivation and time of day (Hoddes et al 1973, Åkerstedt and Gillberg 1990, Babkoff et al 1991, Johnson et al 1991). The KSS is a 9‑point scale that ranges from 1=very alert to 9=very sleepy, great effort to keep awake or fighting sleep. Patients rate the level of sleepiness that occurred within the 5 minutes before the scale is completed (Åkerstedt and Gillberg 1990). The KSS has been commonly used in occupational medicine research.

The ESS, a measure of subjective sleep propensity, is the most commonly administered patient‑completed scale for assessing ES in medicinal research and has been validated in many patient populations. Subjects are instructed to rate their chance of dozing off or falling asleep in 8 different situations varying in their soporific nature using an evaluation interval of the previous 4 weeks. An ESS score of 10 or more is considered representative of ES (Roehrs et al 2000). An ESS score is independent of short-term variations in sleepiness due to time of day and inter-day variations (Johns 1994).

2.6.2 Sleep

The polysomnogram (PSG) is the continuous and simultaneous recording of multiple physiologic variables during sleep. A variety of parameters of sleep can be obtained from a PSG recording. On of the most valuable parameters in patients with ES is sleep efficiency, because it is a good indicator of disturbed sleep. Sleep efficiency is the proportion of total sleep time to time in bed (ICSD 2001).

2.6.3 Quality‑of‑Life Measures and Functional Outcomes

In addition to those measures described above, the impact of ES on health perceptions and functional status can be measured by using non–disease-specific measures such as the Short Form Health Survey 36 (SF‑36) or scales more disease- or symptom-specific such as the Functional Outcomes of Sleep Questionnaire (FOSQ).

The SF‑36 was developed as a generic measure of perceived health status, and has been used across a wide range of clinical settings, providing self-reports of behavioral functioning and perceived psychological well-being.

The FOSQ was specifically designed to assess the impact of disorders of ES on functional outcomes relevant to daily behaviors and quality of life and was developed utilizing patients with OSAHS (Weaver et al 1997).

2.6.4 Overview of Measures of Excessive Sleepiness

Across the disorders of sleep and wakefulness, ES and the impact of ES, can be measured in a variety of ways using both objective and subjective measures. These measurements of ES, or the impact of ES, can be conceptualized as providing information in a way that corresponds to the different manifestations of ES (Figure 2); thus, while these measures are interrelated, they each also provide unique and complementary information. All of the above measures were employed in the assessment of efficacy in Cephalon’s clinical program.

Figure 2: Measurements of Excessive Sleepiness

2.7 Excessive Sleepiness Treatment Considerations

In assessing patients with a symptom of ES, appropriate measures should be taken to diagnose and manage, where possible, the underlying pathology and primary cause of the symptom. For example, in patients with OSAHS, nCPAP is considered appropriate primary therapy and should be instigated prior to initiating a pharmacologic therapy to promote wakefulness. In patients with disorders of circadian misalignment attempts may be made to shift the patient’s circadian rhythm by using light therapy or chronobiotics (Loube et al 1999, Kryger 2000). Often these treatments, however, do not completely resolve the ES (Seidel et al 1984, Walsh et al 1991, Sforza and Krieger 1992, Bédard et al 1993, Engleman et al 1994, Czeisler and Wright 1999, Turek and Czeisler 1999, Stradling and Davies 2000). Patients with ES despite appropriate treatment of the underlying pathology would therefore be candidates for clinical intervention to manage this symptom

2.8 Overall Summary

In summary, ES is a disabling symptom that is associated with many clinical conditions. The Disorders of Sleep and Wakefulness define a subgroup of sleep disorders that are associated with a primary complaint of ES, both in terms of disorders that should be included in this definition, and, as importantly, in terms of those disorders that should be excluded.

Cephalon believes that narcolepsy, OSAHS, and SWSD are representative models of the Disorders of Sleep and Wakefulness with associated ES in terms of prevalence, severity of the symptom of ES, the chronicity of the symptom of ES, and that the data outlined in the sections on efficacy and safety should be translatable to the other disorders of sleep and wakefulness. The manifestations and consequences of ES are consistent across the disorders of sleep and wakefulness, although varying in degree of severity and chronicity. In addition, there are standardized and accepted methods to quantify and measure ES, which are routinely used in clinical research and are sensitive to the effects of therapeutic interventions.

3 Pharmacology of modafinil

Modafinil, the active ingredient in PROVIGIL, is a racemic compound. The product is formulated as white, capsule-shaped, uncoated tablets (100 mg and 200 mg).

Mechanism of action

The precise molecular target(s) for modafinil are not yet known, but at pharmacologically relevant concentrations, modafinil does not bind to most potentially relevant receptors for sleep/wake regulation, including adenosine, benzodiazepines, GABA (gamma aminobutyric acid), histamine-3, hypocretin/orexin (an intact hypocretin/orexin system is not required for modafinil-promoted wakefulness), melatonin, norepinephrine, or serotonin. Modafinil does not inhibit the activities of MAO-B (monoamine oxidase type B) or phosphodiesterases II-IV. Modafinil is not a direct or indirect α₁‑adrenergic agonist. Although modafinil–induced wakefulness can be attenuated by the α₁‑adrenergic receptor antagonist prazosin, in assay systems known to be responsive to α‑adrenergic agonists, modafinil has no activity.

Unlike the wakefulness induced by central nervous system (CNS) stimulants, modafinil-induced wakefulness appears not to be mediated by dopamine. Modafinil is not a direct or indirect dopamine agonist and is inactive in several nonclinical models designed to detect enhanced dopaminergic activity (Akaoka et al 1991, De Sereville et al 1994, Ferraro et al 1997). Modafinil is only a weak inhibitor of the dopamine reuptake site, leading to a small increase in extracellular dopamine but no increase in dopamine release (Mignot et al 1994) (data on file).

Modafinil-induced wakefulness is not antagonized by haloperidol or α-methyl-p-tyrosine, as occurs with stimulants, and there is no effect on the firing rate of dopaminergic neurons in the substantia nigra or of adrenergic neurons in the locus coeruleus with modafinil (Lin et al 1992, Ferraro et al 1997) (data on file).

Increases in the expression of c-fos, an immediate-early gene product, which is a marker of neuronal activation, were used to identify sites of action of amphetamine, methylphenidate, and modafinil. In the cat brain, amphetamine and methylphenidate caused widespread stimulation of neuronal activity. Modafinil appears to selectively increase neuronal activity in discrete areas of the brain, especially the anterior hypothalamus (Lin et al 1996, Engber et al 1998, Scammell et al 2000). Unlike sympathomimetic agents, modafinil treatment does not cause significant locomotor activity and there is no evidence of rebound hypersomnia compared to that observed with amphetamine treatment (Simon et al 1994, Touret et al 1995, Edgar and Seidel 1997). Modafinil has minimal peripheral autonomic effects, including changes in cardiovascular and hemodynamic parameters (data on file).

Modafinil has been reported to promote wakefulness in rats, cats, dogs, nonhuman primates, and drosophilia. Of note, modafinil has been shown to promote wakefulness in dogs with narcolepsy and dogs with sleep apnea. In addition, modafinil treatment attenuates rest in drosophilia, but does not alter circadian synchronization (Hendricks et al 2001).

Pharmacokinetics

Pharmacokinetic evaluations have shown that the absorption of modafinil is rapid with peak plasma concentrations occurring at 2 to 4 hours after oral administration. The single- and multiple-dose pharmacokinetics of modafinil are similar. Steady‑state concentrations of total modafinil are reached after 2 to 4 days of treatment, and the average half-life of modafinil after multiple doses is about 15 hours. The major route of elimination (~90%) is metabolism, primarily by the liver, with subsequent renal elimination of the metabolites. Two metabolites reach appreciable concentrations in plasma, ie, modafinil acid and modafinil sulfone; however, they do not contribute to the wake-promoting activity of modafinil. Food has no effect on overall modafinil bioavailability; however, its absorption (t_max) may be delayed by approximately 1 hour if taken with food.

Drug interactions

The results of clinical drug-drug interaction studies suggest that the likelihood of clinically significant pharmacokinetic interactions with modafinil is low, with the exception of substrates for CYP3A4/5 that undergo substantial gastrointestinal pre‑systemic elimination. In vitro, modafinil was determined to be an inducer of CYP1A2, CYP2B6, and CYP3A4/5 and a suppressor of CYP2C9 in primary cultures of human hepatocytes. Clinical interaction studies were conducted to determine whether sustained treatment with modafinil at 400 mg/day would cause alterations in the pharmacokinetic parameters for substrates for those enzymes, ie, warfarin (CYP2C9, CYP1A2, and CYP3A4/5) or ethinyl estradiol and triazolam (CYP3A4/5). No effect was shown on the pharmacokinetic parameters for either of the enantiomers of warfarin, but evidence of CYP3A4/5 induction was obtained for ethinyl estradiol and triazolam. However, the enzyme induction appeared to be primarily gastrointestinal rather than hepatic. There also has been a single report (Le Cacheux et al 1997) of an apparent interaction of modafinil with cyclosporine, another CYP3A4/5 substrate. The results suggest that the likelihood of clinically significant interactions is highest for medications that undergo extensive gastrointestinal first‑pass metabolic elimination via CYP3A4/5, such as cyclosporine, verapamil, lovastatin, buspirone, and triazolam.

The potential drug interactions of modafinil (200 mg) with methylphenidate (40 mg) and dextroamphetamine (10 mg) were examined in single-dose crossover studies. The only effects observed, ie, approximately 1-hour delays in the t_max for modafinil, were not considered to be clinically significant. The effects of methylphenidate 20 mg per day and dextroamphetamine 20 mg per day at steady state on the pharmacokinetics of modafinil 400 mg per day at steady state were also examined, with administration of the stimulant 8 or 7 hours, respectively, after the daily dose of modafinil. No effects on the pharmacokinetic parameters of modafinil were observed. Overall, modafinil appears to have a low potential for pharmacokinetic drug interactions with dextroamphetamine or methylphenidate.

A crossover study of the potential interaction of modafinil at 200 mg per day for 3 days with clomipramine (50 mg) did not produce evidence of an interaction. However, there has been a single report (Grözinger et al 1998) of an interaction in a patient with narcolepsy who was CYP2D6‑deficient. This result was consistent with in vitro results indicating that modafinil and its sulfone metabolite are selective, reversible inhibitors of the enzyme CYP2C19, which contributes to the metabolic elimination of clomipramine. The results of a subsequent in vitro study, conducted in human liver microsomal preparations, confirmed that modafinil and modafinil sulfone can decrease the rates of metabolism of diazepam, clomipramine, desmethylclomipramine, and fluoxetine, which are substrates of CYP2C19. However, the effects were generally small and highly variable, suggesting that the incidence of clinically significant interactions will be low.

The potential for interactions via the other enzymes on which effects were observed in vitro cannot be definitively ruled out. Therefore, it is recommended that caution be exerted when modafinil is administered concomitantly with substrates of any of these enzymes, particularly if the substrates are drugs with small therapeutic indices (eg, phenytoin, warfarin).

4 Study designs, patient populations, and efficacy and QUALITY‑Of‑Life results

4.1 Overview of Studies and Study Designs for the Evaluation of Efficacy

Six double-blind, placebo-controlled, parallel-group studies (furthered described in Table 2) form the basis of the determination of the efficacy of PROVIGIL treatment to improve wakefulness in adults with ES associated with disorders of sleep and wakefulness. The 6 double‑blind placebo controlled studies, hereafter referred to as the principal studies, are:

· narcolepsy studies C1538a/301/NA/US and C1538a/302/NA/US (hereafter referred to as studies 301 and 302)
Note: These studies were the basis of the approval of PROVIGIL in narcolepsy.

· OSAHS studies C1538a/303/AP/US-UK and C1538a/402/AP/US (hereafter referred to as studies 303 and 402)

· SWSD studies C1538a/305/CM/US and C1538a/306/CM/US-UK (hereafter referred to as studies 305 and 306)

Table 2: Description of Principal Studies

Description	Narcolepsy		OSAHS		SWSD
Description	Study 301	Study 302	Study 303	Study 402	Study 305	Study 306
Double-blind Placebo-controlled Parallel-group	√	√	√	√	√	√
Dosage studied (mg/day)	200, 400	200, 400	200, 400	400	200	200, 300
Visits (screening, (baseline [BL] and week)	1, 3, 6, 9	1, 3, 6, 9	4, 8, 12	1, 4	4, 8, 12	4, 8, 12
Treatment regimen	once daily in the morning		once daily in the morning		intermittently once before night shifts

OSAHS = obstructive sleep apnea/hypopnea syndrome; SWSD = shift work sleep disorder.

In all 6 studies, patients had a documented complaint of ES, met standard accepted diagnostic criteria for the respective disorder of sleep and wakefulness being studied, and had no other cause of ES.

Outcome measures used in the studies included:

· objective measures of sleepiness (measures of physiologic sleepiness [MWT/MSLT])

· objective measures of the impact of sleepiness (PVT/SCPT)

· subjective measures of sleepiness (clinician rating [CGI-C] and patient rating [ESS/KSS])

· other measures (quality of life [SF-36] and functional status [FOSQ])

Outcome measures were designated as either primary or secondary (Table 3).

Table 3: Primary and Secondary Outcome Measures by Study

Measures	Narcolepsy		OSAHS		SWSD
Measures	Study 301	Study 302	Study 303	Study 402	Study 305	Study 306
Efficacy
MWT	P	P	P	---	---	---
MSLT	S	S	---	S	P	---
CGI-C	P	P	P	S	P	---
ESS/KSS	S	S	S	P	S	---
PVT/SCPT	S	S	S	S	S	---