Provigil^®^ (modafinil) Tablets (C-IV)

**Supplemental NDA**

Briefing Document

For

**Peripheral and Central Nervous System Drugs**

**Advisory Committee Meeting**

**25 September 2003**

**Sponsor**

Cephalon, Inc.\
145 Brandywine Parkway\
West Chester, Pennsylvania 19380\
USA

PROVIGIL is a registered trademark of Genelco, S.A., licensed to
Cephalon, Inc.

**TABLE OF CONTENTS**

Page

[List of Figures 5](#__RefHeading___Toc49234225)

[List of Tables 6](#__RefHeading___Toc49234226)

[list of abbreviations and deffinitionS of terms
9](#__RefHeading___Toc49234227)

[1 NEW INDICATION FOR PROVIGIL: EXCESSIVE SLEEPINESS ASSOCIATED WITH
DISORDERS OF SLEEP AND WAKEFULNESS
10](#new-indication-for-provigil-excessive-sleepiness-associated-with-disorders-of-sleep-and-wakefulness)

[2 review of excessive sleepiness and disorders of sleep and wakefulness
13](#review-of-excessive-sleepiness-and-disorders-of-sleep-and-wakefulness)

[2.1 Introduction 13](#introduction)

[2.2 Normal and Excessive Sleepiness
13](#normal-and-excessive-sleepiness)

[2.2.1 Physiology of Normal sleepiness
13](#physiology-of-normal-sleepiness)

[2.2.2 Excessive Sleepiness 14](#excessive-sleepiness)

[2.3 Sleep Disorders 14](#sleep-disorders)

[2.3.1 International Classification of Sleep Disorders (ICSD)
15](#international-classification-of-sleep-disorders-icsd)

[2.3.2 ICSD Differential Diagnosis of Excessive Sleepiness
16](#icsd-differential-diagnosis-of-excessive-sleepiness)

[2.4 Excessive Sleepiness Associated With Disorders of Sleep and
Wakefulness
18](#excessive-sleepiness-associated-with-disorders-of-sleep-and-wakefulness)

[2.4.1 Categorization of Disorders of Sleep and Wakefulness
18](#categorization-of-disorders-of-sleep-and-wakefulness)

[2.4.2 Excessive Sleepiness Associated With Disorders of Sleep‑Wake
Dysregulation
19](#excessive-sleepiness-associated-with-disorders-of-sleepwake-dysregulation)

[2.4.3 Excessive Sleepiness Associated With Disorders of Sleep
Disruption
20](#excessive-sleepiness-associated-with-disorders-of-sleep-disruption)

[2.4.4 Excessive Sleepiness Associated With Disorders of Circadian
Misalignment
20](#excessive-sleepiness-associated-with-disorders-of-circadian-misalignment)

[2.4.5 Appropriateness of Models Used in the Clinical Program
21](#appropriateness-of-models-used-in-the-clinical-program)

[2.5 Manifestations and Consequences of Excessive Sleepiness Associated
With Disorders of Sleep and Wakefulness
22](#manifestations-and-consequences-of-excessive-sleepiness-associated-with-disorders-of-sleep-and-wakefulness)

[2.6 Excessive Sleepiness, Sleep, and Quality-of-Life Measures
23](#excessive-sleepiness-sleep-and-quality-of-life-measures)

[2.6.1 Excessive Sleepiness 23](#excessive-sleepiness-1)

[2.6.1.1 Objective Measures 23](#objective-measures)

[2.6.1.2 Subjective Measures 24](#subjective-measures)

[2.6.2 Sleep 25](#sleep)

[2.6.3 Quality‑of‑Life Measures and Functional Outcomes
25](#qualityoflife-measures-and-functional-outcomes)

[2.6.4 Overview of Measures of Excessive Sleepiness
25](#overview-of-measures-of-excessive-sleepiness)

[2.7 Excessive Sleepiness Treatment Considerations
26](#excessive-sleepiness-treatment-considerations)

[2.8 Overall Summary 26](#overall-summary)

[3 Pharmacology of modafinil 28](#pharmacology-of-modafinil)

[4 Study designs, patient populations, and efficacy and QUALITY‑Of‑Life
results
31](#study-designs-patient-populations-and-efficacy-and-qualityoflife-results)

[4.1 Overview of Studies and Study Designs for the Evaluation of
Efficacy
31](#overview-of-studies-and-study-designs-for-the-evaluation-of-efficacy)

[4.2 Narcolepsy---Studies 301 and 302
32](#narcolepsystudies-301-and-302)

[4.2.1 Narcolepsy Study Design 33](#narcolepsy-study-design)

[4.2.2 Narcolepsy Data Analysis 34](#narcolepsy-data-analysis)

[4.2.3 Narcolepsy Study Population 34](#narcolepsy-study-population)

[4.2.3.1 Patient Disposition 34](#patient-disposition)

[4.2.3.2 Demographic Characteristics 35](#demographic-characteristics)

[4.2.3.3 Baseline Patient Characteristics
36](#baseline-patient-characteristics)

[4.2.4 Narcolepsy Efficacy and Quality-of-Life Results
36](#narcolepsy-efficacy-and-quality-of-life-results)

[4.2.4.1 Primary Efficacy Measures: MWT and CGI‑C
36](#primary-efficacy-measures-mwt-and-cgic)

[4.2.4.2 Secondary Efficacy Measures: MSLT, ESS, and SCPT
38](#secondary-efficacy-measures-mslt-ess-and-scpt)

[4.2.4.3 Quality-of-Life Assessment: SF-36
39](#quality-of-life-assessment-sf-36)

[4.2.5 Conclusions on Narcolepsy 39](#conclusions-on-narcolepsy)

[4.3 Obstructive Sleep Apnea/Hypopnea Syndrome---Studies 303 and 402
40](#obstructive-sleep-apneahypopnea-syndromestudies-303-and-402)

[4.3.1 Study Design for OSAHS Study 303
40](#study-design-for-osahs-study-303)

[4.3.2 Data Analysis for OSAHS Study 303
41](#data-analysis-for-osahs-study-303)

[4.3.3 Study Population for OSAHS Study 303
41](#study-population-for-osahs-study-303)

[4.3.3.1 Patient Disposition 41](#patient-disposition-1)

[4.3.3.2 Demographic Characteristics 42](#demographic-characteristics-1)

[4.3.3.3 Baseline Respiratory Disturbance Index and Oxygen Saturation
43](#baseline-respiratory-disturbance-index-and-oxygen-saturation)

[4.3.3.4 Baseline Patient Characteristics
44](#baseline-patient-characteristics-1)

[4.3.4 Efficacy and Quality-of-Life Results for OSAHS Study 303
45](#efficacy-and-quality-of-life-results-for-osahs-study-303)

[4.3.4.1 Primary Efficacy Measures: MWT and CGI-C
45](#primary-efficacy-measures-mwt-and-cgi-c)

[4.3.4.2 Secondary Efficacy Measures: ESS and PVT
46](#secondary-efficacy-measures-ess-and-pvt)

[4.3.4.3 Quality-of Life Assessments: SF-36 and FOSQ
48](#quality-of-life-assessments-sf-36-and-fosq)

[4.3.5 Study Design for OSAHS Study 402
48](#study-design-for-osahs-study-402)

[4.3.6 Data Analysis for OSAHS Study 402
49](#data-analysis-for-osahs-study-402)

[4.3.7 Study Population for OSAHS Study 402
49](#study-population-for-osahs-study-402)

[4.3.7.1 Patient Disposition 49](#patient-disposition-2)

[4.3.7.2 Demographic Characteristics 50](#demographic-characteristics-2)

[4.3.7.3 Baseline Patient Characteristics
51](#baseline-patient-characteristics-2)

[4.3.8 Efficacy and Quality-of-Life Results for OSAHS Study 402
52](#efficacy-and-quality-of-life-results-for-osahs-study-402)

[4.3.8.1 Primary Efficacy Measure: ESS
52](#primary-efficacy-measure-ess)

[4.3.8.2 Secondary Efficacy Measures: MSLT, CGI-C, PVT
53](#secondary-efficacy-measures-mslt-cgi-c-pvt)

[4.3.8.3 Quality of Life Assessment: FOSQ
55](#quality-of-life-assessment-fosq)

[4.3.9 Conclusions on OSAHS 55](#conclusions-on-osahs)

[4.4 Shift Work Sleep Disorder---Studies 305 and 306
56](#shift-work-sleep-disorderstudies-305-and-306)

[4.4.1 Study Design for SWSD Study 305
56](#study-design-for-swsd-study-305)

[4.4.2 Data Analysis for SWSD Study 305
57](#data-analysis-for-swsd-study-305)

[4.4.3 Study Population for SWSD Study 305
57](#study-population-for-swsd-study-305)

[4.4.3.1 Patient Disposition 57](#patient-disposition-3)

[4.4.3.2 Demographic Characteristics 58](#demographic-characteristics-3)

[4.4.3.3 Baseline Patient Characteristics
59](#baseline-patient-characteristics-3)

[4.4.4 Efficacy and Quality-of-Life Results for SWSD Study 305
60](#efficacy-and-quality-of-life-results-for-swsd-study-305)

[4.4.4.1 Primary Efficacy Measures: MSLT and CGI-C
60](#primary-efficacy-measures-mslt-and-cgi-c)

[4.4.4.2 Secondary Efficacy Measures: KSS and PVT
62](#secondary-efficacy-measures-kss-and-pvt)

[4.4.4.3 Quality of Life Assessment: FOSQ
63](#quality-of-life-assessment-fosq-1)

[4.4.5 Study Design for SWSD Study 306
63](#study-design-for-swsd-study-306)

[4.4.6 Data Analysis for SWSD Study 306
64](#data-analysis-for-swsd-study-306)

[4.4.7 Study Population for SWSD Study 306
64](#study-population-for-swsd-study-306)

[4.4.7.1 Patient Disposition 64](#patient-disposition-4)

[4.4.7.2 Demographic Characteristics 65](#demographic-characteristics-4)

[4.4.7.3 Baseline Patient Characteristics
65](#baseline-patient-characteristics-4)

[4.4.8 Quality of Life Assessments for SWSD Study: SF-36 and FOSQ
66](#quality-of-life-assessments-for-swsd-study-sf-36-and-fosq)

[4.4.9 Conclusions on SWSD 67](#conclusions-on-swsd)

[4.5 Brief Overview of Supportive Efficacy Studies
67](#brief-overview-of-supportive-efficacy-studies)

[4.6 Summary of Results of Primary Efficacy Measures in the Four Pivotal
Studies---Narcolepsy Studies 301 and 302, OSAHS Study 303, and SWSD
Study 305
68](#summary-of-results-of-primary-efficacy-measures-in-the-four-pivotal-studiesnarcolepsy-studies-301-and-302-osahs-study-303-and-swsd-study-305)

[4.6.1 Overview of Efficacy Evaluation in the Four Pivotal Studies
68](#overview-of-efficacy-evaluation-in-the-four-pivotal-studies)

[4.6.2 Patient Populations in the Four Pivotal Studies
68](#patient-populations-in-the-four-pivotal-studies)

[4.6.3 Primary Efficacy Analyses for the Four Pivotal Studies: MWT/MSLT
and CGI‑C at the Final Visit
69](#primary-efficacy-analyses-for-the-four-pivotal-studies-mwtmslt-and-cgic-at-the-final-visit)

[4.6.4 Analysis of MWT/MSLT and CGI-C Over Time in the Four Pivotal
Studies
70](#analysis-of-mwtmslt-and-cgi-c-over-time-in-the-four-pivotal-studies)

[4.7 Consistency of PROVIGIL Effects Across Disorders of Sleep and
Wakefulness in the Principal Studies---Narcolepsy Studies 301 and 302,
OSAHS Studies 303 and 402, and SWSD Study 305
72](#consistency-of-provigil-effects-across-disorders-of-sleep-and-wakefulness-in-the-principal-studiesnarcolepsy-studies-301-and-302-osahs-studies-303-and-402-and-swsd-study-305)

[4.8 Efficacy Conclusions 75](#efficacy-conclusions)

[5 Safety Results 76](#safety-results)

[5.1 Evaluation of Adverse Events 76](#evaluation-of-adverse-events)

[5.1.1 Introduction 76](#introduction-1)

[5.1.2 Principal Studies in Narcolepsy, OSAHS, and SWSD
76](#principal-studies-in-narcolepsy-osahs-and-swsd)

[5.1.2.1 Overview of Adverse Events 76](#overview-of-adverse-events)

[5.1.2.2 Types of Adverse Events 78](#types-of-adverse-events)

[5.1.3 Rationale for Combining Adverse Event Data From the Principal
Studies
81](#rationale-for-combining-adverse-event-data-from-the-principal-studies)

[5.1.4 Principal Studies in Narcolepsy, OSAHS, and SWSD---Data Combined
81](#principal-studies-in-narcolepsy-osahs-and-swsddata-combined)

[5.1.4.1 Treatment Exposure in the Principal Studies
81](#treatment-exposure-in-the-principal-studies)

[5.1.4.2 Overview of Adverse Events 82](#overview-of-adverse-events-1)

[5.1.4.3 Types of Adverse Events 82](#types-of-adverse-events-1)

[5.1.5 Other Adverse Event Data Sets Analyzed
85](#other-adverse-event-data-sets-analyzed)

[5.1.5.1 Overview of Other Adverse Event Data Sets
85](#overview-of-other-adverse-event-data-sets)

[5.1.5.2 Treatment Exposure in All Studies in Narcolepsy, OSAHS, and
SWSD
86](#treatment-exposure-in-all-studies-in-narcolepsy-osahs-and-swsd)

[5.1.5.3 Treatment Exposure in All PROVIGIL Studies
86](#treatment-exposure-in-all-provigil-studies)

[5.1.5.4 Overview of Adverse Events Across the Three Data Sets
(Principal Studies, All Studies in Narcolepsy, OSAHS, and SWSD, and All
Studies)
87](#overview-of-adverse-events-across-the-three-data-sets-principal-studies-all-studies-in-narcolepsy-osahs-and-swsd-and-all-studies)

[5.1.5.5 Adverse Events in the Principal Studies, in All Studies in
Narcolepsy, OSAHS, and SWSD, and in All Studies
88](#adverse-events-in-the-principal-studies-in-all-studies-in-narcolepsy-osahs-and-swsd-and-in-all-studies)

[5.1.6 Adverse Events in the Principal Studies by Dose
89](#adverse-events-in-the-principal-studies-by-dose)

[5.1.7 Adverse Events in the Principal Studies Over Time
89](#adverse-events-in-the-principal-studies-over-time)

[5.1.8 Adverse Events in the Principal Studies and in the Current
PROVIGIL Labeling
91](#adverse-events-in-the-principal-studies-and-in-the-current-provigil-labeling)

[5.2 Clinical Laboratory Evaluations
92](#clinical-laboratory-evaluations)

[5.3 Vital Signs 94](#vital-signs)

[5.3.1 Evaluation of Vital Signs in Patients With Narcolepsy, OSAHS, or
SWSD
94](#evaluation-of-vital-signs-in-patients-with-narcolepsy-osahs-or-swsd)

[5.3.2 Evaluation of Blood Pressure and Heart Rate in Patients With
OSAHS
96](#evaluation-of-blood-pressure-and-heart-rate-in-patients-with-osahs)

[5.4 Electrocardiography 97](#electrocardiography)

[5.5 Overall Summary of Safety Evaluations
97](#overall-summary-of-safety-evaluations)

[5.6 Safety Conclusions 100](#safety-conclusions)

[6 special considerations 101](#special-considerations)

[6.1 Effect on Nighttime/Daytime Sleep
101](#effect-on-nighttimedaytime-sleep)

[6.2 Effect on Nasal Continuous Positive Airway Pressure Usage in
Patients With OSAHS
103](#effect-on-nasal-continuous-positive-airway-pressure-usage-in-patients-with-osahs)

[6.3 Effect on Circadian Phase in Patients With SWSD
104](#effect-on-circadian-phase-in-patients-with-swsd)

[7 Benefit/risk assessment 105](#benefitrisk-assessment)

[8 references 106](#references)

[Appendix 1 International Classification of Sleep Disorders
Classification Outline 111](#__RefHeading___Toc49234351)

[Appendix 2 International Classification of Sleep Disorders Diagnostic
Criteria 115](#__RefHeading___Toc49234352)

[]{#__RefHeading___Toc49234225 .anchor}List of Figures

Page

[Figure 1: Physiologic Determinants of Sleepiness
14](#__RefHeading___Toc49234353)

[Figure 2: Measurements of Excessive Sleepiness
26](#__RefHeading___Toc49234354)

[Figure 3: CGI-C at the Final Visit in Studies 301, 302, 303, and 305
70](#__RefHeading___Toc49234355)

[Figure 4: MWT/MSLT Sleep Latency by Visit in Studies 301, 302, 303, and
305 71](#__RefHeading___Toc49234356)

[Figure 5: CGI-C Ratings by Visit for Patients Whose Conditions Improved
in Studies 301, 302, 303, and 305 72](#__RefHeading___Toc49234357)

[]{#__RefHeading___Toc49234226 .anchor}List of Tables

Page

[Table 1: Pathologic Categories of Disorders of Sleep and Wakefulness
With Associated Excessive Sleepiness 19](#__RefHeading___Toc49234358)

[Table 2: Description of Principal Studies
31](#__RefHeading___Toc49234359)

[Table 3: Primary and Secondary Outcome Measures by Study
32](#__RefHeading___Toc49234360)

[Table 4: Patient Disposition in Narcolepsy Studies 301 and 302
(Randomized Patients) 35](#__RefHeading___Toc49234361)

[Table 5: Demographic Characteristics in Narcolepsy Studies 301 and 302
(Safety Evaluable Set) 35](#__RefHeading___Toc49234362)

[Table 6: Baseline Patient Characteristics in Narcolepsy Studies 301 and
302 (Efficacy Evaluable Set) 36](#__RefHeading___Toc49234363)

[Table 7: Average Sleep Latency (Minutes) From MWT at the Final Visit in
Narcolepsy Studies 301 and 302 (Efficacy Evaluable Set)
37](#__RefHeading___Toc49234364)

[Table 8: CGI‑C Ratings (Number \[%\] in Each Category) at the Final
Visit in Narcolepsy Studies 301 and 302 (Efficacy Evaluable Set)
38](#__RefHeading___Toc49234365)

[Table 9: Mean (SD) Change From Baseline to the Final Visit in MSLT,
ESS, and SCPT Results in Narcolepsy Studies 301 and 302 (Efficacy
Evaluable Set) 39](#__RefHeading___Toc49234366)

[Table 10: Patient Disposition in OSAHS Study 303 (Randomized Patients)
42](#__RefHeading___Toc49234367)

[Table 11: Demographic Characteristics in OSAHS Study 303 (Randomized
Patients) 43](#__RefHeading___Toc49234368)

[Table 12: Historic and Baseline Apnea-Hypopnea Index (AHI) and Baseline
Oxygen Saturation for Patients in OSAHS Study 303
44](#__RefHeading___Toc49234369)

[Table 13: Baseline Patient Characteristics in OSAHS Study 303 (Efficacy
Evaluable Set) 44](#__RefHeading___Toc49234370)

[Table 14: Average Sleep Latency (Minutes) From the MWT at the Final
Visit for OSAHS Study 303 (Efficacy Evaluable Set)
45](#__RefHeading___Toc49234371)

[Table 15: CGI-C Ratings (Number \[%\] in Each Category) at the Final
Visit in OSAHS Study 303 (Efficacy Evaluable Set)
46](#__RefHeading___Toc49234372)

[Table 16: Total Score From ESS at the Final Visit in OSAHS Study 303
(Efficacy Evaluable Set) 47](#__RefHeading___Toc49234373)

[Table 17: Change from Baseline in PVT Number of Lapses at the Final
Visit for OSAHS Study 303 (Efficacy Evaluable Set)
48](#__RefHeading___Toc49234374)

[Table 18: Patient Disposition in OSAHS Study 402 (Randomized Patients)
50](#__RefHeading___Toc49234375)

[Table 19: Demographic Characteristics in OSAHS Study 402 (Randomized
Patients) 51](#__RefHeading___Toc49234376)

[Table 20: Baseline Patient Characteristics in OSAHS Study 402 (Safety
Evaluable Set) 52](#__RefHeading___Toc49234377)

[Table 21: Total Score From ESS at the Final Visit in OSAHS Study 402
(Efficacy Evaluable Set) 53](#__RefHeading___Toc49234378)

[Table 22: Average Sleep Latency From the MSLT Mean Change From Baseline
at the Final Visit for OSAHS Study 402 (Efficacy Evaluable Set)
54](#__RefHeading___Toc49234379)

[Table 23: CGI-C Ratings (Number \[%\] in Each Category) at the Final
Visit in OSAHS Study 402 (Efficacy Evaluable Set)
54](#__RefHeading___Toc49234380)

[Table 24: Change from Baseline in PVT Results at the Final Visit for
OSAHS Study 402 (Efficacy Evaluable Set)
55](#__RefHeading___Toc49234381)

[Table 25: Patient Disposition in SWSD Study 305 (All Randomized
Patients) 58](#__RefHeading___Toc49234382)

[Table 26: Demographic Characteristics in SWSD Study 305 (Safety
Analysis Set) 59](#__RefHeading___Toc49234383)

[Table 27: Baseline Patient Characteristics in SWSD Study 305 (Safety
Analysis Set) 60](#__RefHeading___Toc49234384)

[Table 28: Average Sleep Latency (Minutes) From the MSLT at the Final
Visit in SWSD Study 305 (Efficacy Evaluable Set)
61](#__RefHeading___Toc49234385)

[Table 29: CGI‑C Ratings (Number \[%\] in Each Category) at the Final
Visit in SWSD Study 305 (Efficacy Evaluable Set)
61](#__RefHeading___Toc49234386)

[Table 30: KSS Score at the Final Visit in SWSD Study 305 (Efficacy
Evaluable Set) 62](#__RefHeading___Toc49234387)

[Table 31: Change From Baseline in PVT Results at the Final Visit in
SWSD Study 305 (Efficacy Evaluable Set) 63](#__RefHeading___Toc49234388)

[Table 32: Patient Disposition in SWSD Study 306 (All Randomized
Patients) 64](#__RefHeading___Toc49234389)

[Table 33: Demographic Characteristics in SWSD Study 306 (Safety
Analysis Set) 65](#__RefHeading___Toc49234390)

[Table 34: Baseline Patient Characteristics in SWSD Study 306 (Safety
Analysis Set) 66](#__RefHeading___Toc49234391)

[Table 35: Mean (SD) Change From Baseline in Mean Sleep Latency
(Minutes) 69](#__RefHeading___Toc49234392)

[Table 36: Estimates of Effect Size for the Change From Baseline to the
Final Visit for Continuous Efficacy Variables in Studies 301, 302, 303,
402, and 305 (Efficacy Evaluable Set) 74](#__RefHeading___Toc49234393)

[Table 37: Overview of Adverse Events in Individual Principal Studies
(Safety Analysis Set) 77](#__RefHeading___Toc49234394)

[Table 38: Overview of Adverse Events in the Principal Studies by
Disorder of Sleep and Wakefulness (Safety Analysis Set)
78](#__RefHeading___Toc49234395)

[Table 39: Adverse Events Occurring in 5% of PROVIGIL-Treated Patients
and at a Greater Percentage Than in Placebo-Treated Patients in
Individual Principal Studies (Safety Analysis Set)
79](#__RefHeading___Toc49234396)

[Table 40: Adverse Events Occurring in 5% of PROVIGIL-Treated Patients
and at a Greater Percentage Than in Placebo-Treated Patients in the
Principal Studies by Disorder of Sleep and Wakefulness (Safety Analysis
Set) 81](#__RefHeading___Toc49234397)

[Table 41: Treatment Exposure in Combined Principal Studies (Safety
Analysis Set) 82](#__RefHeading___Toc49234398)

[Table 42: Overview of Adverse Events in the Combined Principal Studies
(Safety Analysis Set) 82](#__RefHeading___Toc49234399)

[Table 43: Adverse Events Occurring in 5% of PROVIGIL-Treated Patients
and at a Greater Percentage Than in Placebo-Treated Patients in the
Combined Principal Studies (Safety Analysis Set)
83](#__RefHeading___Toc49234400)

[Table 44: Serious Adverse Events in the Combined Principal Studies
(Safety Analysis Set) 84](#__RefHeading___Toc49234401)

[Table 45: Most Common (≥5 Patients) Adverse Events Leading to
Withdrawal in PROVIGIL‑Treated Patients in Combined Principal Studies
(Safety Analysis Set) 85](#__RefHeading___Toc49234402)

[Table 46: Treatment Exposure in All Studies in Narcolepsy, OSAHS, and
SWSD (Safety Analysis Set) 86](#__RefHeading___Toc49234403)

[Table 47: Treatment Exposure in All Studies (Safety Analysis Set)
87](#__RefHeading___Toc49234404)

[Table 48: Overview of Adverse Events in the Principal Studies, in All
Studies in Narcolepsy, OSAHS, and SWSD, and in All Studies (Safety
Analysis Set) 87](#__RefHeading___Toc49234405)

[Table 49: Adverse Events Occurring in 5% of PROVIGIL-Treated Patients
and at a Greater Percentage Than in Placebo-Treated Patients in the
Principal Studies, in All Studies in Narcolepsy, OSAHS, and SWSD, and in
All Studies (Safety Analysis Set) 88](#__RefHeading___Toc49234406)

[Table 50: Adverse Events Occurring in 5% of PROVIGIL-Treated Patients
in the Principal Studies by Dose (Safety Analysis Set)
89](#__RefHeading___Toc49234407)

[Table 51: Cumulative Incidence of Adverse Events (Adverse Events
Occurring in 5% of Patients in Any Treatment Group) by Time on Treatment
in the Principal Studies (Safety Analysis Set)
90](#__RefHeading___Toc49234408)

[Table 52: Incidence of Selected Adverse Events Occurring in 5% of
PROVIGIL-Treated Patients by Onset Interval in All Narcolepsy, OSAHS,
and SWSD Studies (Safety Analysis Set) 91](#__RefHeading___Toc49234409)

[Table 53: Adverse Events Occurring in 5% of PROVIGIL-Treated Patients
Data From the Principal Studies Compared With Current PROVIGIL Labeling
91](#__RefHeading___Toc49234410)

[Table 54: Mean (SD) and Mean Change from Baseline by Time Interval for
Alkaline Phosphatase and GGT (All Studies in Narcolepsy, OSAHS, and
SWSD) (Safety Analysis Set) 92](#__RefHeading___Toc49234411)

[Table 55: Clinically Significant Abnormal Chemistry Values (Principal
Studies and All Narcolepsy, OSAHS, and SWSD Studies) (Safety Analysis
Set) 93](#__RefHeading___Toc49234412)

[Table 56: Clinically Significant Abnormal Hematology Values (Principal
Studies and All Narcolepsy, OSAHS, and SWSD Studies) (Safety Analysis
Set) 94](#__RefHeading___Toc49234413)

[Table 57: Changes From Baseline in Vital Signs Values (Principal
Studies and All Narcolepsy, OSAHS, and SWSD Studies) (Safety Analysis
Set) 95](#__RefHeading___Toc49234414)

[Table 58: Clinically Significant Abnormal Vital Signs Values (Principal
Studies and All Narcolepsy, OSAHS, and SWSD Studies) (Safety Analysis
Set) 96](#__RefHeading___Toc49234415)

[Table 59: Evaluation of Blood Pressure and Heart Rate in Patients with
OSAHS (OSAHS Studies 303 and 402) 96](#__RefHeading___Toc49234416)

[Table 60: Patients With High Blood Pressure Values (WHO Criteria) at
the Final Visit by Treatment Group for Patients With OSAHS (OSAHS
Studies 303, 402, and 407) 97](#__RefHeading___Toc49234417)

[Table 61: Patient‑Reported Sleep Efficiency (%) From Daytime Sleep Logs
in SWSD Study 305 101](#__RefHeading___Toc49234418)

[Table 62: Patient-Reported Sleep Efficiency (%) From Daytime Sleep Logs
in SWSD Study 306 102](#__RefHeading___Toc49234419)

[Table 63: Mean Change From Baseline Assessments to the Final Visit in
Apnea‑Hypopnea Index (AHI) and Oxygen Saturation for Patients in OSAHS
Study 303 103](#__RefHeading___Toc49234420)

[]{#__RefHeading___Toc49234227 .anchor}list of abbreviations and
deffinitionS of terms

  ------------------ ----------------------------------------------------
  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
  ------------------ ----------------------------------------------------

# 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.

# review of excessive sleepiness and disorders of sleep and wakefulness

## 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.

## Normal and Excessive Sleepiness

### 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.

> []{#__RefHeading___Toc49234353 .anchor}Figure 1: Physiologic
> Determinants of Sleepiness

![](media/image1.wmf)

### 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.

## 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.

### 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 A. Associated with Mental
  Mental,\                             Disorders\
  Neurologic or Other Medical          B. Associated with Neurologic
  Disorders**                          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.

### 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   | **Associated with                |
| Respiratory Impairment**          | Behavioural/Pyschologic          |
|                                   | Disorders**                      |
| a.  Obstructive Sleep Apnea       |                                  |
|     Syndrome                      | a.  Inadequate Sleep Hygiene     |
|                                   |                                  |
| b.  Central Sleep Apnea Syndrome  | b.  Insufficient Sleep Syndrome  |
|                                   |                                  |
| c.  Central Alveolar              | c.  Limit-Setting Sleep Disorder |
|     Hypoventilation Syndrome      |                                  |
|                                   | d.  Adjustment Sleep Disorder    |
| d.  Sleep‑Related Neurogenic      |                                  |
|     Tachypnea**^†^**              |                                  |
+-----------------------------------+----------------------------------+
| **Associated with Movement        | **Associated with Mental         |
| Disorders**                       | Disorders**                      |
|                                   |                                  |
| a.  Periodic Limb Movement        | a.  Mood Disorders               |
|     Disorder                      |                                  |
|                                   | b.  Psychoses                    |
| b.  Restless Legs Syndrome        |                                  |
|                                   | c.  Alcoholism                   |
+-----------------------------------+----------------------------------+
| **Associated with Disorders of    | **Associated with Environmental  |
| the Timing of the Sleep-Wake      | Factors**                        |
| Pattern**                         |                                  |
|                                   | a.  Environmental Sleep Disorder |
| a.  Long Sleeper**^†^**           |                                  |
|                                   | b.  Toxin-Induced Sleep Disorder |
| 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 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      | **Associated with Neurologic     |
| Disorders (NOS)\                  | Disorders (NOS)\***              |
| **                                |                                  |
|                                   | f.  Fragmentory Myoclonus,       |
| a.  Narcolepsy                    |                                  |
|                                   | g.  Parkinsonism,                |
| b.  Idiopathic Hypersomnia        |                                  |
|                                   | h.  Dementia                     |
| c.  Post‑Traumatic Hypersomnia    |                                  |
|                                   | i.  Sleeping Sickness            |
| d.  Recurrent Hypersomnia         |                                  |
|                                   | j.  Sleep-Related Epilepsy       |
| e.  Subwakefulness                |                                  |
|     Syndrome**^†^**               |                                  |
+-----------------------------------+----------------------------------+

\*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).

## Excessive Sleepiness Associated With Disorders of Sleep and Wakefulness

### 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.]{.underline}
    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]{.underline} 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]{.underline}. 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.

[]{#__RefHeading___Toc49234358 .anchor}Table 1: Pathologic Categories of
Disorders of Sleep and Wakefulness With Associated Excessive Sleepiness

+-----------------+--------------------------+------------------------+
| **Disorders of  |                          |                        |
| sleep and       |                          |                        |
| wakefulness     |                          |                        |
| (ICSD)**        |                          |                        |
+-----------------+--------------------------+------------------------+
| **Sleep--wake\  | **Sleep\                 | **Circadian-rhythm\    |
| dysregulation** | disruption**             | misalignment**         |
+-----------------+--------------------------+------------------------+
| **Narcolepsy**  | **OSAHS**                | **SWSD**               |
|                 |                          |                        |
| Idiopathic      | Central Sleep Apnea      | Advanced Sleep-Phase   |
| Hypersomnia     | Syndrome                 | Syndrome               |
|                 |                          |                        |
| Recurrent       | Central Alveolar         | Delayed Sleep-Phase    |
| Hypersomnia     | Hypoventilation Syndrome | Syndrome               |
|                 |                          |                        |
| Post-Traumatic  | Periodic Limb Movement   | Non-24-hour Sleep-wake |
| Hypersomnia     | Syndrome                 | Syndrome               |
|                 |                          |                        |
|                 | Restless Leg 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.

### 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.

### 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.

### 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.

### 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.

##### 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.

## 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).

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

### 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

#### Objective Measures 

##### 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).

##### 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).

#### 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.

##### 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.

##### 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).

### 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).

### 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).

### 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.

[]{#__RefHeading___Toc49234354 .anchor}Figure 2: Measurements of
Excessive Sleepiness

![](media/image2.wmf){width="6.054861111111111in"
height="4.542361111111111in"}

## 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

## 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.

# 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 α~1~‑adrenergic agonist. Although modafinil--induced
wakefulness can be attenuated by the α~1~‑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).

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

## 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:]{.smallcaps} 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)

[]{#__RefHeading___Toc49234359 .anchor}Table 2: Description of Principal
Studies

+----------------+------+--------+--------+------+--------+--------+
| *              | **   |        | **O    |      | **     |        |
| *Description** | Narc |        | SAHS** |      | SWSD** |        |
|                | olep |        |        |      |        |        |
|                | sy** |        |        |      |        |        |
+----------------+------+--------+--------+------+--------+--------+
|                | **S  | *      | *      | **S  | *      | *      |
|                | tudy | *Study | *Study | tudy | *Study | *Study |
|                | 3    | 302**  | 303**  | 4    | 305**  | 306**  |
|                | 01** |        |        | 02** |        |        |
+----------------+------+--------+--------+------+--------+--------+
| Double-blind   | √    | √      | √      | √    | √      | √      |
|                |      |        |        |      |        |        |
| Plac           |      |        |        |      |        |        |
| ebo-controlled |      |        |        |      |        |        |
|                |      |        |        |      |        |        |
| Parallel-group |      |        |        |      |        |        |
+----------------+------+--------+--------+------+--------+--------+
| Dosage         | 200, | 200,   | 200,   | 400  | 200    | 200,   |
| studied\       | 400  | 400    | 400    |      |        | 300    |
| (mg/day)       |      |        |        |      |        |        |
+----------------+------+--------+--------+------+--------+--------+
| Visits         | 1,   | 1, 3,  | 4, 8,  | 1, 4 | 4, 8,  | 4, 8,  |
| (screening,\   | 3,   | 6, 9   | 12     |      | 12     | 12     |
| (baseline      | 6, 9 |        |        |      |        |        |
| \[BL\] and     |      |        |        |      |        |        |
| week)          |      |        |        |      |        |        |
+----------------+------+--------+--------+------+--------+--------+
| Treatment\     | once |        | once   |      | int    |        |
| regimen        | d    |        | daily  |      | ermitt |        |
|                | aily |        | in the |      | ently\ |        |
|                | in   |        | m      |      | once   |        |
|                | the  |        | orning |      | before |        |
|                | mor  |        |        |      | night  |        |
|                | ning |        |        |      | 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).

[]{#__RefHeading___Toc49234360 .anchor}Table 3: Primary and Secondary
Outcome Measures by Study

  -------------- ---------------- ---------- ----------- ---------- ---------- ----------
  **\            **Narcolepsy**              **OSAHS**              **SWSD**   
  Measures**                                                                   

                 **Study 301**    **Study    **Study     **Study    **Study    **Study
                                  302**      303**       402**      305**      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          \-\--

  **Other**                                                                    

  FOSQ           \-\--            \-\--      S           S          S          S

  SF-36          S                S          S           \-\--      \-\--      S
  -------------- ---------------- ---------- ----------- ---------- ---------- ----------

P = primary; S = secondary; MWT = Maintenance of Wakefulness Test; MSLT
= Multiple Sleep Latency Test; CGI-C = Clinical Global Impression of
Change; ESS = Epworth Sleepiness Scale; KSS = Karolinska Sleepiness
Scale; PVT = Psychomotor Vigilance Task; SCPT = Steer-Clear Performance
Test; FOSQ = Functional Outcomes of Sleep Questionnaire; OSAHS =
obstructive sleep apnea/hypopnea syndrome; SWSD = shift work sleep
disorder; SF-36 = Short Form Health Survey 36.

Of note, 4 of the 6 principal studies are considered pivotal in nature.
These are narcolepsy studies 301 and 302, OSAHS study 303, and SWSD
study 305. Each of these 4 studies had dual primary outcome measures
(MWT/MSLT and CGI‑C), an objective measure and a subjective measure.
With regard to the 2 remaining studies, OSAHS study 402 is not
considered a pivotal study because of its shorter duration and single
primary efficacy measure (ESS), and SWSD study 306 is not considered a
pivotal study because it did not include any predetermined efficacy
measures. A summary of data from the primary efficacy outcome measures
of the 4 pivotal studies follows the individual presentations of
efficacy of the 6 individual studies.

In the sections below for the presentation of efficacy and
quality-of-life data, first the individual studies are described
followed by individual presentations of study population data then
individual presentations of efficacy and quality-of-life results (by
study) relative to primary measures, secondary measures, and
quality-of-life and functional status assessments.

Data from these 6 studies demonstrate that PROVIGIL significantly and
consistently improved wakefulness across the disorders of sleep and
wakefulness and across objective and subjective measures.

## Narcolepsy---Studies 301 and 302

***Narcolepsy studies 301 and 302 (both pivotal)***

Narcolepsy studies 301 and 302 are the pivotal Phase 3 studies that
formed the basis of PROVIGIL's approved indication, ie, to improve
wakefulness in patients with excessive daytime sleepiness associated
with narcolepsy. For that reason, the presentation of results included
herein is brief in comparison to that of the OSAHS and SWSD studies.

### Narcolepsy Study Design

The evaluation of the efficacy of PROVIGIL for the treatment of adult
patients with ES associated with narcolepsy is based on 2 double-blind,
placebo‑controlled studies (studies 301 and 302).

Studies 301 and 302 were conducted at 18 and 21 US centers,
respectively. Patients with narcolepsy were randomized to receive a
daily dose of 200 or 400 mg of PROVIGIL, or a placebo, during a 9‑week,
double‑blind, treatment period. For study 301, a 2‑week wash‑out period
followed the double-blind treatment period, and for study 302 a 2‑week
discontinuation/withdrawal period followed the double‑blind treatment
period, in which the effects of treatment withdrawal were evaluated. For
both studies there were separate 40‑week open-label continuation periods
and subsequent 48‑week open‑label extension phases followed by
3 additional open-label continuous 48-week extension phases of each
study.

Eligible patients had a current diagnosis of narcolepsy according to
criterion A or B as established by the American Sleep Disorders
Association (ASDA), as follows:

-   criterion A: recurrent daytime naps or lapses into sleep that
    occurred almost daily for at least 3 months plus sudden bilateral
    loss of postural muscle tone in association with intense emotion
    (cataplexy)

-   criterion B: a complaint of ES or sudden muscle weakness plus
    associated features: sleep paralysis, hypnagogic hallucinations,
    automatic behaviors, disrupted major sleep episode; plus
    polysomnography demonstrating 1 of the following: (a) sleep latency
    less than 10 minutes; (b) rapid eye movement (REM) sleep latency
    less than 20 minutes and an MSLT with a mean sleep latency of less
    than 5 minutes; or (c) 2 or more sleep onset REM periods; and the
    absence of any medical or psychiatric disorder that could account
    for the symptoms

For inclusion in the study, eligible patients considered under criterion
A (cataplexy) had to have had a mean sleep latency of 8 minutes or less
on the MSLT. Eligible patients considered under criterion B (narcolepsy
and no cataplexy) had to have had a mean sleep latency of 5 minutes or
less on the MSLT. All eligible patients had to have had 2 sleep onset
REM periods documented within the MSLT.

The primary efficacy measures in these studies were the MWT and CGI-C.
The secondary efficacy measures that were evaluated included the MSLT,
ESS, and SCPT; the quality-of-life measure is the SF‑36. The MWT, ESS,
and SCPT were measured at baseline, week 3, week 6, and week 9 (or final
visit). The MWT involved 4 sessions conducted at 2-hour intervals (0800,
1000, 1200, and 1400). The average sleep latency from the 4 sessions was
the primary variable of the MWT. CGI-C was measured at week 3, week 6,
and week 9 (or final visit) relative to baseline CGI-S. MSLT and SF-36
were measured at baseline and at week 9 (or final visit). The MSLT was
performed on the day following the MWT. The MSLT involved 4 naps at
approximately 2‑hour intervals with sleep latency determined from the
average of the 4 tests.

### Narcolepsy Data Analysis

The *efficacy evaluable set* included data from all patients who
received at least 1 dose of study drug (PROVIGIL or placebo) and had at
least 1 postbaseline assessment for both primary efficacy assessments
(MWT and CGI‑C). The primary time point for analysis was defined as the
last postbaseline assessment. All continuous efficacy and
quality-of-life variables (average sleep latency from the MWT, total
score from the ESS, average sleep latency from the MLST, and 8
individual and 2 composite scores from the SF-36) were analyzed as the
change from baseline to the final visit. The change from baseline for
each continuous variable was analyzed using an analysis of covariance
(ANCOVA) with treatment and center as factors and baseline value as a
covariate. Pairwise comparisons between each PROVIGIL treatment group
and the placebo group were performed.

The distribution of the 7 CGI-C categories was compared across the 3
treatment groups by a Cochran-Mantel-Haenszel (CMH) chi-square test
adjusted for center and modified ridit scores were used to account for
the ordered categories of this scale.

### Narcolepsy Study Population

#### Patient Disposition

*Narcolepsy studies 301 and 302*

Together in studies 301 and 302, 350 PROVIGIL-treated patients and 180
placebo-treated patients were considered efficacy evaluable. A summary
of patient disposition for the studies is presented in Table 4.

[]{#__RefHeading___Toc49234361 .anchor}Table 4: Patient Disposition in
Narcolepsy Studies 301 and 302\
(Randomized Patients)

+------------+--------+---------+--------+---------+---------+---------+
|            | **Tre  |         |        |         |         |         |
|            | atment |         |        |         |         |         |
|            | g      |         |        |         |         |         |
|            | roup** |         |        |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
|            | *      |         |        | **Study |         |         |
|            | *Study |         |        | 302**   |         |         |
|            | 301**  |         |        |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| **Analysis | **PRO  | **PR    | **Pla  | **PR    | **PR    | **Pl    |
| set**      | VIGIL\ | OVIGIL\ | cebo** | OVIGIL\ | OVIGIL\ | acebo** |
|            | 200    | 400     |        | 200     | 400     |         |
|            | mg     | m       | **N    | m       | m       | **N     |
|            | /day** | g/day** | (%)**  | g/day** | g/day** | (%)**   |
|            |        |         |        |         |         |         |
|            | **N    | **N     |        | **N     | **N     |         |
|            | (%)**  | (%)**   |        | (%)**   | (%)**   |         |
+------------+--------+---------+--------+---------+---------+---------+
| Randomized | 96     | 95      | 94     | 90      | 90      | 93      |
+------------+--------+---------+--------+---------+---------+---------+
| Efficacy   | 95     | 86 (91) | 92     | 83 (92) | 86 (96) | 88 (95) |
| evaluable  | (99)   |         | (98)   |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| Completed  | 93     | 81 (85) | 87     | 77 (86) | 84 (93) | 82 (88) |
| study      | (97)   |         | (93)   |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| Di         | 3 (3)  | 14 (15) | 5 (5)  | 12 (13) | 5 (6)   | 11 (12) |
| scontinued |        |         |        |         |         |         |
| study      |        |         |        |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| Adverse    | 1 (1)  | 11 (12) | 0      | 6 (7)   | 1 (1)   | 3 (3)   |
| event      |        |         |        |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| Lack of    | 1 (1)  | 0       | 3 (3)  | 2 (2)   | 0       | 2 (2)   |
| efficacy   |        |         |        |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| Consent    | 0      | 2 (2)   | 0      | 3 (3)   | 3 (3)   | 3 (3)   |
| withdrawn  |        |         |        |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| Protocol   | 1 (1)  | 1 (1)   | 0      | 0       | 1 (1)   | 1 (1)   |
| violation  |        |         |        |         |         |         |
+------------+--------+---------+--------+---------+---------+---------+
| Other      | 0      | 0       | 2 (2)  | 1 (1)   | 0       | 2 (2)   |
+------------+--------+---------+--------+---------+---------+---------+

#### Demographic Characteristics

*Narcolepsy studies 301 and 302*

Patient demographic characteristics were similar for the 3 treatment
groups. A summary of patient characteristics including sex, race, age,
weight for the 2 studies is presented in Table 5.

[]{#__RefHeading___Toc49234362 .anchor}Table 5: Demographic
Characteristics in Narcolepsy Studies 301 and 302\
(Safety Evaluable Set)

+-------+-------+--------+--------+-------+---------+--------+-------+
|       |       | **Tre  |        |       |         |        |       |
|       |       | atment |        |       |         |        |       |
|       |       | g      |        |       |         |        |       |
|       |       | roup** |        |       |         |        |       |
+=======+=======+========+========+=======+=========+========+=======+
|       |       | *      |        |       | **Study |        |       |
|       |       | *Study |        |       | 302**   |        |       |
|       |       | 301**  |        |       |         |        |       |
+-------+-------+--------+--------+-------+---------+--------+-------+
| **C   |       | **PRO  | **PRO  | *     | **PR    | **PRO  | *     |
| harac |       | VIGIL\ | VIGIL\ | *Plac | OVIGIL\ | VIGIL\ | *Plac |
| teris |       | 200    | 400    | ebo** | 200     | 400    | ebo** |
| tic** |       | mg     | mg     |       | m       | mg     |       |
|       |       | /day** | /day** | **(N= | g/day** | /day** | **(N= |
|       |       |        |        | 92)** |         |        | 93)** |
|       |       | **(N   | **(N   |       | **(     | **(N   |       |
|       |       | =96)** | =95)** |       | N=89)** | =89)** |       |
+-------+-------+--------+--------+-------+---------+--------+-------+
| Sex,  | Male  | 44     | 43     | 42    | 37 (42) | 44     | 43    |
| N (%) |       | (46)   | (45)   | (46)  |         | (49)   | (46)  |
+-------+-------+--------+--------+-------+---------+--------+-------+
|       | F     | 52     | 52     | 50    | 52 (58) | 45     | 50    |
|       | emale | (54)   | (55)   | (54)  |         | (51)   | (54)  |
+-------+-------+--------+--------+-------+---------+--------+-------+
| Race, | White | 70     | 77     | 73    | 79 (89) | 75     | 81    |
| N (%) |       | (73)   | (81)   | (79)  |         | (84)   | (87)  |
+-------+-------+--------+--------+-------+---------+--------+-------+
|       | Black | 23     | 16     | 17    | 9 (10)  | 6 (7)  | 9     |
|       |       | (24)   | (17)   | (18)  |         |        | (10)  |
+-------+-------+--------+--------+-------+---------+--------+-------+
|       | Other | 3 (3)  | 2 (2)  | 2 (2) | 1 (1)   | 8 (9)  | 3 (3) |
+-------+-------+--------+--------+-------+---------+--------+-------+
| Age   | Mean  | 40     | 44     | 42    | 42      | 42     | 41    |
| (yr)  | (SD)  | (13.5) | (13.7) | (     | (13.1)  | (13.3) | (     |
|       |       |        |        | 12.3) |         |        | 14.1) |
+-------+-------+--------+--------+-------+---------+--------+-------+
|       | Min,  | 18, 67 | 19, 67 | 18,   | 18, 67  | 18, 66 | 17,   |
|       | max   |        |        | 68    |         |        | 66    |
+-------+-------+--------+--------+-------+---------+--------+-------+
| W     | Mean  | 195    | 189    | 186   | 174     | 181    | 179   |
| eight | (SD)  | (42.5) | (44.3) | (     | (44.3)  | (39.1) | (     |
| (lb)  |       |        |        | 45.0) |         |        | 38.2) |
+-------+-------+--------+--------+-------+---------+--------+-------+

> Min = minimum; max = maximum.

#### Baseline Patient Characteristics

*Narcolepsy studies 301 and 302*

The 3 treatment groups were comparable with regard to baseline CGI-S
ratings, MWT sleep latency, and NPSG sleep efficiency (Table 6). At
baseline, more than 80% of all patients studied were at least moderately
ill as assessed by the CGI-S, with MWT sleep latency of approximately 6
minutes.

[]{#__RefHeading___Toc49234363 .anchor}Table 6: Baseline Patient
Characteristics in Narcolepsy Studies 301 and 302\
(Efficacy Evaluable Set)

+--------+---------+--------+--------+------+--------+--------+-----+
| **\    |         | **Tre  |        |      |        |        |     |
| \      |         | atment |        |      |        |        |     |
| \      |         | g      |        |      |        |        |     |
| Ba     |         | roup** |        |      |        |        |     |
| seline |         |        |        |      |        |        |     |
| param  |         |        |        |      |        |        |     |
| eter** |         |        |        |      |        |        |     |
+========+=========+========+========+======+========+========+=====+
|        |         | *      |        |      | *      |        |     |
|        |         | *Study |        |      | *Study |        |     |
|        |         | 301**  |        |      | 302**  |        |     |
+--------+---------+--------+--------+------+--------+--------+-----+
|        |         | **PRO  | **PRO  | **P  | **PRO  | **PRO  | **  |
|        |         | VIGIL\ | VIGIL\ | lace | VIGIL\ | VIGIL\ | Pla |
|        |         | 200    | 400    | bo** | 200    | 400    | ceb |
|        |         | mg     | mg     |      | mg     | mg     | o** |
|        |         | /day** | /day** | **   | /day** | /day** |     |
|        |         |        |        | (N=9 |        |        | *   |
|        |         | **(N   | **(N   | 2)** | **(N   | **(N   | *(N |
|        |         | =95)** | =86)** |      | =83)** | =86)** | =88 |
|        |         |        |        |      |        |        | )** |
+--------+---------+--------+--------+------+--------+--------+-----+
| CGI-S  | Normal  | 0      | 0      | 1    | 0      | 0      | 0   |
| ra     |         |        |        | (1)  |        |        |     |
| ting,\ |         |        |        |      |        |        |     |
| N (%)  |         |        |        |      |        |        |     |
+--------+---------+--------+--------+------+--------+--------+-----+
|        | Bor     | 2 (2)  | 1 (1)  | 2    | 4 (5)  | 1 (1)  | 5   |
|        | derline |        |        | (2)  |        |        | (6) |
|        | ill     |        |        |      |        |        |     |
+--------+---------+--------+--------+------+--------+--------+-----+
|        | Mildly  | 14     | 10     | 10   | 18     | 11     | 12  |
|        | ill     | (15)   | (12)   | (11) | (22)   | (13)   | (   |
|        |         |        |        |      |        |        | 14) |
+--------+---------+--------+--------+------+--------+--------+-----+
|        | Mod     | 38     | 37     | 47   | 38     | 39     | 38  |
|        | erately | (40)   | (43)   | (51) | (46)   | (45)   | (   |
|        | ill     |        |        |      |        |        | 43) |
+--------+---------+--------+--------+------+--------+--------+-----+
|        | M       | 31     | 32     | 28   | 19 23) | 30     | 26  |
|        | arkedly | (33)   | (37)   | (30) |        | (35)   | (   |
|        | ill     |        |        |      |        |        | 30) |
+--------+---------+--------+--------+------+--------+--------+-----+
|        | S       | 0      | 0      | 0    | 0      | 0      | 0   |
|        | everely |        |        |      |        |        |     |
|        | ill     |        |        |      |        |        |     |
+--------+---------+--------+--------+------+--------+--------+-----+
|        | Ex      | 10     | 6 (7)  | 4    | 4 (5)  | 5 (6)  | 7   |
|        | tremely | (11)   |        | (4)  |        |        | (8) |
|        | ill     |        |        |      |        |        |     |
+--------+---------+--------+--------+------+--------+--------+-----+
| Mean   |         | 5.8    | 6.6    | 5.8  | 6.1    | 5.9    | 6.0 |
| (SD)   |         | (5.02) | (5.16) | (4   | (4.86) | (4.37) | (4. |
| MWT    |         |        |        | .67) |        |        | 97) |
| sleep  |         |        |        |      |        |        |     |
| l      |         |        |        |      |        |        |     |
| atency |         |        |        |      |        |        |     |
| in     |         |        |        |      |        |        |     |
| m      |         |        |        |      |        |        |     |
| inutes |         |        |        |      |        |        |     |
+--------+---------+--------+--------+------+--------+--------+-----+
| NPSG   |         |        |        |      |        |        |     |
| sleep  |         |        |        |      |        |        |     |
| effi   |         |        |        |      |        |        |     |
| ciency |         |        |        |      |        |        |     |
| (% of  |         |        |        |      |        |        |     |
| time   |         |        |        |      |        |        |     |
| in bed |         |        |        |      |        |        |     |
| spent  |         |        |        |      |        |        |     |
| a      |         |        |        |      |        |        |     |
| sleep) |         |        |        |      |        |        |     |
+--------+---------+--------+--------+------+--------+--------+-----+
| N      |         | 95     | 86     | 92   | 83     | 86     | 87  |
+--------+---------+--------+--------+------+--------+--------+-----+
| Mean   |         | 86     | 87     | 88   | 87     | 89     | 85  |
| (SD)   |         | (11.2) | (8.7)  | (    | (9.5)  | (7.7)  | (14 |
|        |         |        |        | 8.7) |        |        | .0) |
+--------+---------+--------+--------+------+--------+--------+-----+

> CGI-S = Clinical Global Impression of Severity\
> MWT = Maintenance of Wakefulness Test; NPSG = nocturnal
> polysomnography.
>
> Overall, the patients who participated in narcolepsy studies 301 and
> 302 had baseline subjective and objective evidence of ES (from CGI-S
> and MWT assessments) and had baseline disturbed sleep (from NPSG).

### Narcolepsy Efficacy and Quality-of-Life Results

#### Primary Efficacy Measures: MWT and CGI‑C

##### *MWT sleep latency* {#mwt-sleep-latency .unnumbered}

In narcolepsy study 301, mean sleep latency from the MWT increased from
the baseline assessment to the final visit by 2.3 minutes in both the
200-mg/day and 400-mg/day PROVIGIL groups, while mean sleep latency for
the placebo group decreased by 0.7 minutes. Between‑treatment
comparisons (each PROVIGIL dose vs placebo) were statistically
significant (p\<0.001).

In narcolepsy study 302, mean sleep latency from the MWT increased from
the baseline assessment to the final visit by 2.2 minutes for the
200‑mg/day PROVIGIL group and by 2.0 minutes for the 400-mg/day PROVIGIL
groups, while mean sleep latency for the placebo group decreased by
0.7 minutes. Between‑treatment comparisons (each PROVIGIL dose vs
placebo) were statistically significant (p\<0.001).

MWT sleep latency results for studies 301 and 302 are presented in Table
7.

[]{#__RefHeading___Toc49234364 .anchor}Table 7: Average Sleep Latency
(Minutes) From MWT at the Final Visit\
in Narcolepsy Studies 301 and 302\
(Efficacy Evaluable Set)

+-------------+--------+--------+--------+--------+--------+--------+
|             | *      |        |        | *      |        |        |
|             | *Study |        |        | *Study |        |        |
|             | 301**  |        |        | 302**  |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| **Ob        | **PRO  | **PRO  | **Pla  | **PRO  | **PRO  | **Pla  |
| servation** | VIGIL\ | VIGIL\ | cebo** | VIGIL\ | VIGIL\ | cebo** |
|             | 200    | 400    |        | 200    | 400    |        |
|             | mg     | mg     | **(N   | mg     | mg     | **(N   |
|             | /day** | /day** | =92)** | /day** | /day** | =88)** |
|             |        |        |        |        |        |        |
|             | **(N   | **(N   |        | **(N   | **(N   |        |
|             | =95)** | =86)** |        | =83)** | =86)** |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Baseline    |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Mean (SD)   | 5.8    | 6.6    | 5.8    | 6.1    | 5.9    | 6.0    |
|             | (5.0)  | (5.2)  | (4.7)  | (4.9)  | (4.4)  | (5.0)  |
+-------------+--------+--------+--------+--------+--------+--------+
| Final visit |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Mean (SD)   | 8.2    | 8.9    | 5.1    | 8.3    | 7.9    | 5.3    |
|             | (6.2)  | (6.3)  | (4.7)  | (5.9)  | (5.3)  | (4.5)  |
+-------------+--------+--------+--------+--------+--------+--------+
| Change from |        |        |        |        |        |        |
| baseline    |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| Mean (SD)   | 2.3    | 2.3    | -0.7   | 2.2    | 2.0    | -0.7   |
|             | (4.7)  | (4.9)  | (4.6)  | (4.5)  | (4.8)  | (4.2)  |
+-------------+--------+--------+--------+--------+--------+--------+
| p-value^a^  | \      | \      | \-\--  | \      | \      | \-\--  |
|             | <0.001 | <0.001 |        | <0.001 | <0.001 |        |
+-------------+--------+--------+--------+--------+--------+--------+

> ^a^ The p-value under each PROVIGIL treatment group column is for the
> comparison of that treatment group to the placebo treatment group.
>
> MWT = Maintenance of Wakefulness Test.

##### In both narcolepsy studies, MWT sleep latency was significantly higher for both the 200- and 400‑mg/day PROVIGIL groups compared to the placebo group at each time point (weeks 3, 6, and 9 \[p=0.001\]).  {#in-both-narcolepsy-studies-mwt-sleep-latency-was-significantly-higher-for-both-the-200--and-400mgday-provigil-groups-compared-to-the-placebo-group-at-each-time-point-weeks-3-6-and-9-p0.001. .unnumbered}

##### *CGI-C ratings* {#cgi-c-ratings .unnumbered}

Comparisons of the distribution of CGI‑C ratings at the final visit
showed statistically significant improvement in clinical condition for
patients in both the PROVIGIL 200- and 400-mg/day treatment groups in
the 2 narcolepsy studies (p\<0.00)1 in study 301 and p\<0.003 in study
302 for both PROVIGIL treatment groups) when compared with patients in
the placebo treatment groups. GCI-C rating results for studies 301 and
302 are presented in Table 8.

[]{#__RefHeading___Toc49234365 .anchor}Table 8: CGI‑C Ratings (Number
\[%\] in Each Category) at the Final Visit\
in Narcolepsy Studies 301 and 302\
(Efficacy Evaluable Set)

  -------------------------------------------------------------------------------
  **Narcolepsy      **Response          **Number (%)                
  study**           category**          of patients**               
  ----------------- ------------------- ------------- ------------- -------------
                                        **PROVIGIL\   **PROVIGIL\   **Placebo**
                                        200 mg/day**  400 mg/day**  

  Study 301         Total number of     95            86            92
                    subjects                                        

                    Very much improved  7 (7)         8 (9)         4 (4)

                    Much improved       25 (26)       35 (41)       8 (9)

                    Minimally improved  29 (31)       19 (22)       22 (24)

                    No change           27 (28)       20 (23)       43 (47)

                    Minimally worse     5 (5)         3 (3)         11 (12)

                    Much worse          2 (2)         1 (1)         3 (3)

                    Very much worse     0             0             1 (1)

                    p-value^a^          \<0.0001      \<0.0001      \-\--

  Study 302         Total number of     83            86            88
                    subjects                                        

                    Very much improved  7 (8)         5 (6)         0

                    Much improved       21 (25)       24 (28)       12 (14)

                    Minimally improved  20 (24)       23 (27)       21 (24)

                    No change           27 (33)       26 (30)       42 (48)

                    Minimally worse     7 (8)         5 (6)         9 (10)

                    Much worse          1 (1)         3 (3)         4 (5)

                    Very much worse     0             0             0

                    p-value^a^          0.0011        0.0028        \-\--
  -------------------------------------------------------------------------------

> ^a^ The p-value under each PROVIGIL treatment group column is for the
> comparison of that treatment group to the placebo treatment group.
>
> CGI‑C = Clinical Global Impression of Change.

#### Secondary Efficacy Measures: MSLT, ESS, and SCPT

The positive effect of PROVIGIL treatment in patients with narcolepsy as
assessed by the secondary measures of the MSLT, ESS, and SCPT was
consistent with that observed with the dual primary measures. The
results of secondary measures for studies 301 and 302 are presented in
Table 9.

[]{#__RefHeading___Toc49234366 .anchor}Table 9: Mean (SD) Change From
Baseline to the Final Visit in MSLT, ESS, and SCPT Results in Narcolepsy
Studies 301 and 302\
(Efficacy Evaluable Set)

  -------------- ------------- ------------- ----------- ------------- ------------- -----------
  **Variable**   **Study 301**                           **Study 302**               

                 **PROVIGIL\   **PROVIGIL\   **\         **PROVIGIL\   **PROVIGIL\   **\
                 200 mg/day**  400 mg/day**  Placebo**   200 mg/day**  400 mg/day**  Placebo**

  MSLT\          1.9 (3.18)\   1.9 (4.07)\   0.5 (2.98)  2.0 (3.65)\   2.3 (3.39)\   1.3 (2.64)
  sleep latency  p=0.0059      p=0.0059                  p=0.2033      p=0.0334      

  ESS\           --3.6 (4.7)\  --4.3 (4.8)\  --1.4 (3.7) --4.3 (4.9)\  --5.7 (5.0)\  --1.7 (3.6)
  total score    p\<0.0005     p\<0.0001                 p\<0.0001     p\<0.0001     

  SCPT\          --1.9 (11.6)\ --1.5 (11.6)\ 0.8 (7.2)   --2.3 (8.2)\  --1.7 (6.6)\  0.6 (11.1)
  % obstacles    ns            ns                        p=0.016       p=0.018       
  hit                                                                                
  -------------- ------------- ------------- ----------- ------------- ------------- -----------

Note: The p-value under each PROVIGIL treatment group column is for the
comparison of that treatment group to placebo treatment.

ns = not statistically significant.

MSLT = Multiple Sleep Latency Test; ESS = Epworth Sleepiness Scale; SCPT
= Steer-Clear Performance Test.

#### Quality-of-Life Assessment: SF-36

In narcolepsy study 301, there was no significant effect of PROVIGIL
treatment on the change from the baseline assessment in physical
composite summary score with either dosage; however, the mental
composite summary score was increased significantly for the 400-mg/day
PROVIGIL group compared to the placebo group (p=0.03). For the
individual domains, significant differences from placebo were observed
for vitality (200 mg/day, p=0.04; 400 mg/day, p\<0.001), role physical
(400 mg/day, p=0.009), and social functioning (400 mg/day, p=0.014).

In narcolepsy study 302, there was no significant effect of PROVIGIL
treatment on the change from the baseline assessment in physical
composite summary score with either dosage; however, the mental
composite summary score was increased significantly for both PROVIGIL
groups compared to the placebo group (200 mg/day, p=0.002; 400 mg/day,
p=0.001). For the individual domains, significant differences from
placebo treatment were observed for vitality (200 mg/day, p=0.003;
400 mg/day, p=0.013), role emotional (200 mg/day, p\<0.001; 400 mg/day,
p=0.002), physical functioning (200 mg/day, p=0.016), role physical
(200 mg/day, p=0.036; 400 mg/day, p=0.008), and social functioning
(400 mg/day, p=0.004).

### Conclusions on Narcolepsy 

The efficacy of PROVIGIL in the treatment of patients with narcolepsy
was evaluated in 2 Phase 3 double-blind, placebo-controlled studies
(studies 301 and 302) involving a total of 350 efficacy evaluable
patients treated with PROVIGIL and 180 treated with placebo for up to
9 weeks (double‑blind treatment period). The evaluations of efficacy in
each study show that PROVIGIL treatment provides relief from the
symptoms of ES associated with narcolepsy.

The results of the analyses of the MWT at the final visit demonstrate a
significant increase in sleep latency for PROVIGIL‑treated patients
compared to placebo-treated patients (p\<0.001, both PROVIGIL dosages).
This is corroborated by the results of the analyses of CGI‑C, which
indicate a significant difference between PROVIGIL and placebo treatment
(p\<0.001, both PROVIGIL dosages) in the distribution of CGI-C scores at
the final visit. The results for secondary assessments of efficacy,
including the MSLT, ESS, and SCPT were consistent with those for the
primary assessments (MWT and CGI‑C), with significant improvement in
symptoms of sleepiness observed for both dosages of PROVIGIL compared to
placebo. The data indicate that efficacy was obtained by week 3 and
sustained over the course of the 9‑week double‑blind treatment period.

## Obstructive Sleep Apnea/Hypopnea Syndrome---Studies 303 and 402

*OSAHS studies 303 (pivotal study) and 402*

The efficacy of PROVIGIL for the treatment of adult patients with
residual ES associated with OSAHS was demonstrated in 2 double-blind,
placebo‑controlled studies (studies 303 and 402).

### Study Design for OSAHS Study 303

Study 303 was a randomized, double‑blind, placebo‑controlled,
parallel‑group study conducted at 39 centers by 42 investigators in the
US and 4 centers in the UK. Patients with residual ES associated with
OSAHS were randomized to receive a daily dose of 200 or 400 mg of
PROVIGIL, or a placebo, during a 12-week, double-blind treatment period.
The usage and effectiveness of nCPAP therapy was evaluated during a
pre‑enrollment period that included a screening visit, a 2‑night
evaluation of nCPAP therapy effectiveness, and a 2‑week evaluation of
nCPAP therapy compliance. Initially, patients were stratified into
3 subpopulations (nCPAP‑compliant, partially nCPAP‑compliant, and
nonusers of nCPAP therapy) prior to randomization. However, after
enrollment for the study began, the protocol was amended to discontinue
the nonuser strata from the study. At the time of the amendment,
18 nonusers of nCPAP therapy had been enrolled and were allowed to
continue in the study. After completion of the double‑blind treatment
period, patients were eligible to enter a 12-month open‑label treatment
extension period.

Eligible patients met the ICSD criteria for OSAHS (ICSD Code 780.53-0),
were users of nasal nCPAP therapy, and had residual ES (as indicated by
an ESS score greater than or equal to 10 at screening) associated with
OSAHS. Patients who met the following criteria were enrolled:

-   nCPAP-compliant---nCPAP therapy use was ≥4 hours/night on ≥70% of
    nights, with documentation of prior adequate nCPAP therapy education
    and intervention efforts, and for whom nCPAP therapy was effective
    (had an apnea-hypopnea index \[AHI\] decrease \[\<10 and \>50%\]
    from historic AHI \[ie, while not treated with nCPAP therapy\])

-   partially nCPAP-compliant---nCPAP therapy use was \<4 hours/night on
    \>30% of nights during the 2‑week pre-enrollment evaluation period
    despite documentation of prior adequate nCPAP therapy education and
    intervention efforts, and for whom nCPAP therapy was effective

The primary efficacy measures in this study were the MWT and CGI-C. The
secondary efficacy measures included the ESS and the PVT. The quality of
life measures were the SF-36 and FOSQ. All efficacy and quality-of-life
measures were assessed at baseline, week 4, week 8, and week 12 (or
final visit). At each time point, four 20-minute sessions of the MWT
were performed at 2-hour intervals. The first MWT session was to be
conducted at least 2 hours after the morning dose of study drug. The PVT
sessions were performed prior to each MWT session.

### Data Analysis for OSAHS Study 303

The *efficacy evaluable set* included data from all patients who
received at least 1 dose of study drug (PROVIGIL or placebo) and had at
least 1 postbaseline efficacy evaluation on any measure. Patients who
were nonusers of nCPAP therapy were excluded from the efficacy analysis
since they were excluded from enrollment in an amendment to the
protocol. The primary time point for analysis was defined as the last
postbaseline assessment.

All continuous variables (MWT, ESS, PVT, SF-36, and FOSQ) were analyzed
as the change from baseline; an ANCOVA with treatment and nCPAP strata
(compliant vs partially compliant) as factors and the baseline value as
a covariate was utilized. The CGI-C data were analyzed using the CMH
(Cochran-Mantel-Haenszel) chi-square test adjusted for nCPAP strata,
with modified ridit scores to account for ordered categories of CGI-C.

### Study Population for OSAHS Study 303

#### Patient Disposition

In OSAHS study 303, 191 PROVIGIL-treated patients and 100
placebo-treated patients were considered efficacy evaluable (Table 10).

[]{#__RefHeading___Toc49234367 .anchor}Table 10: Patient Disposition in
OSAHS Study 303\
(Randomized Patients)

<table>
<colgroup>
<col style="width: 17%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 9%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="9"><strong>Number (%) of patients</strong></td>
</tr>
<tr class="even">
<td></td>
<td colspan="3"><strong>PROVIGIL<br />
200 mg/day</strong></td>
<td colspan="3"><strong>PROVIGIL<br />
400 mg/day</strong></td>
<td colspan="3"><strong><br />
Placebo</strong></td>
</tr>
<tr class="odd">
<td><strong><br />
Patient disposition</strong></td>
<td><strong><br />
Compliant</strong></td>
<td><strong>Partially compliant</strong></td>
<td><strong><br />
Nonuser</strong></td>
<td><strong><br />
Compliant</strong></td>
<td><strong>Partially compliant</strong></td>
<td><strong><br />
Nonuser</strong></td>
<td><strong><br />
Compliant</strong></td>
<td><strong>Partially compliant</strong></td>
<td><strong><br />
Nonuser</strong></td>
</tr>
<tr class="even">
<td>Randomized</td>
<td>91 (100)</td>
<td>13 (100)</td>
<td>6 (100)</td>
<td>88 (100)</td>
<td>13 (100)</td>
<td>7 (100)</td>
<td>89 (100)</td>
<td>15 (100)</td>
<td>5 (100)</td>
</tr>
<tr class="odd">
<td>Completed</td>
<td>75 (82)</td>
<td>11 (85)</td>
<td>4 (67)</td>
<td>71 (81)</td>
<td>10 (77)</td>
<td>4 (57)</td>
<td>80 (90)</td>
<td>13 (87)</td>
<td>4 (80)</td>
</tr>
<tr class="even">
<td>Withdrawn</td>
<td>16 (18)</td>
<td>2 (15)</td>
<td>2 (33)</td>
<td>17 (19)</td>
<td>3 (23)</td>
<td>3 (43)</td>
<td>9 (10)</td>
<td>2 (13)</td>
<td>1 (20)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Death</p>
</blockquote></td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Adverse event</p>
</blockquote></td>
<td>8 (9)</td>
<td>2 (15)</td>
<td>0</td>
<td>10 (11)</td>
<td>1 (8)</td>
<td>3 (43)</td>
<td>2 (2)</td>
<td>1 (7)</td>
<td>0</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Lack of efficacy</p>
</blockquote></td>
<td>0</td>
<td>0</td>
<td>1 (17)</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>1 (7)</td>
<td>0</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Consent withdrawn</p>
</blockquote></td>
<td>1 (1)</td>
<td>0</td>
<td>0</td>
<td>6 (7)</td>
<td>1 (8)</td>
<td>0</td>
<td>1 (1)</td>
<td>0</td>
<td>1 (20)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Protocol violation</p>
</blockquote></td>
<td>1 (1)</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>3 (3)</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Noncompliance</p>
</blockquote></td>
<td>3 (3)</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>1 (1)</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Lost to follow‑up</p>
</blockquote></td>
<td>3 (3)</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Other</p>
</blockquote></td>
<td>0</td>
<td>0</td>
<td>1 (17)</td>
<td>1 (1)</td>
<td>1 (8)</td>
<td>0</td>
<td>2 (2)</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="odd">
<td>Combined efficacy population</td>
<td colspan="3">99 (90)</td>
<td colspan="3">92 (85)</td>
<td colspan="3">100 (92)</td>
</tr>
<tr class="even">
<td>Combined safety population</td>
<td colspan="3">109 (99)</td>
<td colspan="3">106 (98)</td>
<td colspan="3">108 (99)</td>
</tr>
</tbody>
</table>

#### Demographic Characteristics

A summary of patient characteristics including sex, race, age, weight,
and body mass index (BMI) for study 303 is presented in Table 11.

[]{#__RefHeading___Toc49234368 .anchor}Table 11: Demographic
Characteristics in OSAHS Study 303\
(Randomized Patients)

+---------------------+---------------+---------------+--------------+
| **Demographic       | **PROVIGIL\   | **PROVIGIL\   | **\          |
| variable**          | 200 mg/day\   | 400 mg/day\   | Placebo\     |
|                     | (N=110)**     | (N=108)**     | (N=109)**    |
+---------------------+---------------+---------------+--------------+
| **Age, years**      |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Mean (SD)         | 47.9 (10.0)   | 48.5 (8.7)    | 50.9 (9.4)   |
+---------------------+---------------+---------------+--------------+
| > Min, max          | 24.0, 68.0    | 28.0, 70.0    | 28.0, 68.0   |
+---------------------+---------------+---------------+--------------+
| **Sex, n (%)**      |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Men               | 95 (86.4)     | 74 (68.5)     | 80 (73.4)    |
+---------------------+---------------+---------------+--------------+
| > Women             | 15 (13.6)     | 34 (31.5)     | 29 (26.6)    |
+---------------------+---------------+---------------+--------------+
| **Race, n (%)**     |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Caucasian         | 97 (88.2)     | 95 (88.0)     | 98 (89.9)    |
+---------------------+---------------+---------------+--------------+
| > Black             | 7 (6.4)       | 9 (8.3)       | 8 (7.3)      |
+---------------------+---------------+---------------+--------------+
| > Asian             | 2 (1.8)       | 1 (0.9)       | 2 (1.8)      |
+---------------------+---------------+---------------+--------------+
| > Hispanic          | 3 (2.7)       | 2 (1.9)       | 1 (0.9)      |
+---------------------+---------------+---------------+--------------+
| > Other             | 1 (0.9)       | 1 (0.9)       | 0            |
+---------------------+---------------+---------------+--------------+
| **Weight, kg**      |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Mean (SD)         | 109.6 (23.3)  | 109.9 (25.9)  | 110.5 (24.4) |
+---------------------+---------------+---------------+--------------+
| **BMI**             |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Mean (SD)         | 35.8 (7.6)    | 36.0 (7.0)    | 36.9 (8.4)   |
+---------------------+---------------+---------------+--------------+

> OSAHS = obstructive sleep apnea/hypopnea syndrome; BMI = body mass
> index;\
> min = minimum; max = maximum.

The distribution of patients across treatment groups was similar with
regard to race, height, and weight with no statistically significant
differences between the combined PROVIGIL treatment group and the
placebo treatment group. Although the mean age and the distribution of
men and women of patients in the placebo group were statistically
significantly different when compared to the PROVIGIL treatment groups,
this was not considered clinically significant. The average BMI
(approximately 36 kg/m^2^) indicates that the patient population in this
study consisted of predominantly obese patients, which is a
characteristic of patients with OSAHS.

#### Baseline Respiratory Disturbance Index and Oxygen Saturation

At entry into OSAHS study 303, the effectiveness of the patients' nCPAP
therapy was demonstrated by relatively low apnea-hypopnea index (AHI)
and high oxygen saturation values (Table 12). Historic (ie, without CPAP
therapy) AHI values are included for comparative purposes.

[]{#__RefHeading___Toc49234369 .anchor}Table 12: Historic and Baseline
Apnea-Hypopnea Index (AHI) and Baseline Oxygen Saturation for Patients
in OSAHS Study 303

+---------------------+---------------+---------------+--------------+
| **Parameter**       | **PROVIGIL\   | **PROVIGIL\   | **\          |
|                     | 200 mg/day\   | 400 mg/day\   | Placebo\     |
|                     | (N=99)**      | (N=92)**      | (N=100)**    |
+---------------------+---------------+---------------+--------------+
| **Historic AHI**    |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Mean (SD)         | 46.8 (26.52)  | 46.9 (28.87)  | 49.6 (31.65) |
+---------------------+---------------+---------------+--------------+
| **Baseline AHI**    |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Mean (SD)         | 4.2 (5.56)    | 4.2 (5.58)    | 5.8 (8.11)   |
+---------------------+---------------+---------------+--------------+
| **Baseline oxygen   |               |               |              |
| saturation**        |               |               |              |
+---------------------+---------------+---------------+--------------+
| Mean (SD)           | 91.0 (3.70)   | 90.7 (3.46)   | 90.1 (5.53)  |
+---------------------+---------------+---------------+--------------+
| OSAHS = obstructive |               |               |              |
| sleep               |               |               |              |
| apnea/hypopnea      |               |               |              |
| syndrome            |               |               |              |
+---------------------+---------------+---------------+--------------+

#### Baseline Patient Characteristics

The 3 treatment groups were comparable with regard to baseline CGI-S,
MWT sleep latency, and NPSG sleep efficiency (Table 13). At baseline,
about 60% of all patients studied were at least moderately ill as
assessed by the CGI-S, with mean MWT sleep latency of approximately
13 minutes.

[]{#__RefHeading___Toc49234370 .anchor}Table 13: Baseline Patient
Characteristics in OSAHS Study 303\
(Efficacy Evaluable Set)

+---------------+------------------+-----------+-----------+----------+
| **\           |                  | **        |           |          |
| \             |                  | Treatment |           |          |
| Baseline      |                  | group**   |           |          |
| parameter**   |                  |           |           |          |
+===============+==================+===========+===========+==========+
|               |                  | **        | **        | **P      |
|               |                  | PROVIGIL\ | PROVIGIL\ | lacebo** |
|               |                  | 200       | 400       |          |
|               |                  | mg/day**  | mg/day**  | **(      |
|               |                  |           |           | N=100)** |
|               |                  | *         | *         |          |
|               |                  | *(N=99)** | *(N=92)** |          |
+---------------+------------------+-----------+-----------+----------+
| CGI-S rating, | Normal           | 2 (1.9)   | 0         | 2 (1.9)  |
| N (%)         |                  |           |           |          |
+---------------+------------------+-----------+-----------+----------+
|               | Borderline ill   | 10 (9.5)  | 7 (7.1)   | 5 (4.8)  |
+---------------+------------------+-----------+-----------+----------+
|               | Mildly ill       | 24 (22.9) | 23 (23.2) | 26       |
|               |                  |           |           | (24.8)   |
+---------------+------------------+-----------+-----------+----------+
|               | Moderately ill   | 45 (42.9) | 39 (39.4) | 47       |
|               |                  |           |           | (44.8)   |
+---------------+------------------+-----------+-----------+----------+
|               | Markedly ill     | 16 (15.2) | 14 (14.1) | 20       |
|               |                  |           |           | (19.1)   |
+---------------+------------------+-----------+-----------+----------+
|               | Severely ill     | 2 (1.9)   | 8 (7.1)   | 0        |
+---------------+------------------+-----------+-----------+----------+
|               | Extremely ill    | 0         | 0         | 0        |
+---------------+------------------+-----------+-----------+----------+
| MWT sleep     |                  |           |           |          |
| latency       |                  |           |           |          |
| (minutes)     |                  |           |           |          |
+---------------+------------------+-----------+-----------+----------+
| > Mean (SD)   |                  | 13.1      | 13.6      | 13.8     |
|               |                  | (5.5)     | (5.4)     | (5.7)    |
+---------------+------------------+-----------+-----------+----------+
| NPSG sleep    |                  |           |           |          |
| efficiency (% |                  |           |           |          |
| of time in    |                  |           |           |          |
| bed spent     |                  |           |           |          |
| asleep)       |                  |           |           |          |
+---------------+------------------+-----------+-----------+----------+
| N             |                  | 95        | 89        | 95       |
+---------------+------------------+-----------+-----------+----------+
| Mean (SD)     |                  | 86.7      | 86.0      | 82.3     |
|               |                  | (8.4)     | (11.7)    | (14.9)   |
+---------------+------------------+-----------+-----------+----------+

> CGI-S = Clinical Global Impression of Severity; OSAHS = obstructive
> sleep apnea/hypopnea syndrome;\
> MWT = Maintenance of Wakefulness Test; NPSG = nocturnal
> polysomnography.

Overall, the patients who participated in OSAHS study 303 had baseline
subjective and objective evidence of ES (from CGI-S and MWT assessments)
and had disturbed sleep at baseline (from NPSG).

### Efficacy and Quality-of-Life Results for OSAHS Study 303

#### Primary Efficacy Measures: MWT and CGI-C

##### *MWT sleep latency* {#mwt-sleep-latency-1 .unnumbered}

In OSAHS study 303, mean sleep latency from the MWT increased from the
baseline assessment to the final visit by 1.6 and 1.5 minutes for
patients in the 200‑mg/day and 400-mg/day PROVIGIL treatment groups,
respectively, while mean sleep latency for the placebo treatment
decreased by 1.1 minutes (p\<0.0001 for the primary comparison between
the combined PROVIGIL and placebo treatment groups). Between-treatment
comparisons (each dose of PROVIGIL vs placebo) were also statistically
significant (p\<0.0001). MWT sleep latency results for study 303 are
presented in Table 14.

[]{#__RefHeading___Toc49234371 .anchor}Table 14: Average Sleep Latency
(Minutes) From the MWT at the Final Visit for\
OSAHS Study 303\
(Efficacy Evaluable Set)

+------------------------+---+--------+---+--------+---+--------+------+
|                        | * |        |   |        |   |        |      |
|                        | * |        |   |        |   |        |      |
|                        | T |        |   |        |   |        |      |
|                        | r |        |   |        |   |        |      |
|                        | e |        |   |        |   |        |      |
|                        | a |        |   |        |   |        |      |
|                        | t |        |   |        |   |        |      |
|                        | m |        |   |        |   |        |      |
|                        | e |        |   |        |   |        |      |
|                        | n |        |   |        |   |        |      |
|                        | t |        |   |        |   |        |      |
|                        | g |        |   |        |   |        |      |
|                        | r |        |   |        |   |        |      |
|                        | o |        |   |        |   |        |      |
|                        | u |        |   |        |   |        |      |
|                        | p |        |   |        |   |        |      |
|                        | * |        |   |        |   |        |      |
|                        | * |        |   |        |   |        |      |
+------------------------+---+--------+---+--------+---+--------+------+
|                        | * |        | * |        | # |        | **\  |
|                        | * |        | * |        | # |        | **   |
|                        | P |        | P |        | # |        |      |
|                        | R |        | R |        | # |        |      |
|                        | O |        | O |        | # |        |      |
|                        | V |        | V |        | # |        |      |
|                        | I |        | I |        | # |        |      |
|                        | G |        | G |        |   |        |      |
|                        | I |        | I |        | P |        |      |
|                        | L |        | L |        | l |        |      |
|                        | * |        | * |        | a |        |      |
|                        | * |        | * |        | c |        |      |
|                        |   |        |   |        | e |        |      |
|                        | * |        | * |        | b |        |      |
|                        | * |        | * |        | o |        |      |
|                        | 2 |        | 4 |        |   |        |      |
|                        | 0 |        | 0 |        | { |        |      |
|                        | 0 |        | 0 |        | # |        |      |
|                        |   |        | m |        | p |        |      |
|                        | m |        | g |        | l |        |      |
|                        | g |        | / |        | a |        |      |
|                        | / |        | d |        | c |        |      |
|                        | d |        | a |        | e |        |      |
|                        | a |        | y |        | b |        |      |
|                        | y |        | * |        | o |        |      |
|                        | * |        | * |        |   |        |      |
|                        | * |        |   |        | . |        |      |
|                        |   |        |   |        | u |        |      |
|                        |   |        |   |        | n |        |      |
|                        |   |        |   |        | n |        |      |
|                        |   |        |   |        | u |        |      |
|                        |   |        |   |        | m |        |      |
|                        |   |        |   |        | b |        |      |
|                        |   |        |   |        | e |        |      |
|                        |   |        |   |        | r |        |      |
|                        |   |        |   |        | e |        |      |
|                        |   |        |   |        | d |        |      |
|                        |   |        |   |        | } |        |      |
+------------------------+---+--------+---+--------+---+--------+------+
| **Time point**         | * | **Mean | * | **Mean | * | **Mean | **   |
|                        | * | (SD)** | * | (SD)** | * | (SD)** | p-va |
|                        | n |        | n |        | n |        | lue^ |
|                        | * |        | * |        | * |        | a^** |
|                        | * |        | * |        | * |        |      |
+------------------------+---+--------+---+--------+---+--------+------+
| Baseline               | 9 | 13.1   | 8 | 13.6   | 1 | 13.8   |      |
|                        | 6 | (5.46) | 9 | (5.37) | 0 | (5.69) |      |
|                        |   |        |   |        | 0 |        |      |
+------------------------+---+--------+---+--------+---+--------+------+
| Week 12 (or final      | 9 | 14.8   | 8 | 15.0   | 9 | 12.6   |      |
| visit)                 | 0 | (5.30) | 8 | (5.29) | 5 | (5.83) |      |
+------------------------+---+--------+---+--------+---+--------+------+
| > Mean change from     | 8 | 1.6    | 8 | 1.5    | 9 | --1.11 |      |
| > baseline to week 12  | 8 | (4.82) | 6 | (5.00) | 5 | (4.56) |      |
| > (or final visit)     |   |        |   |        |   |        |      |
+------------------------+---+--------+---+--------+---+--------+------+
| > p-value^a^           |   | 0.0001 |   | 0.0001 |   | \-\--  | \<0. |
|                        |   |        |   |        |   |        | 0001 |
+------------------------+---+--------+---+--------+---+--------+------+

^a^The p-value under each PROVIGIL treatment group column is for the
comparison of that treatment group to the placebo treatment group. The
p-value in the far-right column is the p-value for the comparison of the
combined PROVIGIL treatment group to the placebo treatment group.

MWT = Maintenance of Wakefulness Test; OSAHS = obstructive sleep
apnea/hypopnea syndrome.

Improvements in mean sleep latency from the MWT were apparent at the
first postbaseline observation (week 4), with mean increases of 1.2 and
2.1 minutes for patients in the 200-mg/day and 400-mg/day PROVIGIL
treatment groups, respectively, and a mean decrease of 1.9 minutes in
the placebo treatment group. The differences in average sleep latency
were statistically significant (p\<0.0001) at weeks 4 and 8 for patients
in the combined PROVIGIL treatment group compared to patients in the
placebo treatment group.

##### *CGI-C ratings* {#cgi-c-ratings-1 .unnumbered}

In OSAHS study 303, comparison of the distribution of CGI‑C ratings at
the final visit showed statistically significant (p\<0.0001) improvement
in clinical condition for patients in the combined PROVIGIL treatment
group compared to patients in the placebo treatment group.
Between-treatment comparisons (each dose of PROVIGIL vs placebo) were
also statistically significant for both the PROVIGIL 200‑mg/day
(p=0.0006) and 400‑mg/day (p\<0.0001) treatment groups. CGI-C rating
results for study 303 are presented in Table 15.

[]{#__RefHeading___Toc49234372 .anchor}Table 15: CGI-C Ratings (Number
\[%\] in Each Category)\
at the Final Visit in OSAHS Study 303\
(Efficacy Evaluable Set)

+----------------------+----------+-------------+----------+---+---------+
| **\                  | **Number |             |          |   |         |
| \                    | (%) of   |             |          |   |         |
| \                    | pa       |             |          |   |         |
| Category**           | tients** |             |          |   |         |
+----------------------+----------+-------------+----------+---+---------+
|                      | **PR     | *           | **\      |   | **\     |
|                      | OVIGIL** | *PROVIGIL** | P        |   | \       |
|                      |          |             | lacebo** |   | p-val   |
|                      | **200    | **400       |          |   | ue^a^** |
|                      | mg/day** | mg/day**    | **(      |   |         |
|                      |          |             | N=100)** |   |         |
|                      | **       | **(N=92)**  |          |   |         |
|                      | (N=99)** |             |          |   |         |
+----------------------+----------+-------------+----------+---+---------+
| Very much improved   | 14 (14)  | 12 (13)     | 6 (6)    |   |         |
+----------------------+----------+-------------+----------+---+---------+
| Much improved        | 27 (27)  | 28 (30)     | 11 (11)  |   |         |
+----------------------+----------+-------------+----------+---+---------+
| Minimally improved   | 19(19)   | 23 (25)     | 20 (20)  |   |         |
+----------------------+----------+-------------+----------+---+---------+
| No change            | 33 (33)  | 22 (24)     | 59 (59)  |   |         |
+----------------------+----------+-------------+----------+---+---------+
| Minimally worse      | 4 (4)    | 5 (5)       | 2 (2)    |   |         |
+----------------------+----------+-------------+----------+---+---------+
| Much worse           | 2 (2)    | 2 (2)       | 2 (2)    |   |         |
+----------------------+----------+-------------+----------+---+---------+
| Very much worse      | 0        | 0           | 0        |   |         |
+----------------------+----------+-------------+----------+---+---------+
| p-value^a^           | 0.0006   | \<0.0001    | \-\--    |   | \       |
|                      |          |             |          |   | <0.0001 |
+----------------------+----------+-------------+----------+---+---------+

> ^a^The p-value under each PROVIGIL treatment group column is for the
> comparison of that treatment group to the placebo treatment group. The
> p-value in the far-right column is the p-value for the comparison of
> the combined PROVIGIL treatment group to the placebo treatment group.

CGI-C = Clinical Global Impression-Change; OSAHS = obstructive sleep
apnea/hypopnea syndrome.

The comparison of the distributions of CGI‑C ratings after 4 and 8 weeks
of treatment showed statistically significant improvement in clinical
condition for patients in the combined PROVIGIL treatment group compared
to patients in the placebo treatment group at these time points
(p=0.0003 and p=0.0013, respectively).

#### Secondary Efficacy Measures: ESS and PVT

The positive effect of PROVIGIL treatment in patients with OSAHS as
assessed by the secondary measures of the ESS and PVT was consistent
with that observed with both primary measures.

***ESS total score***

In OSAHS study 303, at the final visit, decreases from the baseline
assessment in mean total ESS score were 4.5 for both the 200- and
400‑mg/day PROVIGIL groups compared to a decrease of 1.8 for the placebo
group. Between-treatment comparisons (each dose of PROVIGIL vs placebo)
were statistically significant (p\<0.0001). ESS results for study 303
are presented in Table 16.

[]{#__RefHeading___Toc49234373 .anchor}Table 16: Total Score From ESS at
the Final Visit in OSAHS Study 303\
(Efficacy Evaluable Set)

+------------+-------------+---------------+------------+------------+
| **\        | **Treatment |               |            |            |
| \          | group**     |               |            |            |
| Category** |             |               |            |            |
+------------+-------------+---------------+------------+------------+
|            | *           | **PROVIGIL**  | **\        | **\        |
|            | *PROVIGIL** |               | Placebo\   | \          |
|            |             | **400         | (N=100)**  | p-         |
|            | **200       | mg/day**      |            | value^a^** |
|            | mg/day**    |               |            |            |
|            |             | **(N=92)**    |            |            |
|            | **(N=99)**  |               |            |            |
+------------+-------------+---------------+------------+------------+
| No.        | 98          | 92            | 99         |            |
| included   |             |               |            |            |
| in         |             |               |            |            |
| analysis   |             |               |            |            |
+------------+-------------+---------------+------------+------------+
| Baseline   |             |               |            |            |
+------------+-------------+---------------+------------+------------+
| Mean (SD)  | 15.7 (3.41) | 14.9 (3.34)   | 14.7       |            |
|            |             |               | (2.83)     |            |
+------------+-------------+---------------+------------+------------+
| Final      |             |               |            |            |
| visit      |             |               |            |            |
+------------+-------------+---------------+------------+------------+
| Mean (SD)  | 11.2 (4.90) | 10.4 (5.37)   | 12.9       |            |
|            |             |               | (3.81)     |            |
+------------+-------------+---------------+------------+------------+
| Change     |             |               |            |            |
| from       |             |               |            |            |
| baseline   |             |               |            |            |
+------------+-------------+---------------+------------+------------+
| Mean (SD)  | --4.5       | --4.5 (4.31)  | --1.8      |            |
|            | (4.65)      |               | (3.54)     |            |
+------------+-------------+---------------+------------+------------+
| p-value^a^ | \<0.0001    | \<0.0001      | \-\--      | \<0.0001   |
+------------+-------------+---------------+------------+------------+

> ^a^The p-value under each PROVIGIL treatment group column is for the
> comparison of that treatment group to the placebo treatment group. The
> p-value in the far-right column is the p-value for the comparison of
> the combined PROVIGIL treatment group to the placebo treatment group.

OSAHS = obstructive sleep apnea/hypopnea syndrome; ESS = Epworth
Sleepiness Scale.

The mean change from baseline ESS scores to all other time points
(weeks 4, 8, and 12) showed statistically significant (p\<0.0001)
improvement (decrease in ESS score) for patients in the PROVIGIL
treatment group compared with patients in the placebo treatment group.

***PVT results***

In OSAHS study 303, the mean change from baseline to the final visit for
PVT measurements showed a decrease in the number of lapses (reaction
times greater than 500 msec) that was statistically significant
(p=0.0006) for patients in the PROVIGIL treatment group compared with
patients in the placebo treatment group. PVT results for study 303 are
presented in Table 17.

[]{#__RefHeading___Toc49234374 .anchor}Table 17: Change from Baseline in
PVT Number of Lapses at the Final Visit\
for OSAHS Study 303\
(Efficacy Evaluable Set)

<table style="width:100%;">
<colgroup>
<col style="width: 32%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 13%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2"></td>
<td colspan="9"><strong>Treatment group</strong></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2"><strong><br />
PVT parameter</strong></td>
<td colspan="3"><p><strong>PROVIGIL</strong></p>
<p><strong>200 mg/day</strong></p></td>
<td colspan="3"><p><strong>PROVIGIL</strong></p>
<p><strong>400 mg/day</strong></p></td>
<td colspan="3"><strong>Placebo</strong></td>
<td><strong><br />
p-value<sup>a</sup></strong></td>
</tr>
<tr class="odd">
<td><strong>Number of lapses</strong></td>
<td colspan="2"><strong>n</strong></td>
<td><strong>Mean (SD)</strong></td>
<td colspan="2"><strong>n</strong></td>
<td><strong>Mean (SD)</strong></td>
<td colspan="2"><strong>n</strong></td>
<td><strong>Mean (SD)</strong></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Baseline</p>
</blockquote></td>
<td colspan="2">82</td>
<td>5.21 (11.45)</td>
<td colspan="2">79</td>
<td>2.30 (3.85)</td>
<td colspan="2">82</td>
<td>3.71 (6.61)</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Week 12 (or final visit)</p>
</blockquote></td>
<td colspan="2">78</td>
<td>2.30 (7.27)</td>
<td colspan="2">76</td>
<td>1.38 (2.19)</td>
<td colspan="2">80</td>
<td>3.54 (5.37)</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Mean change from baseline to week 12 (or final visit)</td>
<td colspan="2">78</td>
<td>–2.76 (6.46)</td>
<td colspan="2">76</td>
<td>–0.84 (3.48)</td>
<td colspan="2">80</td>
<td>–0.24 (4.97)</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>p-value<sup>a</sup></td>
<td colspan="2"></td>
<td>0.0005</td>
<td colspan="2"></td>
<td>0.0131</td>
<td colspan="2"></td>
<td>---</td>
<td colspan="2">0.0006</td>
</tr>
</tbody>
</table>

^a^The p-value under each PROVIGIL treatment group column is for the
comparison of that treatment group to the placebo treatment group. The
p-value in the far-right column is the p-value for the comparison of the
combined PROVIGIL treatment group to the placebo treatment group.

PVT = Psychomotor Vigilance Task.

#### Quality-of Life Assessments: SF-36 and FOSQ

***SF-36 results***

At the final visit, for the SF-36, a statistically significant
improvement was seen for patients in the combined PROVIGIL treatment
group compared with the placebo treatment group for the physical
composite summary (p=0.0065), general health (p=0.0229), and vitality
(p\<0.0001). For other component scores of the SF-36, positive trends
were generally observed for the PROVIGIL treatment groups compared to
the placebo treatment group; however, statistically significant
differences were not observed for the domains of physical functioning,
role physical, bodily pain, social functioning, role emotional, or
mental heath.

***FOSQ results***

In OSAHS study 303, the mean change from the baseline assessment to the
final visit in the total FOSQ score showed statistically significant
(p=0.001) improvement for patients in the combined PROVIGIL treatment
group compared with patients in the placebo treatment group.
Statistically significant improvements were also seen for the individual
subscales of activity (p=0.0242), general productivity (p=0.0006), and
vigilance (p=0.0007), but not for social outcome or intimate
relationships and sexual activity.

### Study Design for OSAHS Study 402

Study 402 was a randomized, double-blind, placebo-controlled,
parallel‑group study conducted at 22 centers in the US. Patients with
obstructive sleep apnea appropriately treated with nCPAP therapy, but
who had residual sleepiness, were randomized to receive either PROVIGIL
or a placebo during a 4‑week, double-blind treatment period. Prior to
randomization, nCPAP therapy effectiveness was monitored for 2 days
(overnight at screening), and the use of nCPAP therapy was monitored
during a 21‑day assessment period. Patients who were assigned to the
PROVIGIL treatment group received 200 mg/day for 1 week (week 1),
followed by 400 mg/day for the remainder of the double-blind treatment
period (weeks 2, 3, and 4). A 12‑week, open‑label treatment extension
was offered to patients who completed the 4‑week double-blind phase.

Eligible patients met the ICSD criteria for OSAHS (ICSD Code 780.53-0)
and had residual ES (as indicated by an ESS score greater than or equal
to 10 at screening) associated with OSAHS, despite regular use of nCPAP
therapy (defined as 4 or more hours/night, 70% of nights during the
21‑day nCPAP assessment period). All patients were required to have a
current diagnosis of OSAHS, with an historic respiratory disturbance
index (RDI) of 15 or more events/hour prior to or without nCPAP therapy.
The effectiveness of nCPAP therapy was confirmed by baseline NPSG, ie,
RDI of less than 10 and a greater than 50% reduction in RDI as
previously demonstrated.

The primary efficacy measure in this study was the ESS. The secondary
efficacy measures included the MSLT, CGI-C, and PVT. The quality-of-life
measure was the FOSQ. The ESS, CGI-C, and FOSQ were evaluated at
baseline, week 1, and week 4 (or final visit). The MSLT and PVT were
performed at baseline and at week 4 (or final visit).

### Data Analysis for OSAHS Study 402

The *efficacy evaluable set* included data from all patients who
received at least 1 dose of study drug (PROVIGIL or placebo) and had at
least 1 postbaseline efficacy evaluation on any measure.

All continuous variables (ESS, MSLT, PVT, and FOSQ) were analyzed as the
change from baseline; an ANCOVA with treatment and center as factors and
the baseline value as a covariate was utilized for detecting treatment
differences. The discrete variable of CGI-C was analyzed using the CMH
chi-square test adjusted for center with modified ridit scores to
account for ordered categories of CGI-C.

### Study Population for OSAHS Study 402

#### Patient Disposition

In OSAHS study 402, 75 PROVIGIL-treated patients and 80 placebo-treated
patients were considered efficacy evaluable (Table 18).

[]{#__RefHeading___Toc49234375 .anchor}Table 18: Patient Disposition in
OSAHS Study 402\
(Randomized Patients)

  ------------------------------------ ------------------ ----------------
  **\                                  **Number (%)       
  \                                    of patients**      
  Patient disposition**                                   

                                       **PROVIGIL\        **\
                                       400 mg/day**       Placebo**

  Randomized                           77 (100)           80 (100)

  Completed                            66 (85.7)          77 (96.3)

  Withdrawn                            11 (14.3)          3 (3.8)

  Adverse event                        8 (10.4)           1 (1.3)

  Protocol violation                   0 (0.0)            1 (1.3)

  Noncompliance                        2 (2.6)            1 (1.3)

  Other                                1 (1.3)            0 (0.0)

  Efficacy evaluable                   75 (97.4)          80 (100)

  Safety evaluable                     77 (100)           80 (100)
  ------------------------------------ ------------------ ----------------

#### Demographic Characteristics

In OSAHS study 402, patient demographic characteristics were similar for
the 2 treatment groups. A summary of patient characteristics including
sex, race, age, and weight for study 402 is presented in Table 19.

[]{#__RefHeading___Toc49234376 .anchor}Table 19: Demographic
Characteristics in OSAHS Study 402\
(Randomized Patients)

+----------------------------+-------------------+--------------------+
| #######  Demo              | **PROVIGIL**      | **Placebo**        |
| graphic variable {#demogra |                   |                    |
| phic-variable .unnumbered} | **(N = 77)**      | **(N = 80)**       |
+----------------------------+-------------------+--------------------+
| **Age (years)**            |                   |                    |
+----------------------------+-------------------+--------------------+
| Mean (SD)                  | 50.3 (8.5)        | 50.1 (10.0)        |
+----------------------------+-------------------+--------------------+
| Min, max                   | (32, 76)          | (28, 72)           |
+----------------------------+-------------------+--------------------+
| **Sex, n (%)**             |                   |                    |
+----------------------------+-------------------+--------------------+
| Male                       | 61 (79.2)         | 59 (73.8)          |
+----------------------------+-------------------+--------------------+
| Female                     | 16 (20.8)         | 21 (26.3)          |
+----------------------------+-------------------+--------------------+
| **Race, n (%)**            |                   |                    |
+----------------------------+-------------------+--------------------+
| Caucasian                  | 68 (88.3)         | 68 (85.0)          |
+----------------------------+-------------------+--------------------+
| Black                      | 6 (7.8)           | 6 (7.5)            |
+----------------------------+-------------------+--------------------+
| Asian                      | 0 (0.0)           | 1 (1.3)            |
+----------------------------+-------------------+--------------------+
| Hispanic                   | 2 (2.6)           | 4 (5.0)            |
+----------------------------+-------------------+--------------------+
| Other                      | 1 (1.3)           | 1 (1.3)            |
+----------------------------+-------------------+--------------------+
| **Weight (kg)**            |                   |                    |
+----------------------------+-------------------+--------------------+
| Mean (SD)                  | 110.0 (22.0)      | 107.7 (23.5)       |
+----------------------------+-------------------+--------------------+

Min = minimum; max = maximum.

#### Baseline Patient Characteristics

The 2 treatment groups were comparable with regard to baseline GCI-S,
MSLT sleep latency, and NPSG parameters (Table 20). At baseline, about
80% of all patients studied were at least moderately ill as assessed by
the CGI-S, with mean MSLT sleep latency of approximately 7 minutes.

The 3 treatment groups were comparable with regards to the NPSG
parameter of sleep efficiency (percentage of time in bed spent asleep).

[]{#__RefHeading___Toc49234377 .anchor}Table 20: Baseline Patient
Characteristics in OSAHS Study 402\
(Safety Evaluable Set)

+---------------+------------------+---+----------------+----------------+
| **\           |                  | * |                |                |
| \             |                  | * |                |                |
| Baseline      |                  | T |                |                |
| parameter**   |                  | r |                |                |
|               |                  | e |                |                |
|               |                  | a |                |                |
|               |                  | t |                |                |
|               |                  | m |                |                |
|               |                  | e |                |                |
|               |                  | n |                |                |
|               |                  | t |                |                |
|               |                  | g |                |                |
|               |                  | r |                |                |
|               |                  | o |                |                |
|               |                  | u |                |                |
|               |                  | p |                |                |
|               |                  | * |                |                |
|               |                  | * |                |                |
+===============+==================+===+================+================+
|               |                  |   | **PROVIGIL\    | **Placebo**    |
|               |                  |   | 400 mg/day**   |                |
|               |                  |   |                | **(N=80)**     |
|               |                  |   | **(N=77)**     |                |
+---------------+------------------+---+----------------+----------------+
| CGI-S rating, | Normal           |   | 5 (8.8)        | 4 (6.9)        |
| N (%)         |                  |   |                |                |
+---------------+------------------+---+----------------+----------------+
|               | Borderline ill   |   | 3 (5.3)        | 2 (3.4)        |
+---------------+------------------+---+----------------+----------------+
|               | Mildly ill       |   | 4 (7.0)        | 5 (8.6)        |
+---------------+------------------+---+----------------+----------------+
|               | Moderately ill   |   | 31 (54.0)      | 38 (66.0)      |
+---------------+------------------+---+----------------+----------------+
|               | Markedly ill     |   | 14 (25.0)      | 9 (16.0)       |
+---------------+------------------+---+----------------+----------------+
|               | Severely ill     |   | 0              | 0              |
+---------------+------------------+---+----------------+----------------+
|               | Extremely ill    |   | 0              | 0              |
+---------------+------------------+---+----------------+----------------+
| Mean (SD)     |                  |   | 7.4 (4.8)      | 7.5 (4.6)      |
| MSLT sleep    |                  |   |                |                |
| latency       |                  |   |                |                |
| (minutes)     |                  |   |                |                |
+---------------+------------------+---+----------------+----------------+
| NPSG sleep    |                  |   |                |                |
| efficiency (% |                  |   |                |                |
| of time in    |                  |   |                |                |
| bed spent     |                  |   |                |                |
| asleep)       |                  |   |                |                |
+---------------+------------------+---+----------------+----------------+
| N             |                  |   | 77             | 80             |
+---------------+------------------+---+----------------+----------------+
| Mean (SD)     |                  |   | 87.1 (9.5)     | 87.3 (77.9)    |
+---------------+------------------+---+----------------+----------------+

> Note: In study 402, the number of patients with CGI-S ratings is less
> than the number of efficacy evaluable patients because the CGI-C
> assessment was not part of the original protocol but was added in an
> amendment after the start of the study.
>
> CGI-S = Clinical Global Impression of Severity; MSLT = Multiple Sleep
> Latency Test; NPSG = nocturnal polysomnography.
>
> Overall, the patients who participated in OSAHS study 402 had baseline
> subjective and objective evidence of ES (from CGI-S and MSLT
> assessments) and had baseline disturbed sleep (from NPSG).

### Efficacy and Quality-of-Life Results for OSAHS Study 402

#### Primary Efficacy Measure: ESS

In OSAH study 402, mean ESS total score decreased from the baseline
assessment to the final visit by 4.6 for the PROVIGIL group and 2.0 for
the placebo group. The comparison was statistically significant
(p\<0.0001). ESS results for study 402 are presented in Table 21.

[]{#__RefHeading___Toc49234378 .anchor}Table 21: Total Score From ESS at
the Final Visit in OSAHS Study 402\
(Efficacy Evaluable Set)

+------------------------+---------------------+-----------------------+
| **\                    | **Treatment group** |                       |
| \                      |                     |                       |
| Category**             |                     |                       |
+------------------------+---------------------+-----------------------+
|                        | **PROVIGIL**        | **\                   |
|                        |                     | Placebo**             |
|                        | **400 mg/day**      |                       |
|                        |                     | **(N=80)**            |
|                        | **(N=75)**          |                       |
+------------------------+---------------------+-----------------------+
| No. included in        | 75                  | 80                    |
| analysis               |                     |                       |
+------------------------+---------------------+-----------------------+
| Baseline               |                     |                       |
+------------------------+---------------------+-----------------------+
| Mean (SD)              | 14.2 (2.94)         | 14.4 (3.19)           |
+------------------------+---------------------+-----------------------+
| Final visit            |                     |                       |
+------------------------+---------------------+-----------------------+
| Mean (SD)              | 9.6 (4.78)          | 12.4 (4.50)           |
+------------------------+---------------------+-----------------------+
| Change from baseline   |                     |                       |
+------------------------+---------------------+-----------------------+
| Mean (SD)              | --4.6 (4.33)        | --2.0 (3.61)          |
+------------------------+---------------------+-----------------------+
| p-value                | \<0.0001            | \-\--                 |
+------------------------+---------------------+-----------------------+

The mean change from baseline in ESS scores showed a statistically
significant improvement at week 1 and week 4 (both, p\<0.01) for the
PROVIGIL treatment group compared to the placebo treatment group.

#### Secondary Efficacy Measures: MSLT, CGI-C, PVT

The positive effect of PROVIGIL treatment in patients with OSAHS as
assessed by the secondary measures of the MSLT, CGI-C, and PVT was
consistent with that observed with the primary measure.

***MSLT sleep latency***

In OSAHS study 402, mean sleep latency from the MSLT increased for
PROVIGIL-treated patients by approximately 1 minute from the baseline
assessment to the final visit compared to a decrease of 0.2 minutes for
patients in the placebo treatment group. The comparison was
statistically significant (p=0.0212). MSLT sleep latency results for
study 402 are presented in Table 22.

[]{#__RefHeading___Toc49234379 .anchor}Table 22: Average Sleep Latency
From the MSLT Mean Change From Baseline\
at the Final Visit for OSAHS Study 402\
(Efficacy Evaluable Set)

+--------------------------------+----+-------------+----+---------+---+
| **\                            | *  |             |    |         |   |
| \                              | *T |             |    |         |   |
| \                              | re |             |    |         |   |
| MSLT variable**                | at |             |    |         |   |
|                                | me |             |    |         |   |
|                                | nt |             |    |         |   |
|                                | g  |             |    |         |   |
|                                | ro |             |    |         |   |
|                                | up |             |    |         |   |
|                                | ** |             |    |         |   |
+--------------------------------+----+-------------+----+---------+---+
|                                | ** |             | *  |         |   |
|                                | PR |             | *P |         |   |
|                                | OV |             | la |         |   |
|                                | IG |             | ce |         |   |
|                                | IL |             | bo |         |   |
|                                | ** |             | ** |         |   |
|                                |    |             |    |         |   |
|                                | *  |             |    |         |   |
|                                | *4 |             |    |         |   |
|                                | 00 |             |    |         |   |
|                                | mg |             |    |         |   |
|                                | /d |             |    |         |   |
|                                | ay |             |    |         |   |
|                                | ** |             |    |         |   |
+--------------------------------+----+-------------+----+---------+---+
|                                | *  | **Mean      | *  | **Mean  |   |
|                                | *N | (SD)**      | *N | (SD)**  |   |
|                                | ** |             | ** |         |   |
+--------------------------------+----+-------------+----+---------+---+
| Average sleep latency (min)    |    |             |    |         |   |
+--------------------------------+----+-------------+----+---------+---+
| Baseline                       | 77 | 7.4 (4.78)  | 80 | 7.5     |   |
|                                |    |             |    | (4.60)  |   |
+--------------------------------+----+-------------+----+---------+---+
| Final visit                    | 67 | 8.6 (5.07)  | 77 | 7.2     |   |
|                                |    |             |    | (4.40)  |   |
+--------------------------------+----+-------------+----+---------+---+
| Mean change from baseline to   | 67 | 1.0 (3.65)  | 77 | --0.2   |   |
| final visit                    |    |             |    | (4.06)  |   |
+--------------------------------+----+-------------+----+---------+---+
| p-value                        |    | 0.0212      |    | \-\--   |   |
+--------------------------------+----+-------------+----+---------+---+

***CGI-C ratings***

In OSAHS study 402, comparison of the distribution of CGI-C ratings
indicated statistically significant differences between the PROVIGIL and
placebo treatment groups at the final visit (p=0.0157). CGI-C rating
results for study 402 are presented in Table 23.

[]{#__RefHeading___Toc49234380 .anchor}Table 23: CGI-C Ratings (Number
\[%\] in Each Category) at the Final Visit\
in OSAHS Study 402\
(Efficacy Evaluable Set)

+--------------------+-------------------------+-----------------------+
|                    | **Number (%) of         |                       |
|                    | patients**              |                       |
+--------------------+-------------------------+-----------------------+
| **\                | **PROVIGIL**            | **\                   |
| Category**         |                         | Placebo**             |
|                    | **400 mg/day**          |                       |
+--------------------+-------------------------+-----------------------+
| n                  | 56                      | 58                    |
+--------------------+-------------------------+-----------------------+
| Very much improved | 8 (14)                  | 4 (7)                 |
+--------------------+-------------------------+-----------------------+
| Much improved      | 6 (11)                  | 10 (17)               |
+--------------------+-------------------------+-----------------------+
| Minimally improved | 23 (41)                 | 6 (10)                |
+--------------------+-------------------------+-----------------------+
| No change          | 17 (30)                 | 37 (64)               |
+--------------------+-------------------------+-----------------------+
| Minimally worse    | 2 (4)                   | 1 (2)                 |
+--------------------+-------------------------+-----------------------+
| Much worse         | 0                       | 0                     |
+--------------------+-------------------------+-----------------------+
| Very much worse    | 0                       | 0                     |
+--------------------+-------------------------+-----------------------+
| p-value            | 0.0157                  | \-\--                 |
+--------------------+-------------------------+-----------------------+

> Note: In study 402, the number of patients with CGI-C ratings is less
> than the number of efficacy evaluable patients because the CGI-C
> assessment was not part of the original protocol but was added in an
> amendment after the start of the study.

CGI-C=Clinical Global Impression-Change.

***PVT results***

For OSAHS study 402, a numerical difference in favor of the
PROVIGIL‑treated group was observed between the 2 treatment groups with
respect to number of lapses. However, this change was not statistically
significant. PVT results for study 402 are presented in Table 24.

[]{#__RefHeading___Toc49234381 .anchor}Table 24: Change from Baseline in
PVT Results at the Final Visit\
for OSAHS Study 402\
(Efficacy Evaluable Set)

+--------------------------+-----+---------+---+----------+---------+
| **\                      | **P |         | * |          | **\     |
| PVT parameter**          | ROV |         | * |          | p-val   |
|                          | IGI |         | P |          | ue^a^** |
|                          | L** |         | l |          |         |
|                          |     |         | a |          |         |
|                          | **  |         | c |          |         |
|                          | 400 |         | e |          |         |
|                          | mg  |         | b |          |         |
|                          | /da |         | o |          |         |
|                          | y** |         | * |          |         |
|                          |     |         | * |          |         |
+--------------------------+-----+---------+---+----------+---------+
| **Number of lapses**     | **  | **Mean  | * | **Mean   |         |
|                          | N** | (SE)**  | * | (SE)**   |         |
|                          |     |         | N |          |         |
|                          |     |         | * |          |         |
|                          |     |         | * |          |         |
+--------------------------+-----+---------+---+----------+---------+
| Baseline                 | 46  | 4.03    | 5 | 2.75     |         |
|                          |     | (0.73)  | 8 | (0.66)   |         |
+--------------------------+-----+---------+---+----------+---------+
| Week 4/final visit       | 46  | 2.66    | 5 | 2.63     |         |
|                          |     | (0.60)  | 8 | (0.67)   |         |
+--------------------------+-----+---------+---+----------+---------+
| Change from baseline     | 46  | --1.38  | 5 | --0.12   | 0.1102  |
|                          |     | (0.48)  | 8 | (0.61)   |         |
+--------------------------+-----+---------+---+----------+---------+

> ^a^ p-values for between group comparisons were based on a t-test with
> a pooled standard deviation estimate.\
> PVT = Psychomotor Vigilance Task.

#### Quality of Life Assessment: FOSQ

In OSAHS study 402, statistically significant differences between the
PROVIGIL treatment group and the placebo treatment group were observed
for the mean change from baseline assessments to the final visit in
total FOSQ score (p=0.0211) and the individual subscales of activity
level (p=0.0383) and vigilance (p=0.0102), but not for general
productivity, social outcome, or intimate relationships and sexual
activity.

### Conclusions on OSAHS

The efficacy of PROVIGIL in the treatment of patients with residual ES
associated with OSAHS was evaluated in a 12-week double-blind,
placebo-controlled study (study 303) involving 191 efficacy evaluable
patients treated with PROVIGIL (200 or 400 mg/day) and 100 treated with
placebo for up to 12 weeks. A second double-blind, placebo-controlled
study (study 402) involved 75 efficacy evaluable patients treated with
PROVIGIL (400 mg/day) and 80 treated with placebo for up to 4 weeks. The
evaluations of efficacy in each study showed that treatment with
PROVIGIL improved wakefulness in patients with residual sleepiness
associated with OSAHS who were receiving nCPAP therapy.

In study 303, the analysis of average sleep latency from the MWT at the
final visit indicated a significant increase from baseline in sleep
latency for PROVIGIL‑treated patients compared to placebo-treated
patients; the difference was significant for the combined PROVIGIL group
and for both the 200- and 400-mg/day PROVIGIL groups (all p\<0.0001).
Similar results were observed for average sleep latency from the MSLT
obtained in study 402, with significant increases in sleep latency for
the PROVIGIL group compared to the placebo group at the final visit
(p=0.0212).

For the common efficacy measure of CGI-C, the results of study 303
indicate a significant difference between PROVIGIL and placebo treatment
in the distribution of CGI-C ratings at the final visit (p\<0.001) for
the combined PROVIGIL group and both PROVIGIL dosages. For study 402,
there was also a significant difference between PROVIGIL and placebo
treatment in the distribution of CGI-C ratings at the final visit
(p\<0.05). In both studies, the CGI-C results corroborate the sleep
latency results.

In study 303, a significant improvement in ESS score with PROVIGIL
treatment was observed (p\<0.0001 for both dosages of PROVIGIL and the
combined PROVIGIL group compared to placebo). In study 402, a
significant improvement (p\<0.0001) with PROVIGIL treatment over placebo
treatment was also observed in ESS score.

In study 303, a significant decrease (p=0.0006) in the number of lapses
from the PVT was observed for patients treated with PROVIGIL compared to
those treated with placebo. In study 402, a difference (though not
significant) between the treatment groups was observed.

## Shift Work Sleep Disorder---Studies 305 and 306

*SWSD studies* *305 (pivotal study) and 306*

The efficacy data in patients with chronic SWSD are derived from study
305. Study 306 was a study of the safety and quality of life of PROVIGIL
in patients with ES associated with SWSD.

### Study Design for SWSD Study 305

Study 305 was a randomized, double-blind, placebo-controlled,
parallel-group study conducted at 28 centers in the US. Patients with ES
associated with chronic SWSD were randomized to receive a daily dose of
200 mg of PROVIGIL or a placebo during a 12-week, double-blind treatment
period. Efficacy measures were obtained overnight in a laboratory
setting (overnight clinic visit), which took place at the study center
during nighttime hours (approximately 2000 to 0900 hours) similar to
those that the patient routinely worked. The overnight clinic visit
occurred on the night immediately following the last night of work for
the night shift work period (minimum of 3 consecutive nights). After
completion of the double-blind treatment period, patients were allowed
to enter a 12-month open-label treatment extension period.

Eligible patients had a CGI-S score of moderately ill as related to
sleepiness on work nights (including the commute to and from work). In
addition, patients enrolled in SWSD study 305 had a mean sleep latency
of 6 minutes or less on the screening MSLT, and a sleep efficiency of
87.5% or less on daytime PSG.

Patients met the ICSD criteria for chronic SWSD (ICSD Code 307.45-1) and
worked a minimum of 5 night shifts per month with at least 3 of the
nights being consecutive. The night shifts included at least 6 hours
between the hours of 2200 and 0800 and were no more than 12 hours in
duration. An effort was made to enroll at least 20% of patients who
worked 5 to 10 night shifts per month and at least 20% of patients who
worked more than 10 night shifts per month. Study drug administration
was intermittent, ie, patients took their dose of study drug
approximately 30 minutes to 1 hour before the start of each night shift
worked, but not on the days (and nights) not at work.

The primary efficacy measures in this study were the MSLT and CGI‑C.
Mean sleep latency from the MSLT was based on four 20-minute naps
performed at 0200, 0400, 0600, and 0800 of overnight in a laboratory
setting, with study drug administered at 2200. The CGI‑C scale assessed
the severity of sleepiness during night shifts (including the commute to
and from work), was performed during clinic visits after the overnight
clinic visit. The secondary efficacy measures included the KSS, which
was performed at hourly intervals (from 2400 to 0800) during each
overnight clinic visit, and the PVT, which was performed 1 hour prior to
each MSLT nap. The quality-of-life measure was the FOSQ. All efficacy
and quality-of-life measures were assessed at baseline and at 3
postbaseline visits (ie, visits 4, 5, and 6), which were to occur
approximately every 4 weeks (weeks 4, 8, and 12). These visits were to
occur the night after working at least a 3-night shift work period.

### Data Analysis for SWSD Study 305

The *efficacy evaluable set* included data from all patients who
received at least 1 dose of study drug (PROVIGIL or placebo) and had at
least 1 postbaseline observation for at least 1 primary efficacy
measure. The primary efficacy variables were the change from baseline in
the mean sleep latency from the MSLT performed at the last postbaseline
overnight clinic visit, using a last observation carried forward (LOCF)
approach, and the CGI‑C rating at the last postbaseline visit using the
LOCF approach.

All continuous variables (MSLT, KSS, PVT, and FOSQ) were analyzed as the
change from baseline using an analysis of variance (ANOVA) with
treatment and center as factors. The discrete variable of CGI-C rating
was summarized with frequency and percentage for each category and for
each treatment group. The CGI-C data were analyzed using a CMH
chi-square test adjusted for center with modified ridit scores to
account for the ordered categories of the CGI-C. The percentage of
patients who experienced some improvement on the CGI-C scale was
analyzed using a CMH chi-square test adjusted for site.

### Study Population for SWSD Study 305

#### Patient Disposition

In SWSD study 305, 89 PROVIGIL-treated patients and 104 placebo-treated
patients were considered efficacy evaluable (Table 25).

[]{#__RefHeading___Toc49234382 .anchor}**Table 25: Patient Disposition
in SWSD Study 305\
(All Randomized Pati**ents)

+-------------------+--------------------------+---------------------+---+
| **Patient         | **Number (%) of          |                     |   |
| disposition^a^**  | patients**               |                     |   |
+-------------------+--------------------------+---------------------+---+
|                   | **PROVIGIL\              | **Placebo\          |   |
|                   | 200 mg\                  | (N=110)**           |   |
|                   | (N=99)**                 |                     |   |
+-------------------+--------------------------+---------------------+---+
| Randomized        | 99 (100)                 | 110 (100)           |   |
+-------------------+--------------------------+---------------------+---+
| Randomized but    | 3 (3)                    | 2 (2)               |   |
| not treated       |                          |                     |   |
+-------------------+--------------------------+---------------------+---+
| Safety analysis   | 96 (97)                  | 108 (98)            |   |
| set               |                          |                     |   |
+-------------------+--------------------------+---------------------+---+
| Efficacy          | 89 (90)                  | 104 (95)            |   |
| evaluable         |                          |                     |   |
+-------------------+--------------------------+---------------------+---+
| Completed         | 72 (73)                  | 81 (74)             |   |
+-------------------+--------------------------+---------------------+---+
| Withdrawn         | 27 (27)                  | 29 (26)             |   |
+-------------------+--------------------------+---------------------+---+
| > Death           | 0                        | 0                   |   |
+-------------------+--------------------------+---------------------+---+
| > Adverse event   | 3 (3)                    | 4 (4)               |   |
+-------------------+--------------------------+---------------------+---+
| > Lack of         | 0                        | 0                   |   |
| > efficacy        |                          |                     |   |
+-------------------+--------------------------+---------------------+---+
| > Consent         | 6 (6)                    | 8 (7)               |   |
| > withdrawn       |                          |                     |   |
+-------------------+--------------------------+---------------------+---+
| > Protocol        | 1 (1)                    | 1 (\<1)             |   |
| > violation       |                          |                     |   |
+-------------------+--------------------------+---------------------+---+
| > Noncompliance   | 0                        | 3 (3)               |   |
+-------------------+--------------------------+---------------------+---+
| > Lost to         | 7 (7)                    | 8 (7)               |   |
| > follow‑up       |                          |                     |   |
+-------------------+--------------------------+---------------------+---+
| > Other^b^        | 10 (10)                  | 5 (5)               |   |
+-------------------+--------------------------+---------------------+---+

^a^In total, 609 patients were screened for enrollment into the study.\
^b^All patients who withdrew for "other" reasons were withdrawn due to a
change in night shift work status.

The placebo treatment group had 11 more patients than the PROVIGIL
treatment group. This imbalance was mostly due to the stratum of
patients who worked 5 through 10 night shifts per month (2 patients in
the PROVIGIL treatment group and 11 patients in the placebo treatment
group). The distribution of patients across treatment groups who worked
more than 10 night shifts per month was 94 patients in the PROVIGIL
treatment group and 97 patients in the placebo treatment group. However,
the number of patients who worked 5 through 10 night shifts per month
was higher in the placebo treatment group. The randomization procedure
was designed to balance patients (1:1) within each of the 2 strata
defined by the number of night shifts per month and the low number of
patients in the stratum of patients who worked 5 through 10 night shifts
per month is the most likely cause for the imbalance observed.

#### Demographic Characteristics

Patient demographic characteristics were similar for the 2 treatment
groups. A summary of patient characteristics including sex, race, age,
and weight for study 305 is presented in Table 26.

[]{#__RefHeading___Toc49234383 .anchor}*Table 26: Demographic
Characteristics in SWSD Study 305\
(Safety Analysis Set)*

+----------------+---------------------------+-----------------------+---+
| **Demographic  | **Treatment group**       |                       |   |
| variable**     |                           |                       |   |
+----------------+---------------------------+-----------------------+---+
|                | **PROVIGIL\               | **Placebo\            |   |
|                | 200 mg\                   | (N = 108)**           |   |
|                | (N = 96)**                |                       |   |
+----------------+---------------------------+-----------------------+---+
| **Age, years** |                           |                       |   |
+----------------+---------------------------+-----------------------+---+
| > n            | 96                        | 108                   |   |
+----------------+---------------------------+-----------------------+---+
| > Mean (SD)    | 37.5 (9.24)               | 38.8 (9.06)           |   |
+----------------+---------------------------+-----------------------+---+
| **Sex, n (%)** |                           |                       |   |
+----------------+---------------------------+-----------------------+---+
| > Male         | 58 (60)                   | 67 (62)               |   |
+----------------+---------------------------+-----------------------+---+
| > Female       | 38 (40)                   | 41 (38)               |   |
+----------------+---------------------------+-----------------------+---+
| **Race, n      |                           |                       |   |
| (%)**          |                           |                       |   |
+----------------+---------------------------+-----------------------+---+
| > White        | 62 (65)                   | 75 (69)               |   |
+----------------+---------------------------+-----------------------+---+
| > Black        | 25 (26)                   | 27 (25)               |   |
+----------------+---------------------------+-----------------------+---+
| > Asian        | 1 (1)                     | 0                     |   |
+----------------+---------------------------+-----------------------+---+
| > Other        | 8 (8)                     | 6 (6)                 |   |
+----------------+---------------------------+-----------------------+---+
| **Weight, kg** |                           |                       |   |
+----------------+---------------------------+-----------------------+---+
| > n            | 96                        | 108                   |   |
+----------------+---------------------------+-----------------------+---+
| > Mean (SD)    | 88.5 (18.55)              | 87.0 (17.53)          |   |
+----------------+---------------------------+-----------------------+---+

#### Baseline Patient Characteristics

The 2 treatment groups were comparable with regard to baseline CGI-S,
MSLT sleep latency, daytime PSG, and type of shift worker (Table 27).

[]{#__RefHeading___Toc49234384 .anchor}Table 27: Baseline Patient
Characteristics in SWSD Study 305\
(Safety Analysis Set)

+---------------+-------------------+---------------+---+-------------+
| **\           |                   | **Treatment   |   |             |
| \             |                   | group**       |   |             |
| Baseline      |                   |               |   |             |
| parameter**   |                   |               |   |             |
+===============+===================+===============+===+=============+
|               |                   | **PROVIGIL\   |   | **Placebo** |
|               |                   | 200 mg/day**  |   |             |
|               |                   |               |   | **(N=108)** |
|               |                   | **(N=96)**    |   |             |
+---------------+-------------------+---------------+---+-------------+
| CGI-S rating, | Normal            | 0             |   | 0           |
| N (%)         |                   |               |   |             |
+---------------+-------------------+---------------+---+-------------+
|               | Borderline ill    | 0             |   | 0           |
+---------------+-------------------+---------------+---+-------------+
|               | Mildly ill        | 0             |   | 0           |
+---------------+-------------------+---------------+---+-------------+
|               | Moderately ill    | 49 (51)       |   | 53 (49)     |
+---------------+-------------------+---------------+---+-------------+
|               | Markedly ill      | 29 (30)       |   | 34 (31)     |
+---------------+-------------------+---------------+---+-------------+
|               | Severely ill      | 17 (17)       |   | 17 (16)     |
+---------------+-------------------+---------------+---+-------------+
|               | Extremely ill     | 2 (2)         |   | 4 (4)       |
+---------------+-------------------+---------------+---+-------------+
| Mean (SD)     |                   | 2.07 (1.5)    |   | 2.04 (1.8)  |
| MSLT sleep    |                   |               |   |             |
| latency       |                   |               |   |             |
| (minutes)     |                   |               |   |             |
+---------------+-------------------+---------------+---+-------------+
| PSG sleep     |                   |               |   |             |
| efficiency (% |                   |               |   |             |
| of time in    |                   |               |   |             |
| bed spent     |                   |               |   |             |
| asleep)       |                   |               |   |             |
+---------------+-------------------+---------------+---+-------------+
| Mean (SD)     |                   | 73.7 (11.7)   |   | 74.1 (12.6) |
+---------------+-------------------+---------------+---+-------------+
| Type of shift |                   |               |   |             |
| worker        |                   |               |   |             |
+---------------+-------------------+---------------+---+-------------+
| Permanent     |                   | 89 (93)       |   | 95 (88)     |
| (not          |                   |               |   |             |
| rotating)     |                   |               |   |             |
+---------------+-------------------+---------------+---+-------------+
| Rotating      |                   | 7 (7)         |   | 13 (12)     |
+---------------+-------------------+---------------+---+-------------+

> CGI-S = Clinical Global Impression of Severity; MSLT = Multiple Sleep
> Latency Test; PSG = polysomnography.
>
> Overall, the patients who participated in SWSD study 305 had baseline
> subjective and objective evidence of ES (from CGI-S and MSLT
> assessments) and had disturbed sleep at baseline (from daytime PSG).

### Efficacy and Quality-of-Life Results for SWSD Study 305

#### Primary Efficacy Measures: MSLT and CGI-C

***MSLT sleep latency***

In SWSD study 305, mean sleep latency from the MSLT increased from the
baseline assessment to the final visit by 1.7 minutes for patients in
the PROVIGIL treatment group compared to an increase of 0.3 minutes in
the placebo treatment group. The comparison was statistically
significant (p=0.0022). Sleep latency results for study 305 are
presented in Table 28.

[]{#__RefHeading___Toc49234385 .anchor}Table 28: Average Sleep Latency
(Minutes) From the MSLT at the Final Visit\
in SWSD Study 305\
(Efficacy Evaluable Set)

+------------------------+---------------+---------------+------------+
| **Time point\          | **PROVIGIL\   | **Placebo\    | *          |
| Statistic**            | 200 mg\       | (N=104)**     | *p-value** |
|                        | (N=89)**      |               |            |
+------------------------+---------------+---------------+------------+
| Baseline               |               |               |            |
+------------------------+---------------+---------------+------------+
| > n                    | 86            | 96            |            |
+------------------------+---------------+---------------+------------+
| > Mean (SD)            | 2.1 (1.53)    | 2.0 (1.82)    |            |
+------------------------+---------------+---------------+------------+
| Final visit            |               |               |            |
+------------------------+---------------+---------------+------------+
| > n                    | 86            | 96            |            |
+------------------------+---------------+---------------+------------+
| > Mean (SD)            | 3.8 (4.32)    | 2.4 (2.73)    |            |
+------------------------+---------------+---------------+------------+
| Change from baseline   |               |               |            |
| at the final visit     |               |               |            |
+------------------------+---------------+---------------+------------+
| > n                    | 86            | 96            |            |
+------------------------+---------------+---------------+------------+
| > Mean (SD)            | 1.7 (3.79)    | 0.3 (2.77)    | 0.0022     |
+------------------------+---------------+---------------+------------+

MSLT = Multiple Sleep Latency Test.

***CGI-C ratings***

In SWSD study 305, comparisons of the distribution of CGI-C ratings at
the final visit showed statistically significant (p\<0.0001) improvement
in sleepiness during the night shift (including the commute home) for
the PROVIGIL treatment group when compared to the placebo treatment
group (Table 29).

[]{#__RefHeading___Toc49234386 .anchor}Table 29: CGI‑C Ratings (Number
\[%\] in Each Category) at the Final Visit\
in SWSD Study 305\
(Efficacy Evaluable Set)

+----------------+----------------------------+------------------------+
| **\            | **Number (%) of patients** |                        |
| \              |                            |                        |
| Category**     |                            |                        |
+----------------+----------------------------+------------------------+
|                | **PROVIGIL\                | **Placebo\             |
|                | 200 mg**                   | (N=104)**              |
|                |                            |                        |
|                | **(N=89)**                 |                        |
+----------------+----------------------------+------------------------+
| Very much      | 21 (24)                    | 8 (8)                  |
| improved       |                            |                        |
+----------------+----------------------------+------------------------+
| Much improved  | 28 (31)                    | 13 (13)                |
+----------------+----------------------------+------------------------+
| Minimally      | 17 (19)                    | 16 (15)                |
| improved       |                            |                        |
+----------------+----------------------------+------------------------+
| No change      | 20 (22)                    | 61 (59)                |
+----------------+----------------------------+------------------------+
| Minimally      | 2 (2)                      | 4 (4)                  |
| worse          |                            |                        |
+----------------+----------------------------+------------------------+
| Much worse     | 1 (1)                      | 2 (2)                  |
+----------------+----------------------------+------------------------+
| Very much      | 0                          | 0                      |
| worse          |                            |                        |
+----------------+----------------------------+------------------------+
| p-value^a^     | \<0.0001                   | \-\--                  |
+----------------+----------------------------+------------------------+

CGI-C = Clinical Global Impression of Change.

CGI-C ratings at all postbaseline visits (weeks 4, 8, and 12) showed
statistically significant (p\<0.0001 at all time points) improvement in
sleepiness during the night shift (including the commute home) for the
PROVIGIL treatment group when compared to the placebo treatment group.

#### Secondary Efficacy Measures: KSS and PVT

The positive effect of PROVIGIL treatment in patients with SWSD as
assessed by the secondary measures of the KSS and PVT was consistent
with that observed with both primary measures.

***KSS results***

In SWSD study 305, the mean KSS score decreased from the baseline
assessment to the final visit by 1.5 for patients in the PROVIGIL
treatment group compared to a decrease of 0.4 for patients in the
placebo treatment group (Table 30). The comparison was statistically
significant (p\<0.0001).

[]{#__RefHeading___Toc49234387 .anchor}Table 30: KSS Score at the Final
Visit in SWSD Study 305\
(Efficacy Evaluable Set)

+---------------------+------------------------+-----------------------+
| **Category**        | **Treatment group**    |                       |
+---------------------+------------------------+-----------------------+
|                     | **PROVIGIL**           | **Placebo**           |
|                     |                        |                       |
|                     | **200 mg/day**         |                       |
+---------------------+------------------------+-----------------------+
| Baseline            |                        |                       |
+---------------------+------------------------+-----------------------+
| > n                 | 85                     | 95                    |
+---------------------+------------------------+-----------------------+
| > Mean (SD)         | 7.3 (1.04)             | 7.1 (1.20)            |
+---------------------+------------------------+-----------------------+
| Final visit         |                        |                       |
+---------------------+------------------------+-----------------------+
| > n                 | 86                     | 97                    |
+---------------------+------------------------+-----------------------+
| > Mean (SD)         | 5.8 (1.45)             | 6.7 (1.54)            |
+---------------------+------------------------+-----------------------+
| Change from         |                        |                       |
| baseline            |                        |                       |
+---------------------+------------------------+-----------------------+
| > n                 | 85                     | 95                    |
+---------------------+------------------------+-----------------------+
| > Mean (SD)         | --1.5 (1.52)           | --0.4 (1.50)          |
+---------------------+------------------------+-----------------------+
| p-value             | \<0.0001               | \-\--                 |
+---------------------+------------------------+-----------------------+

> KSS = Karolinska Sleepiness Scale; n = number of patients with values
> at specified interval.

***PVT results***

In SWSD study 305, the mean change from the baseline assessment to the
final visit for the PVT parameter of number of lapses (reaction times
greater than 500 msec) showed a decrease that was statistically
significant (p=0.0065) for patients in the PROVIGIL treatment group
compared with patients in the placebo treatment group. PVT results for
study 305 are presented in Table 31.

[]{#__RefHeading___Toc49234388 .anchor}**Table** **31: Change From
Baseline in PVT Results at the Final Visit in SWSD Study 305\
(Efficacy Evaluable Set)**

+---------------+--------+-------------+--------+--------------+------+
| **PVT         | **Tre  |             |        |              |      |
| parameter**   | atment |             |        |              |      |
|               | g      |             |        |              |      |
|               | roup** |             |        |              |      |
+---------------+--------+-------------+--------+--------------+------+
|               | **PRO  |             | **Pl   |              |      |
|               | VIGIL\ |             | acebo\ |              |      |
|               | 200 m  |             | (N =   |              |      |
|               | g/day\ |             | 104)** |              |      |
|               | (N =   |             |        |              |      |
|               | 89)**  |             |        |              |      |
+---------------+--------+-------------+--------+--------------+------+
|               | **Base | **Change    | **Base | **Change     | **p  |
|               | line** | from        | line** | from         | -val |
|               |        | baseline**  |        | baseline**   | ue** |
+---------------+--------+-------------+--------+--------------+------+
| **Number of   |        |             |        |              |      |
| lapses**      |        |             |        |              |      |
+---------------+--------+-------------+--------+--------------+------+
| > n           | 77     | 77          | 83     | 83           |      |
+---------------+--------+-------------+--------+--------------+------+
| > Mean (SD)   | 22.9   | --4.1       | 22.4   | 6.1 (20.6)   | 0.   |
|               | (21.5) | (20.14)     | (24.4) |              | 0065 |
+---------------+--------+-------------+--------+--------------+------+

PVT = Psychomotor Vigilance Task.

#### Quality of Life Assessment: FOSQ

***FOSQ results***

No statistically significant improvements in any of the subscale scores
(total score, vigilance, activity level, general productivity, social
outcome, or intimate relationships and sexual activity) from the FOSQ
were observed for patients in the PROVIGIL treatment group when compared
to patients in the placebo treatment group.

### Study Design for SWSD Study 306

Study 306 was a randomized, double-blind, placebo-controlled,
parallel-group study conducted at 31 centers in the US. Patients with ES
associated with chronic SWSD were randomized to receive a daily dose of
200 or 300 mg of PROVIGIL, or a placebo, during a 12‑week, double‑blind
treatment period. This was primarily a safety and tolerability study
including evaluation of quality-of-life measures (FOSQ and SF-36). Study
visits occurred on the mornings immediately after working the last night
of a night shift work period of at least 3 consecutive nights. After
completion of the double-blind treatment period, patients were allowed
to enter a 12‑month open‑label treatment extension period.

Eligible patients had a CGI-S score of at least moderately ill as
related to sleepiness on work nights (including the commute to and from
work). Patients met the ICSD criteria for chronic SWSD (ICSD Code
307.45-1) and worked a minimum of 5 night shifts per month with at least
3 of the nights being consecutive. The night shifts included at least
6 hours between the hours of 2200 and 0800, and were no more than
12 hours in duration. Study drug administration was intermittent, ie,
patients took their dose of study drug approximately 30 minutes to
1 hour before the start of each night shift worked, but not on the days
(and nights) not at work.

This was a safety and quality-of-life study for which no primary or
secondary efficacy variables were specified. The quality-of-life
measures, the FOSQ and SF-36, were evaluated at baseline, week 4, and
week 12 (or final visit).

### Data Analysis for SWSD Study 306

Quality-of-life (continuous) variables (FOSQ, SF-36) were analyzed as
the change from baseline and an analysis of covariance (ANCOVA) with
treatment and center as factors and the baseline value as a covariate
was utilized for detecting treatment differences.

The change from baseline at week 12 (or final visit) for the 5
individual subscales and the total score from the FOSQ were analyzed
using an ANCOVA with treatment and center as factors and baseline value
as a covariate. The presence of a treatment by covariate interaction was
evaluated using an ANCOVA with treatment, center, baseline, and
treatment\*baseline as factors.

### Study Population for SWSD Study 306

#### Patient Disposition

In SWSD study 306, 176 PROVIGIL-treated patients and 86 placebo-treated
patients were considered efficacy evaluable (Table 32).

[]{#__RefHeading___Toc49234389 .anchor}Table 32: Patient Disposition in
SWSD Study 306\
(All Randomized Patients)

+------------------------+--------------+--------------+--------------+
|                        | **Number (%) |              |              |
|                        | of           |              |              |
|                        | patients**   |              |              |
+------------------------+--------------+--------------+--------------+
| **Patient              | **PROVIGIL\  | **PROVIGIL\  | **\          |
| disposition^a^**       | 200 mg/day\  | 300 mg/day\  | Placebo\     |
|                        | (N=92)**     | (N=93)**     | (N=93)**     |
+------------------------+--------------+--------------+--------------+
| Randomized             | 92 (100)     | 93 (100)     | 93 (100)     |
+------------------------+--------------+--------------+--------------+
| Completed              | 68 (74)      | 61 (66)      | 60 (65)      |
+------------------------+--------------+--------------+--------------+
| Withdrawn              | 24 (26)      | 32 (34)      | 33 (35)      |
+------------------------+--------------+--------------+--------------+
| > Death                | 0            | 0            | 0            |
+------------------------+--------------+--------------+--------------+
| > Adverse event        | 6 (7)        | 18 (19)      | 5 (5)        |
+------------------------+--------------+--------------+--------------+
| > Lack of efficacy     | 0            | 1 (1)        | 0            |
+------------------------+--------------+--------------+--------------+
| > Consent withdrawn    | 3 (3)        | 3 (3)        | 6 (6)        |
+------------------------+--------------+--------------+--------------+
| > Protocol violation   | 5 (5)        | 2 (2)        | 3 (3)        |
+------------------------+--------------+--------------+--------------+
| > Noncompliance        | 0            | 2 (2)        | 5 (5)        |
+------------------------+--------------+--------------+--------------+
| > Lost to follow‑up    | 6 (7)        | 3 (3)        | 7 (8)        |
+------------------------+--------------+--------------+--------------+
| > Other                | 4 (4)        | 3 (3)        | 7 (8)        |
+------------------------+--------------+--------------+--------------+
| Patients in efficacy   | 86 (93)      | 90 (97)      | 86 (92)      |
| evaluable set          |              |              |              |
+------------------------+--------------+--------------+--------------+
| Patients in the safety | 87 (95)      | 90 (97)      | 86 (92)      |
| analysis set           |              |              |              |
+------------------------+--------------+--------------+--------------+

^a^In total, 482 patients were screened for enrollment into the study.

#### Demographic Characteristics

In SWSD study 306, patient demographic characteristics were similar for
the 3 treatment groups. A summary of patient characteristics including
sex, race, age, and weight for study 306 is presented in Table 33.

[]{#__RefHeading___Toc49234390 .anchor}*Table 33: Demographic
Characteristics in SWSD Study 306\
(Safety Analysis Set)*

+--------------------+----------------+--------------+----------------+
|                    | **Treatment    |              |                |
|                    | group**        |              |                |
+--------------------+----------------+--------------+----------------+
| **\                | **PROVIGIL\    | **PROVIGIL\  | **\            |
| Demographic        | 200 mg/day\    | 300 mg/day\  | Placebo\       |
| variable**         | (N = 87)**     | (N = 90)**   | (N = 86)**     |
+--------------------+----------------+--------------+----------------+
| **Age, years**     |                |              |                |
+--------------------+----------------+--------------+----------------+
| > Mean (SD)        | 40.0 (9.3)     | 40.2 (9.7)   | 39.9 (8.9)     |
+--------------------+----------------+--------------+----------------+
| **Sex, n (%)**     |                |              |                |
+--------------------+----------------+--------------+----------------+
| > Male             | 44 (51)        | 43 (48)      | 38 (44)        |
+--------------------+----------------+--------------+----------------+
| > Female           | 43 (49)        | 47 (52)      | 48 (56)        |
+--------------------+----------------+--------------+----------------+
| **Race, n (%)**    |                |              |                |
+--------------------+----------------+--------------+----------------+
| > White            | 67 (77)        | 67 (74)      | 57 (66)        |
+--------------------+----------------+--------------+----------------+
| > Black            | 14 (16)        | 15 (17)      | 19 (22)        |
+--------------------+----------------+--------------+----------------+
| > Asian            | 1 (1)          | 1 (1)        | 0              |
+--------------------+----------------+--------------+----------------+
| > Pacific Islander | 0              | 0            | 1 (1)          |
+--------------------+----------------+--------------+----------------+
| > Other            | 5 (6)          | \(8\)        | 9 (10)         |
+--------------------+----------------+--------------+----------------+
| **Weight, kg**     |                |              |                |
+--------------------+----------------+--------------+----------------+
| > Mean (SD)        | 90.9 (19.6)    | 88.2 (24.6)  | 88.3 (21.1)    |
+--------------------+----------------+--------------+----------------+

#### Baseline Patient Characteristics

The 3 treatment groups were comparable with regard to baseline CGI-S
(Table 34).

[]{#__RefHeading___Toc49234391 .anchor}Table 34: Baseline Patient
Characteristics in SWSD Study 306\
(Safety Analysis Set)

+---------------+------------------+-----------+-----------+----------+
| **\           |                  | **        |           |          |
| \             |                  | Treatment |           |          |
| Baseline      |                  | group**   |           |          |
| parameter**   |                  |           |           |          |
+===============+==================+===========+===========+==========+
|               |                  | **        | **        | **P      |
|               |                  | PROVIGIL\ | PROVIGIL\ | lacebo** |
|               |                  | 200       | 300       |          |
|               |                  | mg/day**  | mg/day**  | **       |
|               |                  |           |           | (N=86)** |
|               |                  | *         | *         |          |
|               |                  | *(N=87)** | *(N=90)** |          |
+---------------+------------------+-----------+-----------+----------+
| CGI-S rating, | Normal           | 0         | 0         | 0        |
| N (%)         |                  |           |           |          |
+---------------+------------------+-----------+-----------+----------+
|               | Borderline ill   | 0         | 0         | 0        |
+---------------+------------------+-----------+-----------+----------+
|               | Mildly ill       | 0         | 0         | 0        |
+---------------+------------------+-----------+-----------+----------+
|               | Moderately ill   | 64 (74)   | 59 (66)   | 65 (76)  |
+---------------+------------------+-----------+-----------+----------+
|               | Markedly ill     | 13 (15)   | 19 (21)   | 17 (20)  |
+---------------+------------------+-----------+-----------+----------+
|               | Severely ill     | 10 (11)   | 12 (13)   | 4 (5)    |
+---------------+------------------+-----------+-----------+----------+
|               | Extremely ill    | 0         | 0         | 0        |
+---------------+------------------+-----------+-----------+----------+

> CGI-S = Clinical Global Impression of Severity
>
> Overall, the patients who participated in SWSD study 306 had
> subjective evidence of ES at baseline (from CGI-S).

### Quality of Life Assessments for SWSD Study: SF-36 and FOSQ

***SF-36 results***

In SWSD study 306, improvement from the baseline assessment to the final
visit for the mental composite summary score from the SF-36 was
statistically significant for the patients in the PROVIGIL 300‑mg/day
treatment group (mean change 3.20, p=0.0113) and the PROVIGIL 200‑mg/day
treatment group (mean change 3.66, p=0.015) in comparison to the placebo
group (mean change 0.68).

Statistically significant improvements at the final visit were also seen
for individual domains for patients in both PROVIGIL treatment groups
when compared with patients in the placebo treatment group: vitality
(PROVIGIL-300 mg/day \[p\<0.0001\] and PROVIGIL‑200 mg/day \[p=0.0003\]
groups versus the placebo group), and role emotional
(PROVIGIL‑300 mg/day group versus placebo group \[p=0.0444\]). There was
no evidence of consistent trends in improvement in the physical
component and the other domains of bodily pain, general health, mental
health, physical functioning, role physical, and social functioning.

***FOSQ results***

In SWSD study 306, improvement was observed in total FOSQ score at all
time points for patients in the PROVIGIL‑treated groups compared with
the placebo‑treated group. Improvement from baseline to week 12 (or
final visit) in the total score was statistically significantly higher
(p=0.0126) for the patients in the PROVIGIL-300 mg/day group (mean
change from baseline 2.26) compared with patients in the placebo-treated
group (mean change from baseline 1.58). Although not statistically
significant, the p-values for the change from baseline for the
PROVIGIL-200 mg/day treatment group showed a trend toward significance.
Statistically significant improvements at week 12 (or final visit) were
also seen for the following individual domains: activity level
(PROVIGIL-300 mg/day and PROVIGIL-200 mg/day groups versus placebo
group), and vigilance and general productivity (PROVIGIL-300 mg/day
group versus placebo group). Although improvements were seen in the
PROVIGIL treatment groups for the domains of social outcome and intimate
relationships and sexual activity in comparison to placebo**,** at the
final visit these changes did not reach statistical significance.

### Conclusions on SWSD

The efficacy of PROVIGIL in the treatment of patients with ES associated
with chronic SWSD was evaluated in double-blind, placebo-controlled
study 305 involving 89 efficacy evaluable patients treated with PROVIGIL
(200 mg/day) and 104 treated with placebo for up to 12 weeks of
double‑blind treatment. The evaluations of efficacy in SWSD study 305
show that intermittent administration with PROVIGIL provides improvement
in measures of excessive sleepiness in patients with chronic SWSD.

In SWSD study 305, the results of the CGI-C corroborate the results of
the MSLT, ie, both primary efficacy measures indicated significant
improvement for patients receiving PROVIGIL compared to those receiving
placebo. The analysis of average sleep latency from the MSLT at the
final visit indicated a significant increase from baseline in sleep
latency for PROVIGIL‑treated patients compared to placebo-treated
patients (p=0.0022). A significant difference between the PROVIGIL and
placebo treatment groups was also observed for the distribution of CGI-C
ratings at the final visit (p\<0.0001). A significant improvement in
mean KSS score was observed for the PROVIGIL treatment group compared to
the placebo treatment group at the final visit (p\<0.0001). Significant
decreases in the number of lapses compared to baseline from the PVT were
observed at the final visit for patients treated with PROVIGIL compared
to those treated with placebo.

In addition to patients in SWSD study 305, the effect of PROVIGIL on
quality-of-life measures in patients with chronic SWSD was evaluated
double-blind, placebo-controlled study 306 involving 176 efficacy
evaluable patients treated with PROVIGIL (200 or 300 mg/day) and 86
treated with placebo for up to 12 weeks of double‑blind treatment. The
results of quality-of-life assessments obtained suggest that PROVIGIL
may also improve some aspects of patient well‑being. However, the
results from the quality-of-life measures were inconsistent between the
2 studies. Those for study 305 showed no significant differences between
the PROVIGIL and placebo treatment groups for total FOSQ score or
individual subscale scores. However, in study 306, significant
improvement for the PROVIGIL 300-mg/day dosage group compared to the
placebo group was observed for total FOSQ score and 3 of the 5 subscale
scores, and significant improvement relative to placebo treatment was
observed for both the 200- and 300‑mg/day dosages for the mental
composite score and vitality domain of the SF-36.

## Brief Overview of Supportive Efficacy Studies

As mentioned above, the presentation of data from the 6 principal
studies is the focus of the efficacy evaluation of PROVIGIL treatment,
but there is supportive evidence for the efficacy of PROVGIL from
14 other studies.

Supportive evidence of the efficacy of PROVIGIL for the treatment of
patients with excessive sleepiness associated with narcolepsy is
provided by the results of 3 studies conducted by Cephalon in the US and
UK (study C1538a/406/NA/US, study C1538a/401/NA/US, and a named patient
program), and 8 studies conducted outside the US (MOD‑024, MOD‑025,
MOD94003, MOD‑026, MOD‑027, MOD‑028, E1027 and E1028). In these studies,
which included 1234 patients with narcolepsy, PROVIGIL was administered
from 1 to 4 times daily at dosages ranging from 50 to 1000 mg/day. Study
durations ranged from 2 - 40 weeks to 2 - 8 years. The efficacy of
PROVIGIL was demonstrated using objective measures of sleep latency, as
well as subjective measures of sleepiness and quality of life. Observed
in studies utilizing objective assessments were improvements in
wakefulness as measured by the MWT, and decreases in the numbers of
sleep episodes/attacks, diurnal yawns, and episodes of
somnolence/sleepiness. There was also improvement with regard to
subjective measures of clinical condition and quality of life.

Additional studies of efficacy in residual ES in patients with sleep
apnea include 1 Cephalon‑sponsored study (C1538a/407/AP/UK) conducted in
the UK and 2 studies sponsored by other licensees (E1030, MOD-02), in
which 91 patients were enrolled from 1 day to 6 weeks. The results of
these placebo-controlled, crossover studies indicate positive trends for
PROVIGIL treatment (300 to 400 mg/day) on objective and subjective
measures in patients with excessive sleepiness associated with OSAHS.
These measures include the MWT, MSLT, ESS, apnea index, and vigilance
testing.

## Summary of Results of Primary Efficacy Measures in the Four Pivotal Studies---Narcolepsy Studies 301 and 302, OSAHS Study 303, and SWSD Study 305

### Overview of Efficacy Evaluation in the Four Pivotal Studies

Across the 4 pivotal studies (narcolepsy studies 301 and 302, OSAHS
study 303, and SWSD study 305), 630 patients were treated with PROVIGIL
and underwent efficacy evaluations (ie, efficacy evaluable patients),
with an additional 384 placebo-treated patients evaluated for
comparative purposes (total 1014).

### Patient Populations in the Four Pivotal Studies

The patient populations in the narcolepsy and SWSD studies were similar
with respect to demographic characteristics (ie, age, sex, race, and
body weight). Compared with these populations, the patient population in
the OSAHS studies was slightly older and there were more men than women.
This finding is consistent with the characteristics of patients with
OSAHS in general.

The patient populations studied had varying degrees of ES at study
entry, ie, patients with OSAHS tended to have less severe ES that those
with narcolepsy or SWSD. At the baseline evaluations, however, all
populations had objective evidence of ES as assessed by the MWT/MSLT,
and all had evidence of significant illness as assessed by the CGI-S.
All had evidence of disturbed sleep.

### Primary Efficacy Analyses for the Four Pivotal Studies: MWT/MSLT and CGI‑C at the Final Visit

With regard to the primary objective outcome measures in the 4 pivotal
studies, for patients treated with PROVIGIL at either 200 or 400 mg/day,
statistically significant improvements, as compared to placebo
treatment, were observed in mean sleep latency as measured by the MWT in
the narcolepsy and OSAHS studies, and by the MSLT in the SWSD studies
(Table 35).

[]{#__RefHeading___Toc49234392 .anchor}Table 35: Mean (SD) Change From
Baseline in Mean Sleep Latency (Minutes)

  ------------ ----------- ----------- ------------- ------------- -------------
  **\          **\         **\         **Treatment                 
  Disorder**   Study no.** Measure**   group**                     

                                       **200         **400         **Placebo**
                                       mg/day**      mg/day**      

  Narcolepsy   301         MWT         2.3           2.3           --0.7 (4.6)
                                       (4.7)\*\*\*   (4.9)\*\*\*   

               302         MWT         2.2 (4.5)\*\* 2.0 (4.8)\*\* --0.7 (4.2)

  OSAHS        303         MWT         1.6           1.5           --1.1 (4.6)
                                       (4.8)\*\*\*   (5.0)\*\*\*   

  SWSD         305         MSLT        1.7           \-\--         0.3 ± 2.8
                                       (3.8)\*\*\*                 
  ------------ ----------- ----------- ------------- ------------- -------------

OSAHS = obstructive sleep apnea/hypopnea syndrome; SWSD = shift work
sleep disorder;\
MWT = Maintenance of Wakefulness Test; MSLT = Multiple Sleep Latency
Test.\
\*p\<0.05; \*\*p\<0.01; \*\*\*p\<0.001.

With regard to the primary subjective outcome measure in the 4 pivotal
studies, for patients treated with PROVIGIL at either 200 or 400 mg/day,
statistically significant improvements compared to placebo-treated
patients were observed in clinical condition as assessed by the
difference in distribution of CGI-C ratings (Figure 3).

[]{#__RefHeading___Toc49234355 .anchor}Figure 3: CGI-C at the Final
Visit in Studies 301, 302, 303, and 305

![](media/image3.wmf)

> CGI-C = Clinical Global Impression of Change; OSAHS = obstructive
> sleep apnea/hypopnea syndrome; SWSD = shift work sleep disorder.

The results of the analyses of both the primary objective and subjective
outcome measures demonstrate the efficacy or PROVIGIL treatment over
placebo treatment. The clinical significance of the 1.5- to 2.3-minute
change seen on laboratory-based measures (ie, MWT and MSLT) is
corroborated by the statistically significant (p\<0.05) improvements
seen in clinical condition, as assessed by the clinician‑based measure
CGI-C.

### Analysis of MWT/MSLT and CGI-C Over Time in the Four Pivotal Studies

For patients treated with PROVIGIL at either 200 or 400 mg/day,
improvements in mean sleep latency (Figure 4) and clinical condition
(ie, CGI-C) (Figure 5) were observed beginning with the first
postbaseline visit and sustained throughout the double‑blind treatment
periods of all 4 pivotal studies. All improvements were statistically
significant, in favor of PROVIGIL treatment over placebo treatment, with
the exception, in the SWSD study, of the sleep latency value of sleep
latency for the 200-mg/day PROVIGIL treatment group at week 8.

> []{#__RefHeading___Toc49234356 .anchor}Figure 4: MWT/MSLT Sleep
> Latency by Visit\
> in Studies 301, 302, 303, and 305

![](media/image4.wmf)

> MWT = Maintenance of Wakefulness Test; MSLT = Multiple Sleep Latency
> Test.\
> \*p\<0.05 (between-treatment comparisons \[each PROVIGIL dose vs
> placebo\]).
>
> []{#__RefHeading___Toc49234357 .anchor}Figure 5: CGI-C Ratings by
> Visit for Patients Whose Conditions Improved in Studies 301, 302, 303,
> and 305

![](media/image5.wmf)

> CGI-C -- Clinical Global Impression of Change (patients who improved
> at least minimally).

## Consistency of PROVIGIL Effects Across Disorders of Sleep and Wakefulness in the Principal Studies---Narcolepsy Studies 301 and 302, OSAHS Studies 303 and 402, and SWSD Study 305

For continuous efficacy variables assessed in the principal studies
(narcolepsy studies 301 and 302, OSAHS studies 303 and 402, and SWSD
study 305 \[study 306 did not contribute efficacy data for SWSD\]),
including MSLT, MWT, ESS, and KSS, effect sizes for the change from
baseline assessment to the final visit were calculated within sleep
disorder model to facilitate evaluation of the consistency of effect of
PROVIGIL across the patient populations. Effect size was calculated as
follows: (change from baseline in PROVIGIL group minus change from
baseline in placebo group)/common estimate of standard deviation.

Individual studies demonstrated positive efficacy effects with PROVIGIL
treatment over placebo treatment, which allowed for effect-size analyses
to be done on combined data from the pairs of narcolepsy and OSAHS
studies.

The results of these analyses indicate that the positive effects of
PROVIGIL treatment on wakefulness are consistent across disorders of
sleep and wakefulness (Table 36). For the variables from measures of
MSLT, MWT, and ESS/KSS, the effect sizes were consistent for the 3 study
populations. In addition, the percentage of patients with some
improvement from baseline as assessed by CGI‑C was consistent across all
3 populations.

[]{#__RefHeading___Toc49234393 .anchor}Table 36: Estimates of Effect
Size for the Change From Baseline to the Final Visit\
for Continuous Efficacy Variables in Studies 301, 302, 303, 402, and
305\
(Efficacy Evaluable Set)

+------+-------------+-------+-------+---------+-----------+---------+
|      |             |       | **E   |         |           | **Perce |
|      |             |       | ffect |         |           | ntage** |
|      |             |       | siz   |         |           |         |
|      |             |       | e^a^\ |         |           |         |
|      |             |       | (95%  |         |           |         |
|      |             |       | confi |         |           |         |
|      |             |       | dence |         |           |         |
|      |             |       | i     |         |           |         |
|      |             |       | nterv |         |           |         |
|      |             |       | al)** |         |           |         |
+------+-------------+-------+-------+---------+-----------+---------+
| **\  | **\         | *     | **\   | **\     | **\       | **Im    |
| Di   | Study**     | *Trea | M     | MWT**   | ESS       | proved\ |
| sord |             | tment | SLT** |         | /KSS^b^** | CGI-C** |
| er** |             | gr    |       |         |           |         |
|      |             | oup** |       |         |           |         |
+------+-------------+-------+-------+---------+-----------+---------+
| Na   | 301 and     | 200   | 0.32\ | 0.64\   | --0.54\   | 61      |
| rcol | 302\        | m     | (     | (0.62,  | (-0.56,   |         |
| epsy | (combined   | g/day | 0.29, | 0.67)   | -0.51)    |         |
|      | analysis)   |       | 0.34) |         |           |         |
+------+-------------+-------+-------+---------+-----------+---------+
|      |             | 400   | 0.37\ | 0.61\   | --0.77\   | 66      |
|      |             | m     | (     | (0.59,  | (--0.7    |         |
|      |             | g/day | 0.35, | 0.64)   | 9,--0.74) |         |
|      |             |       | 0.39) |         |           |         |
+------+-------------+-------+-------+---------+-----------+---------+
| O    | 303 and     | 200   | \-\-- | 0.56    | --0.65\   | 61      |
| SAHS | 402\        | m     |       | **^c^** | (--0.68,  |         |
|      | (combined   | g/day |       |         | --0.61)   |         |
|      | analysis)   |       |       | (0.52,  |           |         |
|      |             |       |       | 0.61)   |           |         |
+------+-------------+-------+-------+---------+-----------+---------+
|      |             | 400   | 0.31\ | 0.53*   | --0.62\   | 68      |
|      |             | m     | (     | *^c^**\ | (--0.64,  |         |
|      |             | g/day | 0.26, | (0.49,  | 0.67)     |         |
|      |             |       | 0.37) | 0.58)   |           |         |
+------+-------------+-------+-------+---------+-----------+---------+
| SWSD | 305         | 200   | 0.41\ | \-\--   | --0.52\   | 74      |
|      |             | m     | (     |         | (--0.52,  |         |
|      |             | g/day | 0.37, |         | --0.51)   |         |
|      |             |       | 0.46) |         |           |         |
+------+-------------+-------+-------+---------+-----------+---------+

^a^ Effect size calculated as (change from baseline in PROVIGIL group
minus change from baseline in placebo group)/common estimate of standard
deviation.

^b^ KSS assessed in SWSD study 305 only.

**^c^** MWT was not measured in study 402.

CGI-C = Clinical Global Impression of Change; ESS = Epworth Sleepiness
Scale; KSS = Karolinska Sleepiness Scale; MSLT = Multiple Sleep Latency
Test; MWT = Maintenance of Wakefulness Test; OSAHS = obstructive sleep
apnea/hypopnea syndrome; SWSD = shift work sleep disorder.

## Efficacy Conclusions

The efficacy of PROVIGIL treatment to promote wakefulness in patients
with ES associated with disorders of sleep and wakefulness was
demonstrated in 6 double‑blind, placebo‑controlled studies conducted in
patient populations representing disorders of sleep and wakefulness,
specifically, narcolepsy, OSAHS, and SWSD. The results of these studies
support the following conclusions:

-   PROVIGIL significantly improved ES across the disorders of sleep and
    wakefulness as assessed by the dual primary outcome measures of
    MWT/MSLT and CGI‑C in the pivotal studies.

-   The efficacy of PROVIGIL shown by the primary outcome measures is
    supported by the positive results of other outcome measures.

-   Consistent and reproducible treatment effects were observed across
    both objective and subjective measures and across patient
    populations.

-   Treatment effect was demonstrated at the first posttreatment visit
    and sustained over time.

-   The efficacy of PROVIGIL was observed at all dosages studied.

# Safety Results

## Evaluation of Adverse Events

### Introduction

A key review of the safety data of PROVIGIL treatment in patients with
narcolepsy, OSAHS, and SWSD involved an evaluation of adverse events
from the double‑blind treatment periods of the 6 principal studies
(narcolepsy studies 301 and 302, OSAHS studies 303 and 402, and SWSD
studies 305 and 306), where comparisons of safety parameters were made
between PROVIGIL and placebo treatment and among the 3 disorders of
sleep and wakefulness. These evaluations were made on data from
individual studies and from combined data.

The information below addressing adverse events begins with an overview
of adverse event categories and types of adverse events for individual
studies (across the 6 studies by treatment groups) and for combined data
by disorder (narcolepsy, OSAHS, and SWSD by treatment group).

Following the determination of the consistency in adverse event profiles
among the studies and the disorders, an additional higher-level review
of treatment exposure and adverse events was undertaken where these data
were combined for the 6 principal studies by treatment group (PROVIGIL
or placebo).

Further review of treatment exposure and adverse event data was done for
other PROVIGIL safety data sets.

### Principal Studies in Narcolepsy, OSAHS, and SWSD

#### Overview of Adverse Events

A review of the adverse event categories for each of the individual
principal studies is presented by treatment group (Table 37) and for
these studies combined (Table 38). The parameters reviewed were adverse
events, treatment-related adverse events, serious adverse events,
adverse events leading to withdrawal, and deaths.

The percentages of PROVIGIL-treated patients who experienced adverse
events ranged from 83% to 90% for narcolepsy, 66% to 78% for OSAHS, and
67% to 74% for SWSD. The percentages of PROVIGIL-treated patients who
experienced serious adverse events were low overall (at most 3%). The
percentages of PROVIGIL-treated patients who experienced adverse events
leading to withdrawal ranged from 1% to 12% for narcolepsy, 9% to 13%
for OSAHS, and 3% to 21% for SWSD. With the exception of narcolepsy
study 302, generally there were more withdrawals due to adverse events
from the higher PROVIGIL dose groups. In general, more PROVIGIL‑treated
patients withdrew due to adverse events than placebo-treated patients.

[]{#__RefHeading___Toc49234394 .anchor}Table 37: Overview of Adverse
Events in Individual Principal Studies\
(Safety Analysis Set)

+------------------+--------+---+----+------+--------+----+---+-------+
| **Patient        | **     |   |    |      |        |    |   |       |
| population**     | Number |   |    |      |        |    |   |       |
|                  | (%) of |   |    |      |        |    |   |       |
|                  | pati   |   |    |      |        |    |   |       |
|                  | ents** |   |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > **Adverse      | *      |   |    |      | *      |    |   |       |
| > event          | *Study |   |    |      | *Study |    |   |       |
| > category**     | 301**  |   |    |      | 302**  |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| **Narcolepsy**   | **PRO  | * |    | **P  | **PRO  | *  |   | *     |
|                  | VIGIL\ | * |    | lace | VIGIL\ | *P |   | *Plac |
|                  | 20     | P |    | bo** | 20     | RO |   | ebo** |
|                  | 0 mg** | R |    |      | 0 mg** | VI |   |       |
|                  |        | O |    |      |        | GI |   |       |
|                  |        | V |    |      |        | L\ |   |       |
|                  |        | I |    |      |        | 40 |   |       |
|                  |        | G |    |      |        | 0  |   |       |
|                  |        | I |    |      |        | mg |   |       |
|                  |        | L |    |      |        | ** |   |       |
|                  |        | \ |    |      |        |    |   |       |
|                  |        | 4 |    |      |        |    |   |       |
|                  |        | 0 |    |      |        |    |   |       |
|                  |        | 0 |    |      |        |    |   |       |
|                  |        |   |    |      |        |    |   |       |
|                  |        | m |    |      |        |    |   |       |
|                  |        | g |    |      |        |    |   |       |
|                  |        | * |    |      |        |    |   |       |
|                  |        | * |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Number of      | 96     | 9 |    | 92   | 89     | 89 |   | 93    |
| > patients       |        | 5 |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Adverse events | 86     | 8 |    | 76   | 74     | 79 |   | 76    |
| > (AEs)          | (90)   | 2 |    | (83) | (83)   | (8 |   | (82)  |
|                  |        | ( |    |      |        | 9) |   |       |
|                  |        | 8 |    |      |        |    |   |       |
|                  |        | 6 |    |      |        |    |   |       |
|                  |        | ) |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > T              | 11     | 2 |    | 5    | 5 (6)  | 10 |   | 3 (3) |
| reatment‑related | (11)   | 0 |    | (5)  |        | (1 |   |       |
| > AEs            |        | ( |    |      |        | 1) |   |       |
|                  |        | 2 |    |      |        |    |   |       |
|                  |        | 1 |    |      |        |    |   |       |
|                  |        | ) |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Serious        | 0      | 3 |    | 2    | 3 (3)  | 3  |   | 3 (3) |
| > adverse events |        | ( |    | (2)  |        | (  |   |       |
|                  |        | 3 |    |      |        | 3) |   |       |
|                  |        | ) |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > AEs leading to | 1 (1)  | 1 |    | 0    | 6 (7)  | 1  |   | 3 (3) |
| > withdrawal     |        | 1 |    |      |        | (  |   |       |
|                  |        | ( |    |      |        | 1) |   |       |
|                  |        | 1 |    |      |        |    |   |       |
|                  |        | 2 |    |      |        |    |   |       |
|                  |        | ) |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Deaths         | 0      | 0 |    | 0    | 0      | 0  |   | 0     |
+------------------+--------+---+----+------+--------+----+---+-------+
|                  | *      |   |    |      | *      |    |   |       |
|                  | *Study |   |    |      | *Study |    |   |       |
|                  | 303**  |   |    |      | 402**  |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| **OSAHS**        | **PRO  | * |    | **P  | **PRO  |    | * |       |
|                  | VIGIL\ | * |    | lace | VIGIL\ |    | * |       |
|                  | 20     | P |    | bo** | 40     |    | P |       |
|                  | 0 mg** | R |    |      | 0 mg** |    | l |       |
|                  |        | O |    |      |        |    | a |       |
|                  |        | V |    |      |        |    | c |       |
|                  |        | I |    |      |        |    | e |       |
|                  |        | G |    |      |        |    | b |       |
|                  |        | I |    |      |        |    | o |       |
|                  |        | L |    |      |        |    | * |       |
|                  |        | \ |    |      |        |    | * |       |
|                  |        | 4 |    |      |        |    |   |       |
|                  |        | 0 |    |      |        |    |   |       |
|                  |        | 0 |    |      |        |    |   |       |
|                  |        |   |    |      |        |    |   |       |
|                  |        | m |    |      |        |    |   |       |
|                  |        | g |    |      |        |    |   |       |
|                  |        | * |    |      |        |    |   |       |
|                  |        | * |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Number of      | 109    | 1 |    | 108  | 77     |    | 8 |       |
| > patients       |        | 0 |    |      |        |    | 0 |       |
|                  |        | 6 |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Adverse events | 85     | 8 |    | 70   | 51     |    | 3 |       |
| > (AES)          | (78)   | 1 |    | (65) | (66)   |    | 9 |       |
|                  |        | ( |    |      |        |    | ( |       |
|                  |        | 7 |    |      |        |    | 4 |       |
|                  |        | 6 |    |      |        |    | 9 |       |
|                  |        | ) |    |      |        |    | ) |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > T              | 55     | 4 |    | 22   | 34     |    | 2 |       |
| reatment‑related | (52)   | 5 |    | (20) | (44)   |    | 0 |       |
| > (AEs)          |        | ( |    |      |        |    | ( |       |
|                  |        | 4 |    |      |        |    | 2 |       |
|                  |        | 1 |    |      |        |    | 5 |       |
|                  |        | ) |    |      |        |    | ) |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Serious        | 2 (2)  | 2 |    | 0    | 1 (1)  |    | 0 |       |
| > adverse events |        | ( |    |      |        |    |   |       |
|                  |        | 2 |    |      |        |    |   |       |
|                  |        | ) |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > AEs leading to | 10 (9) | 1 |    | 3    | 8 (10) |    | 1 |       |
| > withdrawal     |        | 4 |    | (3)  |        |    | ( |       |
|                  |        | ( |    |      |        |    | 1 |       |
|                  |        | 1 |    |      |        |    | ) |       |
|                  |        | 3 |    |      |        |    |   |       |
|                  |        | ) |    |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Deaths         | 0      | 0 |    | 0    | 0      |    | 0 |       |
+------------------+--------+---+----+------+--------+----+---+-------+
|                  | *      |   |    |      | *      |    |   |       |
|                  | *Study |   |    |      | *Study |    |   |       |
|                  | 305**  |   |    |      | 306**  |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| **SWSD**         | **PRO  |   | *  |      | **PRO  | *  |   | *     |
|                  | VIGIL\ |   | *P |      | VIGIL\ | *P |   | *Plac |
|                  | 20     |   | la |      | 20     | RO |   | ebo** |
|                  | 0 mg** |   | ce |      | 0 mg** | VI |   |       |
|                  |        |   | bo |      |        | GI |   |       |
|                  |        |   | ** |      |        | L\ |   |       |
|                  |        |   |    |      |        | 30 |   |       |
|                  |        |   |    |      |        | 0  |   |       |
|                  |        |   |    |      |        | mg |   |       |
|                  |        |   |    |      |        | ** |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Number of      | 96     |   | 1  |      | 87     | 90 |   | 86    |
| > patients       |        |   | 08 |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Adverse events | 64     |   | 68 |      | 59     | 67 |   | 50    |
| > (AEs)          | (67)   |   | (6 |      | (68)   | (7 |   | (58)  |
|                  |        |   | 3) |      |        | 4) |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > T              | 37     |   | 25 |      | 26     | 40 |   | 15    |
| reatment‑related | (39)   |   | (2 |      | (30)   | (4 |   | 17)   |
| > AEs            |        |   | 3) |      |        | 4) |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Serious        | 0      |   | 1  |      | 2 (2)  | 1  |   | 2 (2) |
| > adverse events |        |   | (  |      |        | (  |   |       |
|                  |        |   | \< |      |        | 1) |   |       |
|                  |        |   | 1) |      |        |    |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > AEs leading to | 3 (3)  |   | 4  |      | 5 (6)  | 19 |   | 4 (5) |
| > withdrawal     |        |   | (  |      |        | (2 |   |       |
|                  |        |   | 4) |      |        | 1) |   |       |
+------------------+--------+---+----+------+--------+----+---+-------+
| > Deaths         | 0      |   | 0  |      | 0      | 0  |   | 0     |
+------------------+--------+---+----+------+--------+----+---+-------+

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

[]{#__RefHeading___Toc49234395 .anchor}Table 38: Overview of Adverse
Events in the Principal Studies by\
Disorder of Sleep and Wakefulness\
(Safety Analysis Set)

+---------------------+--------+------+--------+------+--------+------+
| **\                 | **     |      |        |      |        |      |
| \                   | Number |      |        |      |        |      |
| \                   | (%) of |      |        |      |        |      |
| Adverse event       | pati   |      |        |      |        |      |
| category**          | ents** |      |        |      |        |      |
+---------------------+--------+------+--------+------+--------+------+
|                     | *      |      | **     |      | *      |      |
|                     | *Narco |      | OSAHS\ |      | *SWSD\ |      |
|                     | lepsy\ |      | S      |      | S      |      |
|                     | S      |      | tudies |      | tudies |      |
|                     | tudies |      | 303    |      | 305    |      |
|                     | 301    |      | and    |      | and    |      |
|                     | and    |      | 402**  |      | 306**  |      |
|                     | 302**  |      |        |      |        |      |
+---------------------+--------+------+--------+------+--------+------+
|                     | **PROV | **P  | **PROV | **P  | **PROV | **P  |
|                     | IGIL** | lace | IGIL** | lace | IGIL** | lace |
|                     |        | bo** |        | bo** |        | bo** |
+---------------------+--------+------+--------+------+--------+------+
| > Number of         | 369    | 185  | 292    | 188  | 273    | 194  |
| > patients          |        |      |        |      |        |      |
+---------------------+--------+------+--------+------+--------+------+
| > Adverse events    | 321    | 152  | 217    | 109  | 190    | 118  |
| > (AEs)             | (87)   | (82) | (74)   | (58) | (70)   | (61) |
+---------------------+--------+------+--------+------+--------+------+
| > Treatment‑related | 46     | 8    | 134    | 42   | 103    | 40   |
| > AEs               | (12)   | (4)  | (46)   | (22) | (38)   | (21) |
+---------------------+--------+------+--------+------+--------+------+
| > Serious adverse   | 9 (2)  | 5    | 5 (2)  | 0    | 3 (1)  | 3    |
| > events            |        | (3)  |        |      |        | (2)  |
+---------------------+--------+------+--------+------+--------+------+
| > AEs leading to    | 19 (5) | 3    | 32     | 4    | 27     | 8    |
| > withdrawal        |        | (2)  | (11)   | (2)  | (10)   | (4)  |
+---------------------+--------+------+--------+------+--------+------+
| > Deaths            | 0      | 0    | 0      | 0    | 0      | 0    |
+---------------------+--------+------+--------+------+--------+------+

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

#### Types of Adverse Events

A review was undertaken of adverse event types for the individual
principal studies by treatment group (Table 39) and for these studies
combined (Table 40). In this review, the focus was placed on adverse
events that occurred frequently among PROVIGIL-treated patients (≥5%)
and more frequently than in placebo-treated patients. Overall, an
essentially consistent safety profile was observed across studies,
disorders, and treatment groups.

The adverse event profile with PROVIGIL treatment is consistently
composed primarily of 2 categories, those adverse events related to the
CNS and those related to the digestive system. The most common adverse
events observed with PROVIGIL treatment across all the studies are
headache, nausea, and nervousness.

[]{#__RefHeading___Toc49234396 .anchor}Table 39: Adverse Events
Occurring in 5% of PROVIGIL-Treated Patients and at a Greater Percentage
Than in Placebo-Treated Patients in Individual Principal Studies\
(Safety Analysis Set)

+------------+--------+-------+---+--------+---------+---+----+---------+
| **Patient  | **     |       |   |        |         |   |    |         |
| po         | Number |       |   |        |         |   |    |         |
| pulation** | (%) of |       |   |        |         |   |    |         |
|            | pati   |       |   |        |         |   |    |         |
|            | ents** |       |   |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | *      |       |   |        | **Study |   |    |         |
|  **Adverse | *Study |       |   |        | 302**   |   |    |         |
| > event**  | 301**  |       |   |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| **Na       | **PRO  | *     |   | **Pl   | **PR    | * |    | **P     |
| rcolepsy** | VIGIL\ | *PROV |   | acebo\ | OVIGIL\ | * |    | lacebo\ |
|            | 2      | IGIL\ |   | (N     | 200 mg\ | P |    | (       |
|            | 00 mg\ | 40    |   | =92)** | (       | R |    | N=93)** |
|            | (N     | 0 mg\ |   |        | N=89)** | O |    |         |
|            | =96)** | (N=   |   |        |         | V |    |         |
|            |        | 95)** |   |        |         | I |    |         |
|            |        |       |   |        |         | G |    |         |
|            |        |       |   |        |         | I |    |         |
|            |        |       |   |        |         | L |    |         |
|            |        |       |   |        |         | \ |    |         |
|            |        |       |   |        |         | 4 |    |         |
|            |        |       |   |        |         | 0 |    |         |
|            |        |       |   |        |         | 0 |    |         |
|            |        |       |   |        |         |   |    |         |
|            |        |       |   |        |         | m |    |         |
|            |        |       |   |        |         | g |    |         |
|            |        |       |   |        |         | \ |    |         |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | N |    |         |
|            |        |       |   |        |         | = |    |         |
|            |        |       |   |        |         | 8 |    |         |
|            |        |       |   |        |         | 9 |    |         |
|            |        |       |   |        |         | ) |    |         |
|            |        |       |   |        |         | * |    |         |
|            |        |       |   |        |         | * |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| Number of  | 86     | 82    |   | 76     | 74 (83) | 7 |    | 76 (82) |
| patients   | (90)   | (86)  |   | (83)   |         | 9 |    |         |
| with at    |        |       |   |        |         | ( |    |         |
| least      |        |       |   |        |         | 8 |    |         |
| 1 adverse  |        |       |   |        |         | 9 |    |         |
| event      |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Headache | 50     | 48    |   | 33     | 37 (42) | 4 |    | 41 (44) |
|            | (52)   | (51)  |   | (36)   |         | 8 |    |         |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 5 |    |         |
|            |        |       |   |        |         | 4 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Nausea   | 12     | 12    |   | 5 (5)  | 12 (13) | 1 |    | 2 (2)   |
|            | (13)   | (13)  |   |        |         | 1 |    |         |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 1 |    |         |
|            |        |       |   |        |         | 2 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | 13     | 14    |   | 18     | 10 (11) | 1 |    | 11 (12) |
|  Infection | (14)   | (15)  |   | (20)   |         | 4 |    |         |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 1 |    |         |
|            |        |       |   |        |         | 6 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Rhinitis | 10     | 14    |   | 11     | 10 (11) | 8 |    | 3 (3)   |
|            | (10)   | (15)  |   | (12)   |         | ( |    |         |
|            |        |       |   |        |         | 9 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > N        | 9 (9)  | 9 (9) |   | 5 (5)  | 8 (9)   | 4 |    | 7 (8)   |
| ervousness |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 4 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Dry      | 8 (8)  | 4 (4) |   | 0      | 0       | 7 |    | 1 (1)   |
| > mouth    |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 8 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Back     | 8 (8)  | 8 (8) |   | 3 (3)  | 9 (10)  | 1 |    | 13 (14) |
| > pain     |        |       |   |        |         | 0 |    |         |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 1 |    |         |
|            |        |       |   |        |         | 1 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | 8 (8)  | 2 (2) |   | 8 (9)  | 8 (9)   | 8 |    | 6 (6)   |
|  Dyspepsia |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 9 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Diarrhea | 7 (7)  | 7 (7) |   | 4 (4)  | 7 (8)   | 9 |    | 4 (4)   |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 1 |    |         |
|            |        |       |   |        |         | 0 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Anorexia | 6 (6)  | 3 (3) |   | 1 (1)  | 2 (2)   | 6 |    | 1 (1)   |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 7 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Flu      | 5 (5)  | 3 (3) |   | 4 (4)  | 3 (3)   | 2 |    | 3 (3)   |
| > syndrome |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 2 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Anxiety  | 3 (3)  | 2 (2) |   | 0      | 2 (2)   | 6 |    | 1 (1)   |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 7 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | 4 (4)  | 2 (2) |   | 3 (3)  | 5 (6)   | 6 |    | 4 (4)   |
|  Dizziness |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 7 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > P        | 4 (4)  | 7 (7) |   | 3 (3)  | 4 (4)   | 8 |    | 2 (2)   |
| haryngitis |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 9 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Pain     | 4 (4)  | 4 (4) |   | 2 (2)  | 3 (3)   | 5 |    | 5 (5)   |
| > abdomen  |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 6 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | 3 (3)  | 6 (6) |   | 5 (5)  | 3 (3)   | 2 |    | 0       |
| Depression |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 2 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | 3 (3)  | 7 (7) |   | 1 (1)  | 1 (1)   | 1 |    | 3 (3)   |
|  Cataplexy |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 1 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Insomnia | 2 (2)  | 7 (7) |   | 1 (1)  | 1 (1)   | 1 |    | 1 (1)   |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 1 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Fever    | 2 (2)  | 2 (2) |   | 4 (4)  | 1 (1)   | 5 |    | 2 (2)   |
|            |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 6 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Cough    | 2 (2)  | 3 (3) |   | 4 (4)  | 2 (2)   | 5 |    | 2 (2)   |
| >          |        |       |   |        |         | ( |    |         |
|  increased |        |       |   |        |         | 6 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Eo       | 2 (2)  | 1 (1) |   | 0      | 5 (6)   | 0 |    | 0       |
| sinophilia |        |       |   |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Rash     | 1 (1)  | 7 (7) |   | 4 (4)  | 3 (3)   | 0 |    | 3 (3)   |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Lung     | 0      | 3 (3) |   | 2 (2)  | 4 (4)   | 6 |    | 1 (1)   |
| > disorder |        |       |   |        |         | ( |    |         |
|            |        |       |   |        |         | 7 |    |         |
|            |        |       |   |        |         | ) |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
|            | *      |       |   |        | **Study |   |    |         |
|            | *Study |       |   |        | 402**   |   |    |         |
|            | 303**  |       |   |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| **OSAHS**  | **PRO  | *     | * |        | **PR    |   | ** |         |
|            | VIGIL\ | *PROV | * |        | OVIGIL\ |   | Pl |         |
|            | 2      | IGIL\ | P |        | 400 mg\ |   | ac |         |
|            | 00 mg\ | 40    | l |        | (       |   | eb |         |
|            | (N=    | 0 mg\ | a |        | N=77)** |   | o\ |         |
|            | 109)** | (N=1  | c |        |         |   | (N |         |
|            |        | 06)** | e |        |         |   | =8 |         |
|            |        |       | b |        |         |   | 0) |         |
|            |        |       | o |        |         |   | ** |         |
|            |        |       | \ |        |         |   |    |         |
|            |        |       | ( |        |         |   |    |         |
|            |        |       | N |        |         |   |    |         |
|            |        |       | = |        |         |   |    |         |
|            |        |       | 1 |        |         |   |    |         |
|            |        |       | 0 |        |         |   |    |         |
|            |        |       | 8 |        |         |   |    |         |
|            |        |       | ) |        |         |   |    |         |
|            |        |       | * |        |         |   |    |         |
|            |        |       | * |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| Number of  | 85     | 81    | 7 |        | 51 (66) |   | 39 |         |
| patients   | (78)   | (76)  | 0 |        |         |   | (4 |         |
| with at    |        |       | ( |        |         |   | 9) |         |
| least      |        |       | 6 |        |         |   |    |         |
| 1 adverse  |        |       | 5 |        |         |   |    |         |
| event      |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Headache | 24     | 31    | 1 |        | 18 (23) |   | 9  |         |
|            | (22)   | (29)  | 3 |        |         |   | (1 |         |
|            |        |       | ( |        |         |   | 1) |         |
|            |        |       | 1 |        |         |   |    |         |
|            |        |       | 2 |        |         |   |    |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Nausea   | 12     | 12    | 2 |        | 5 (6)   |   | 3  |         |
|            | (11)   | (11)  | ( |        |         |   | (  |         |
|            |        |       | 2 |        |         |   | 4) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Diarrhea | 8 (7)  | 7 (7) | 8 |        | 2 (3)   |   | 2  |         |
|            |        |       | ( |        |         |   | (  |         |
|            |        |       | 7 |        |         |   | 3) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Insomnia | 7 (6)  | 5 (5) | 1 |        | 4 (5)   |   | 1  |         |
|            |        |       | ( |        |         |   | (  |         |
|            |        |       | 1 |        |         |   | 1) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Anxiety  | 7 (6)  | 11    | 2 |        | 5 (6)   |   | 1  |         |
|            |        | (10)  | ( |        |         |   | (  |         |
|            |        |       | 2 |        |         |   | 1) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > N        | 6 (6)  | 6 (6) | 2 |        | 9 (12)  |   | 2  |         |
| ervousness |        |       | ( |        |         |   | (  |         |
|            |        |       | 2 |        |         |   | 3) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | 6 (6)  | 7 (7) | 3 |        | 5 (6)   |   | 3  |         |
|  Dizziness |        |       | ( |        |         |   | (  |         |
|            |        |       | 3 |        |         |   | 4) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Rhinitis | 6 (6)  | 6 (6) | 8 |        | 6 (8)   |   | 2  |         |
|            |        |       | ( |        |         |   | (  |         |
|            |        |       | 7 |        |         |   | 3) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Hy       | 5 (5)  | 8 (8) | 2 |        | 1 (1)   |   | 1  |         |
| pertension |        |       | ( |        |         |   | (  |         |
|            |        |       | 2 |        |         |   | 1) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| > Anorexia | 1 (1)  | 5 (5) | 1 |        | 2 (3)   |   | 2  |         |
|            |        |       | ( |        |         |   | (  |         |
|            |        |       | 1 |        |         |   | 3) |         |
|            |        |       | ) |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+
| >          | 1 (1)  | 5 (5) | 0 |        | 0       |   | 0  |         |
| Somnolence |        |       |   |        |         |   |    |         |
+------------+--------+-------+---+--------+---------+---+----+---------+

**Table 39:** **Adverse Events Occurring in 5% of PROVIGIL-Treated
Patients and at a Greater Percentage Than in Placebo-Treated Patients in
Individual Principal Studies\
(Safety Analysis Set)****\
(Continued)**

+--------------+------------+---------+-----------+---------+--------+
|              | **Study    |         | **Study   |         |        |
|              | 305**      |         | 306**     |         |        |
+--------------+------------+---------+-----------+---------+--------+
| **SWSD**     | *          | **P     | **        | **PR    | **Pl   |
|              | *PROVIGIL\ | lacebo\ | PROVIGIL\ | OVIGIL\ | acebo\ |
|              | 200 mg\    | (N      | 200 mg\   | 300 mg\ | (N     |
|              | (N=96)**   | =108)** | (N=87)**  | (       | =86)** |
|              |            |         |           | N=90)** |        |
+--------------+------------+---------+-----------+---------+--------+
| Number of    | 64 (67)    | 68 (63) | 59 (68)   | 67 (74) | 50     |
| patients     |            |         |           |         | (58)   |
| with at      |            |         |           |         |        |
| least        |            |         |           |         |        |
| 1 adverse    |            |         |           |         |        |
| event        |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| > Headache   | 25 (26)    | 21 (19) | 15 (17)   | 23 (26) | 16     |
|              |            |         |           |         | (19)   |
+--------------+------------+---------+-----------+---------+--------+
| > Nausea     | 9 (9)      | 3 (3)   | 5 (6)     | 17 (19) | 4 (5)  |
+--------------+------------+---------+-----------+---------+--------+
| >            | 6 (6)      | 1 (\<1) | 3 (3)     | 9 (10)  | 2 (2)  |
|  Nervousness |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| > Insomnia   | 6 (6)      | 0       | 8 (9)     | 4 (4)   | 2 (2)  |
+--------------+------------+---------+-----------+---------+--------+
| > Infection  | 6 (6)      | 11 (10) | 4 (5)     | 2 (2)   | 3 (3)  |
+--------------+------------+---------+-----------+---------+--------+
| > Pain       | 6 (6)      | 2 (2)   | 0         | 3 (3)   | 4 (5)  |
| > abdomen    |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| > Accidental | 6 (6)      | 9 (8)   | 0         | 6 (7)   | 0      |
| > injury     |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| > Dry mouth  | 5 (5)      | 4 (4)   | 0         | 4 (4)   | 4 (5)  |
+--------------+------------+---------+-----------+---------+--------+
| > Tooth      | 5 (5)      | 1 (\<1) | 2 (2)     | 1 (1)   | 0      |
| > disorder   |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| > Diarrhea   | 3 (3)      | 4 (4)   | 3 (3)     | 7 (8)   | 4 (5)  |
+--------------+------------+---------+-----------+---------+--------+
| > Dizziness  | 2 (2)      | 3 (3)   | 0         | 6 (7)   | 4 (5)  |
+--------------+------------+---------+-----------+---------+--------+
| > Anorexia   | 2 (2)      | 1 (\<1) | 3 (3)     | 5 (6)   | 0      |
+--------------+------------+---------+-----------+---------+--------+
| > Sinusitis  | 3 (3)      | 1 (\<1) | 5 (6)     | 3 (3)   | 4 (5)  |
+--------------+------------+---------+-----------+---------+--------+
| > Flu        | 2 (2)      | 4 (4)   | 7 (8)     | 5 (6)   | 1 (1)  |
| > syndrome   |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| >            | 1 (1)      | 2 (2)   | 6 (7)     | 4 (4)   | 5 (6)  |
|  Pharyngitis |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| >            | 1 (1)      | 0       | 3 (3)     | 6 (7)   | 0      |
| Hypertension |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| > Cough      | 0          | 1 (\<1) | 4 (5)     | 1 (1)   | 1 (1)  |
| > increased  |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+
| >            | 0          | 0       | 4 (5)     | 1 (1)   | 2 (2)  |
|  Periodontal |            |         |           |         |        |
| > abscess    |            |         |           |         |        |
+--------------+------------+---------+-----------+---------+--------+

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

[]{#__RefHeading___Toc49234397 .anchor}Table 40: Adverse Events
Occurring in 5% of PROVIGIL-Treated Patients and at a Greater Percentage
Than in Placebo-Treated Patients in the Principal Studies by Disorder of
Sleep and Wakefulness\
(Safety Analysis Set)

+-----------+----------+-------+----------+-------+----------+------+
| **\       | **Number |       |          |       |          |      |
| \         | (%) of   |       |          |       |          |      |
| \         | pa       |       |          |       |          |      |
| Adverse   | tients** |       |          |       |          |      |
| event**   |          |       |          |       |          |      |
+-----------+----------+-------+----------+-------+----------+------+
|           | **Narc   |       | *        |       | **SWSD** |      |
|           | olepsy** |       | *OSAHS** |       |          |      |
+-----------+----------+-------+----------+-------+----------+------+
|           | **All    | *     | **All    | *     | **All    | **P  |
|           | PR       | *Plac | PR       | *Plac | PR       | lace |
|           | OVIGIL** | ebo** | OVIGIL** | ebo** | OVIGIL** | bo** |
|           |          |       |          |       |          |      |
|           | **(      | *     | **(      | *     | **(      | **(  |
|           | N=369)** | *(n=1 | N=292)** | *(n=1 | N=273)** | n=19 |
|           |          | 85)** |          | 88)** |          | 4)** |
+-----------+----------+-------+----------+-------+----------+------+
| Headache  | 183 (50) | 74    | 73 (25)  | 22    | 63 (23)  | 37   |
|           |          | (40)  |          | (12)  |          | (19) |
+-----------+----------+-------+----------+-------+----------+------+
| Nausea    | 47 (13)  | 7 (4) | 29 (10)  | 5 (3) | 31 (11)  | 7    |
|           |          |       |          |       |          | (4)  |
+-----------+----------+-------+----------+-------+----------+------+
| Rhinitis  | 42 (11)  | 14    | 18 (6)   | 10    | 9 (3)    | 9    |
|           |          | (8)   |          | (5)   |          | (5)  |
+-----------+----------+-------+----------+-------+----------+------+
| Ne        | 30 (8)   | 12    | 21 (7)   | 4 (2) | 18 (7)   | 3    |
| rvousness |          | (6)   |          |       |          | (2)  |
+-----------+----------+-------+----------+-------+----------+------+
| Diarrhea  | 30 (8)   | 8 (4) | 16 (5)   | 10    | 12 (4)   | 8    |
|           |          |       |          | (5)   |          | (4)  |
+-----------+----------+-------+----------+-------+----------+------+
| Ph        | 23 (6)   | 5 (3) | 5 (2)    | 2 (1) | 11 (4)   | 7    |
| aryngitis |          |       |          |       |          | (4)  |
+-----------+----------+-------+----------+-------+----------+------+
| Dry mouth | 19 (5)   | 1     | 9 (3)    | 3 (2) | 9 (3)    | 5    |
|           |          | (\<1) |          |       |          | (3)  |
+-----------+----------+-------+----------+-------+----------+------+
| Anorexia  | 17 (5)   | 2 (1) | 8 (3)    | 3 (2) | 10 (4)   | 1    |
|           |          |       |          |       |          | (    |
|           |          |       |          |       |          | \<1) |
+-----------+----------+-------+----------+-------+----------+------+
| Dizziness | 17 (5)   | 7 (4) | 18 (6)   | 6 (3) | 8 (3)    | 7    |
|           |          |       |          |       |          | (4)  |
+-----------+----------+-------+----------+-------+----------+------+
| Flu       | 13 (4)   | 7 (4) | 10 (3)   | 5 (3) | 14 (5)   | 5    |
| syndrome  |          |       |          |       |          | (3)  |
+-----------+----------+-------+----------+-------+----------+------+
| Anxiety   | 13 (4)   | 1     | 23 (8)   | 3 (2) | 8 (3)    | 1    |
|           |          | (\<1) |          |       |          | (    |
|           |          |       |          |       |          | \<1) |
+-----------+----------+-------+----------+-------+----------+------+
| Insomnia  | 11 (3)   | 2 (1) | 16 (5)   | 2 (1) | 18 (7)   | 2    |
|           |          |       |          |       |          | (1)  |
+-----------+----------+-------+----------+-------+----------+------+
| Hyp       | 6 (2)    | 0     | 14 (5)   | 3 (2) | 10 (4)   | 0    |
| ertension |          |       |          |       |          |      |
+-----------+----------+-------+----------+-------+----------+------+

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

### Rationale for Combining Adverse Event Data From the Principal Studies

Because of the consistent adverse event profile, including categories
and types of adverse events, that was observed in the 6 individual
principal studies and across the disorders of narcolepsy, OSAHS, and
SWSD, it was determined that it was appropriate to integrate adverse
event data from the principal studies by all PROVIGIL-treated and all
placebo‑treated patients. The primary evaluation of safety (and the
remainder of the safety presentations) is therefore made on the
integrated data from 2 studies each in narcolepsy, OSAHS, and SWSD. For
specific disorders, however, targeted safety reviews were additionally
conducted as described in section 5.3.2.

### Principal Studies in Narcolepsy, OSAHS, and SWSD---Data Combined

#### Treatment Exposure in the Principal Studies

For the principal studies combined the majority of PROVIGIL-treated
patients (83%) were treated for a month or more, with few patients (5%)
treated for 3 months or more) (Table 41). Overall treatment exposure is
a reflection of the duration of the double-blind treatment periods.

[]{#__RefHeading___Toc49234398 .anchor}Table 41: Treatment Exposure in
Combined Principal Studies\
(Safety Analysis Set)

  ----------------- -------------------------- --------------------------
  **\               **Number (%) of patients** 
  Months of                                    
  exposure**                                   

                    **PROVIGIL (N=934)**       **Placebo (N=567)**

  ≥ 1               773 (82.76)                435 (76.72)

  ≥ 3               45 (4.82)                  24 (4.23)

  ≥ 6               1 (0.11)                   0
  ----------------- -------------------------- --------------------------

#### Overview of Adverse Events

Overall, in the integrated data sets from the principal studies
(double-blind treatment periods), 78% of PROVIGIL-treated patients and
67% of placebo-treated patients experienced adverse events (Table 42).
The percentage of PROVIGIL‑treated patients (30%) with treatment-related
adverse events was about twice that of placebo-treated patients (16%).
The frequency of serious adverse events was low (PROVIGIL 2%, placebo
1%), as was the frequency of withdrawals due to adverse events
(PROVIGIL 8%, placebo 3%).

[]{#__RefHeading___Toc49234399 .anchor}Table 42: Overview of Adverse
Events in the Combined Principal Studies\
(Safety Analysis Set)

  ------------------------ ----------------------- -----------------------
  **\                      **Number (%) of         
  Adverse event category** patients**              

                           **PROVIGIL**            **Placebo**

  Number of patients       934                     567

  Adverse events (AEs)     728 (78)                379 (67)

  Treated-related AEs      283 (30)                90 (16)

  Serious adverse events   17 (2)                  8 (1)

  AEs leading to           78 (8)                  15 (3)
  withdrawal                                       

  Deaths                   0                       0
  ------------------------ ----------------------- -----------------------

#### Types of Adverse Events

The most common adverse events among patients who received PROVIGIL were
headache (34%), nausea (11%), and nervousness (7%) (Table 43). In
addition to these, adverse events that occurred in at least 5% of
PROVIGIL-treated patients and more frequently with PROVIGIL treatment
than with placebo treatment were rhinitis, diarrhea, back pain,
insomnia, dyspepsia, anxiety, and dizziness. Most of the adverse events
were mild or moderate in severity (91%).

[]{#__RefHeading___Toc49234400 .anchor}Table 43: Adverse Events
Occurring in 5% of PROVIGIL-Treated Patients and at a Greater Percentage
Than in Placebo-Treated Patients in the Combined Principal Studies\
(Safety Analysis Set)

  --------------------- ------------------------ -------------------- -- --
  **Adverse event**     **Number (%) of                                  
                        patients**                                       

                        **PROVIGIL\              **Placebo\              
                        (N=934)**                (N=567)**               

  Headache              319 (34)                 133 (23)                

  Nausea                107 (11)                 19 (3)                  

  Nervousness           69 (7)                   19 (3)                  

  Rhinitis              69 (7)                   33 (6)                  

  Diarrhea              58 (6)                   26 (5)                  

  Back pain             52 (6)                   26 (5)                  

  Insomnia              45 (5)                   6 (1)                   

  Dyspepsia             44 (5)                   21 (4)                  

  Anxiety               44 (5)                   5 (\<1)                 

  Dizziness             43 (5)                   20 (4)                  
  --------------------- ------------------------ -------------------- -- --

In the integrated data sets for the principal studies, 18 serious
adverse events were reported for 17 (2%) of 934 patients who received
PROVIGIL and 9 were reported for 8 (1%) of 567 patients who received
placebo (Table 44). Only 1 serious adverse event, chest pain, was
reported by more than 1 patient in the principal studies (1 occurrence
each in PROVIGIL-treated patients in narcolepsy study 302, OSAHS study
402, and SWSD study 306). For the 17 patients with serious adverse
events in the PROVIGIL treatment group, 7 events were considered
treatment‑related: chest pain (1 of 3 reported), palpitation and
ventricular extrasystoles in 1 patient, and liver function tests
abnormal, leukopenia, dyspnea, and hypoventilation, reported as
treatment-related for 1 patient each. There were no deaths reported in
any of the principal studies.

[]{#__RefHeading___Toc49234401 .anchor}Table 44: Serious Adverse Events
in the Combined Principal Studies\
(Safety Analysis Set)

+----------------------+-----------+-----------+-----------+-----------+
| **\                  | **Number  |           |           |           |
| \                    | (%) of    |           |           |           |
| \                    | p         |           |           |           |
| Adverse event**      | atients** |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
|                      | **All     |           | *         |           |
|                      | serious   |           | *Treatmen |           |
|                      | adverse   |           | t-related |           |
|                      | events    |           | SAEs**    |           |
|                      | (SAEs)**  |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
|                      | **All     | **        | **All     | **        |
|                      | P         | Placebo** | P         | Placebo** |
|                      | ROVIGIL** |           | ROVIGIL** |           |
|                      |           | **        |           | **        |
|                      | **        | (N=567)** | **        | (N=567)** |
|                      | (N=934)** |           | (N=934)** |           |
+----------------------+-----------+-----------+-----------+-----------+
| No. of patients with | 17 (2)    | 8 (1)     | 6 (\<1)   | 0         |
| at least 1 SAE       |           |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
| Chest pain           | 3 (\<1)   | 0         | 1 (\<1)   | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Accidental overdose  | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Cellulitis           | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Hernia               | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Palpitation          | 1 (\<1)   | 0         | 1 (\<1)   | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Ventricular          | 1 (\<1)   | 0         | 1 (\<1)   | 0         |
| extrasystoles        |           |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
| Liver function tests | 1 (\<1)   | 0         | 1 (\<1)   | 0         |
| abnormal             |           |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
| Vomiting             | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Leukopenia           | 1 (\<1)   | 0         | 1 (\<1)   | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Osteomyelitis        | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Depersonalization    | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Dyspnea              | 1 (\<1)   | 0         | 1 (\<1)   | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Hypoventilation      | 1 (\<1)   | 0         | 1 (\<1)   | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Pneumonia            | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Skin carcinoma       | 1 (\<1)   | 0         | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Unintended           | 1 (\<1)   | 1 (\<1)   | 0         | 0         |
| pregnancy^a^         |           |           |           |           |
+----------------------+-----------+-----------+-----------+-----------+
| Abdominal pain       | 0         | 2 (\<1)   | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Accidental injury    | 0         | 3 (\<1)   | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Infection            | 0         | 1 (\<1)   | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Cholecystitis        | 0         | 1 (\<1)   | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+
| Urogenital neoplasia | 0         | 1 (\<1)   | 0         | 0         |
+----------------------+-----------+-----------+-----------+-----------+

^a^Pregnancies were not uniformly reported as serious adverse events.\
SAE = serious adverse event.

The overall percentage of patients who withdrew from any of the
principal studies due to adverse events is relatively low. Adverse
events leading to withdrawal from study were reported for 74 (8%) of
934 patients who received PROVIGIL and 15 (3%) of 567 patients who
received placebo (Table 45). The most frequent reasons for withdrawal
were consistent with the overall adverse event profile of PROVIGIL.

[]{#__RefHeading___Toc49234402 .anchor}Table 45: Most Common (≥5
Patients) Adverse Events Leading to Withdrawal in PROVIGIL‑Treated
Patients in Combined Principal Studies\
(Safety Analysis Set)

  ------------------------------------ ------------------ ----------------
  **\                                  **Number (%) of    
  Adverse events leading to            patients**         
  withdrawal**                                            

                                       **PROVIGIL\        **Placebo\
                                       (N=934)**          (n=567)**

  No. of patients who withdrew due to  74 (8)             15 (3)
  adverse events                                          

  Headache                             16 (2)             3 (\<1)

  Nausea                               9 (\<1)            0

  Anxiety                              9 (\<1)            0

  Dizziness                            9 (\<1)            1 (\<1)

  Insomnia                             9 (\<1)            1 (\<1)

  Chest pain                           8 (\<1)            3 (\<1)

  Nervousness                          7 (\<1)            0
  ------------------------------------ ------------------ ----------------

### Other Adverse Event Data Sets Analyzed

#### Overview of Other Adverse Event Data Sets

Presented above is an evaluation of adverse event data for PROVIGIL
treatment in patients with disorders of sleep and wakefulness made on
the basis of the 6 principal studies, 2 each in patients with narcolepsy
(studies 301 and 302), OSAHS (studies 303 and 402), and SWSD (studies
305 and 306).

Another review of the adverse event data that was undertaken involved
all studies done specifically in disorders of sleep and wakefulness (ie,
all narcolepsy, OSAHS, and SWSD studies combined, including open-label
extension periods of the principal studies and other supportive
controlled and uncontrolled studies.). This database is referred to as
"all narcolepsy, OSAHS, and SWSD studies." In total, this data set
includes data from 10 narcolepsy studies, 3 OSAHS studies, and 2 SWSD
studies.

A further review of adverse event data from adults in studies with
PROVIGIL was undertaken in any phase of clinical research and in any
indication. This database, referred to as "all studies"[^1] includes 95
studies submitted in the original NDA (14 studies conducted in the
United States \[US\] and the United Kingdom \[UK\] and 81 studies
conducted in Europe) and an additional 39 studies submitted with the
supplemental application (23 studies conducted in the US and UK and 16
studies conducted in Europe). Among the 95 studies originally submitted,
there were pharmacokinetic and pharmacodynamic studies in healthy
subjects, and controlled and uncontrolled studies in patients with
narcolepsy, OSAHS, and SWSD. There were also a number of controlled and
uncontrolled studies in patients with disorders other than narcolepsy,
OSAHS, and SWSD.

#### Treatment Exposure in All Studies in Narcolepsy, OSAHS, and SWSD

In all narcolepsy, OSAHS, and SWSD studies, for patients treated with
PROVIGIL, there were 1286 patients with narcolepsy, 485 patients with
OSAHS, and 375 patients with SWSD (Table 46). For these studies combined
(including open-label extension periods of double-blind studies), the
mean duration of exposure to PROVIGIL was 349 days (a total of 2083
patient‑years), with more than 740 patients exposed to PROVIGIL for a
year or more.

[]{#__RefHeading___Toc49234403 .anchor}Table 46: Treatment Exposure in
All Studies in Narcolepsy, OSAHS, and SWSD\
(Safety Analysis Set)

  ------------ --------------------- -------------- ------------- -------------
  **\          **Number (%) of                                    
  \            subjects/patients**                                
  Months\                                                         
  of                                                              
  exposure**                                                      

               **All narcolepsy,     **All\         **All\        **All\
               OSAHS, and SWSD       narcolepsy     OSAHS         SWSD studies\
               studies\              studies\       studies\      (N=375)**
               (n=2146)**            (N=1286)**     (N=485)**     

  ≥ 1          1778 (83)             1058 (82)      405 (84)      315 (84)

  ≥ 3          1348 (63)             778 (61)       333 (69)      237 (63)

  ≥ 6          1031 (48)             612 (48)       218 (45)      201 (54)

  ≥ 9          872 (41)              540 (42)       194 (40)      138 (37)

  ≥ 12         741 (35)              485 (38)       166 (34)      90 (24)
  ------------ --------------------- -------------- ------------- -------------

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

[**Note:**]{.smallcaps} At the time of the submission of this briefing
document, the open-label treatment period of SWSD study 305 is ongoing.
It is anticipated that patient participation in this study will end in
October. At that time, it is estimated that safety data will be
available from approximately 165 patients with SWSD exposed to PROVIGIL
for 12 months.

#### Treatment Exposure in All PROVIGIL Studies

Across all studies in all indications (in adults), there were 3598
unique subjects/patients who received PROVIGIL. The mean duration of
exposure to PROVIGIL was 220 days (a total of 2200 patient-years), with
738 patients exposed to PROVIGIL for a year or more and 309 patients
exposed for over 2 years.

[]{#__RefHeading___Toc49234404 .anchor}Table 47: Treatment Exposure in
All Studies\
(Safety Analysis Set)

  ----------------------------------- -----------------------------------
  **\                                 **Number (%) of subjects/patients**
  \                                   
  Months of exposure**                

                                      **All studies\
                                      (N=3598)**

  ≥ 1                                 2183 (61)

  ≥ 3                                 1422 (40)

  ≥ 6                                 1069 (30)

  ≥ 9                                 860 (24)

  ≥ 12                                738 (21)

  ≥ 24                                309 (9)
  ----------------------------------- -----------------------------------

#### Overview of Adverse Events Across the Three Data Sets (Principal Studies, All Studies in Narcolepsy, OSAHS, and SWSD, and All Studies)

The percentages of PROVIGIL-treated patients who experienced adverse
events were comparable among the 3 safety data sets for the principal
studies (78%); all narcolepsy, OSAHS, and SWSD studies (68%); and all
studies (64%). The percentage of patients who experienced serious
adverse events was low overall (2% to 5%). The percentage of patients
who experienced adverse events leading to withdrawal for the 3 data sets
ranged from 8% to 10% (Table 48).

[]{#__RefHeading___Toc49234405 .anchor}Table 48: Overview of Adverse
Events in the Principal Studies, in All Studies in Narcolepsy, OSAHS,
and SWSD, and in All Studies\
(Safety Analysis Set)

+---------------------+---------+--------+-------------+---+---------+---+
| **\                 | *       |        |             |   |         |   |
| \                   | *Number |        |             |   |         |   |
| \                   | (%) of  |        |             |   |         |   |
| Adverse event       | pat     |        |             |   |         |   |
| category**          | ients** |        |             |   |         |   |
+---------------------+---------+--------+-------------+---+---------+---+
|                     | **\     |        | **All       |   | **\     |   |
|                     | Pr      |        | Narcolepsy, |   | All     |   |
|                     | incipal |        | OSAHS, and  |   | st      |   |
|                     | st      |        | SWSD        |   | udies** |   |
|                     | udies** |        | studies**   |   |         |   |
+---------------------+---------+--------+-------------+---+---------+---+
|                     | **PRO   | **Pla  | *           |   | **PRO   |   |
|                     | VIGIL** | cebo** | *PROVIGIL** |   | VIGIL** |   |
+---------------------+---------+--------+-------------+---+---------+---+
| > Number of         | 934     | 567    | 2146        |   | 3796    |   |
| > patients          |         |        |             |   |         |   |
+---------------------+---------+--------+-------------+---+---------+---+
| > Adverse events    | 728     | 379    | 1470 (68)   |   | 2434    |   |
| > (AEs)             | (78)    | (67)   |             |   | (64)    |   |
+---------------------+---------+--------+-------------+---+---------+---+
| > Treatment‑related | 283     | 90     | 845 (39)    |   | 1578    |   |
| > AEs               | (30)    | (16)   |             |   | (42)    |   |
+---------------------+---------+--------+-------------+---+---------+---+
| > Serious adverse   | 17 (2)  | 8 (1)  | 99 (5)      |   | 132 (3) |   |
| > events            |         |        |             |   |         |   |
+---------------------+---------+--------+-------------+---+---------+---+
| > AEs leading to    | 78 (8)  | 15 (3) | 211 (10)    |   | 345 (9) |   |
| > withdrawal        |         |        |             |   |         |   |
+---------------------+---------+--------+-------------+---+---------+---+
| > Deaths            | 0       | 0      | 2 (\<1)     |   | 13      |   |
|                     |         |        |             |   | (\<1)   |   |
+---------------------+---------+--------+-------------+---+---------+---+

Of interest is the rate of serious adverse events for PROVIGIL-treated
patients per 100 patient‑treatment‑years in all narcolepsy, OSAHS, and
SWSD studies, which is 4.8, lower than that for placebo-treated patients
in the principal studies, which is 9.6.

None of the 13 deaths that were reported for patients who participated
in clinical studies was related to PROVIGIL treatment. Two deaths (1
accidental injury, 1 cardiomyopathy) are from the data set for all
narcolepsy, OSAHS, and SWSD studies. The causes of death were reported
as:

-   accident

-   cardiomyopathy

-   progression of amyotropic lateral sclerosis (ALS)

-   heart failure, renal function abnormal

-   syncope and dyspnea

-   myocardial infarction

-   progression of alcoholic cirrhosis

-   suicide (patient with history of attempts)

-   postoperative complications in a patient with Alzheimer's disease

-   lymphoproliferative disorder in a patient with Parkinson's disease

-   cancer progression (3 patients)

#### Adverse Events in the Principal Studies, in All Studies in Narcolepsy, OSAHS, and SWSD, and in All Studies

Consistent with the adverse event data from the principal studies data
set, the most common adverse events reported in the data set for all
narcolepsy, OSAHS, and SWSD studies and the data set for all studies
were headache (28% and 23%, respectively), nausea (10% and 9%,
respectively), and nervousness (9% and 10%, respectively) (Table 49).

[]{#__RefHeading___Toc49234406 .anchor}Table 49: Adverse Events
Occurring in 5% of PROVIGIL-Treated Patients and at a Greater Percentage
Than in Placebo-Treated Patients in the Principal Studies,\
in All Studies in Narcolepsy, OSAHS, and SWSD, and in All Studies\
(Safety Analysis Set)

  ---------------------- ------------- ------------ ------------------ -------------
  **Adverse event**      **Number (%                                   
                         of                                            
                         patients)**                                   

                         **\                        **All narcolepsy,  **\
                         Principal                  OSAHS, and SWSD    All studies**
                         studies**                  studies**          

                         **PROVIGIL\   **Placebo\   **PROVIGIL\        **PROVIGIL\
                         (N=934)**     (N=567)**    (N=2146)**         (N=3796)**

  Headache               319 (34)      133 (23)     601 (28)           881 (23)

  Nausea                 107 (11)      19 (3)       219 (10)           342 (9)

  Nervousness            69 (7)        19 (3)       195 (9)            371 (10)

  Rhinitis               69 (7)        33 (6)       188 (9)            220 (6)

  Diarrhea               58 (6)        26 (5)       123 (6)            160 (4)

  Back pain              52 (6)        26 (5)       134 (6)            150 (4)

  Insomnia               45 (5)        6 (1)        150 (7)            348 (9)

  Dyspepsia              44 (5)        21 (4)       132 (6)            163 (4)

  Anxiety                44 (5)        5 (\<1)      124 (6)            248 (7)

  Dizziness              43 (5)        20 (4)       108 (5)            158 (4)
  ---------------------- ------------- ------------ ------------------ -------------

### Adverse Events in the Principal Studies by Dose

The overall incidence of adverse events was similar for the 3 PROVIGIL
dosage groups (Table 50). There were no clear dose-related trends with
respect to the frequency of specific adverse events except for headache,
for which the incidence was higher among patients receiving 400 mg/day
of PROVIGIL (40%) compared to those receiving 200 mg/day (32%).

[]{#__RefHeading___Toc49234407 .anchor}Table 50: Adverse Events
Occurring in 5% of PROVIGIL-Treated Patients\
in the Principal Studies by Dose\
(Safety Analysis Set)

+-------------------------+-----------+---------+---------+---+---------+
|                         | **Number  |         |         |   |         |
|                         | (%) of    |         |         |   |         |
|                         | p         |         |         |   |         |
|                         | atients** |         |         |   |         |
+-------------------------+-----------+---------+---------+---+---------+
| **Adverse event**       | **P       | **PRO   | **PRO   |   | **\     |
|                         | ROVIGIL** | VIGIL** | VIGIL** |   | Pl      |
|                         |           |         |         |   | acebo** |
|                         | **200     | **300   | **400   |   |         |
|                         | mg/day**  | m       | m       |   | **(N    |
|                         |           | g/day** | g/day** |   | =567)** |
|                         | **        |         |         |   |         |
|                         | (N=477)** | **(     | **(N    |   |         |
|                         |           | N=90)** | =367)** |   |         |
+-------------------------+-----------+---------+---------+---+---------+
| No. of patients with at | 368 (77)  | 67 (74) | 289     |   | 373     |
| least 1 adverse event   |           |         | (79)    |   | (66)    |
+-------------------------+-----------+---------+---------+---+---------+
| Headache                | 151 (32)  | 23 (26) | 145     |   | 133     |
|                         |           |         | (40)    |   | (23)    |
+-------------------------+-----------+---------+---------+---+---------+
| Infection               | 53 (11)   | 2 (2)   | 42 (11) |   | 68 (12) |
+-------------------------+-----------+---------+---------+---+---------+
| Nausea                  | 50 (10)   | 17 (19) | 40 (11) |   | 19 (3)  |
+-------------------------+-----------+---------+---------+---+---------+
| Nervousness             | 32 (7)    | 9 (10)  | 28 (8)  |   | 19 (3)  |
+-------------------------+-----------+---------+---------+---+---------+
| Rhinitis                | 32 (7)    | 3 (3)   | 34 (9)  |   | 33 (6)  |
+-------------------------+-----------+---------+---------+---+---------+
| Diarrhea                | 27 (6)    | 7 (8)   | 24 (7)  |   | 26 (5)  |
+-------------------------+-----------+---------+---------+---+---------+
| Pain                    | 29 (6)    | 5 (6)   | 11 (3)  |   | 33 (6)  |
+-------------------------+-----------+---------+---------+---+---------+
| Back pain               | 25 (5)    | 4 (4)   | 23 (6)  |   | 26 (5)  |
+-------------------------+-----------+---------+---------+---+---------+
| Flu syndrome            | 22 (5)    | 5 (6)   | 10 (3)  |   | 17 (3)  |
+-------------------------+-----------+---------+---------+---+---------+
| Dyspepsia               | 25 (5)    | 4 (4)   | 15 (4)  |   | 21 (4)  |
+-------------------------+-----------+---------+---------+---+---------+
| Insomnia                | 24 (5)    | 4 (4)   | 17 (5)  |   | 6 (1)   |
+-------------------------+-----------+---------+---------+---+---------+
| Dizziness               | 17 (4)    | 6 (7)   | 20 (5)  |   | 20 (4)  |
+-------------------------+-----------+---------+---------+---+---------+
| Pharyngitis             | 18 (4)    | 4 (4)   | 17 (5)  |   | 14 (2)  |
+-------------------------+-----------+---------+---------+---+---------+
| Accidental injury       | 16 (3)    | 6 (7)   | 8 (2)   |   | 30 (5)  |
+-------------------------+-----------+---------+---------+---+---------+
| Hypertension            | 12 (3)    | 6 (7)   | 12 (3)  |   | 3 (\<1) |
+-------------------------+-----------+---------+---------+---+---------+
| Dry mouth               | 16 (3)    | 4 (4)   | 17 (5)  |   | 9 (2)   |
+-------------------------+-----------+---------+---------+---+---------+
| Anorexia                | 14 (3)    | 5 (6)   | 16 (4)  |   | 6 (1)   |
+-------------------------+-----------+---------+---------+---+---------+
| Anxiety                 | 16 (3)    | 4 (4)   | 24 (7)  |   | 5 (\<1) |
+-------------------------+-----------+---------+---------+---+---------+

**[Note:]{.smallcaps}** Narcolepsy studies 301 and 302, OSAHS studies
303 and 402, and SWSD studies 305 and 306 utilized PROVIGIL doses of 200
and/or 400 mg/day. Only SWSD study 306 utilized a PROVIGIL dose of 300
mg/day.\
OSAHS = obstructive sleep apnea/hypopnea syndrome; SWSD = shift work
sleep disorder.

### Adverse Events in the Principal Studies Over Time

In the 6 principal studies, the majority (68%) of adverse events
occurred in the first month of treatment, and the most of these adverse
events occurred in the first week of treatment (Table 51).

[]{#__RefHeading___Toc49234408 .anchor}Table 51: Cumulative Incidence of
Adverse Events (Adverse Events Occurring in 5% of Patients in Any
Treatment Group) by Time on Treatment\
in the Principal Studies\
(Safety Analysis Set)

  ---------------- ------------- ------------ ------------- ------------ ------------- ------------
                   **First week               **First month              **0 to 3      
                   of                         of                         months of     
                   treatment**                treatment**                treatment**   

  **Adverse        **PROVIGIL\   **Placebo\   **PROVIGIL\   **Placebo\   **PROVIGIL\   **Placebo\
  event**          (N=934)**     (N=567)**    (N=934)**     (N=567)**    (N=934)**     (N=567)**

  No. of patients  451 (48)      166 (29)     632 (68)      288 (51)     718 (77)      367 (65)
  with at least 1                                                                      
  adverse event                                                                        

  Headache         188 (20)      50 (9)       271 (29)      104 (18)     318 (34)      132 (23)

  Nausea           67 (7)        12 (2)       90 (10)       17 (3)       107 (11)      19 (3)

  Nervousness      49 (5)        8 (1)        62 (7)        13 (2)       69 (7)        19 (3)

  Insomnia         33 (4)        5 (\<1)      42 (4)        6 (1)        45 (5)        6 (1)

  Diarrhea         25 (3)        12 (2)       43 (5)        17 (3)       58 (6)        24 (4)

  Dry mouth        29 (3)        7 (1)        35 (4)        9 (2)        37 (4)        9 (2)

  Anxiety          25 (3)        3 (\<1)      42 (4)        5 (\<1)      44 (5)        5 (\<1)

  Dizziness        25 (3)        9 (2)        37 (4)        19 (3)       43 (5)        20 (4)

  Back pain        19 (2)        5 (\<1)      31 (3)        16 (3)       52 (6)        26 (5)

  Dyspepsia        16 (2)        11 (2)       28 (3)        17 (3)       43 (5)        21 (4)

  Anorexia         23 (2)        5 (\<1)      31 (3)        6 (1)        35 (4)        6 (1)

  Rhinitis         18 (2)        5 (\<1)      47 (5)        15 (3)       69 (7)        32 (6)
  ---------------- ------------- ------------ ------------- ------------ ------------- ------------

With prolonged exposure to PROVIGIL treatment (up to 24 months), the
overall incidence of adverse events and of the most frequently occurring
adverse events were highest within the first 3 months of treatment with
the exception of infection, which occurred at a consistent rate across
the treatment intervals (Table 52).

[]{#__RefHeading___Toc49234409 .anchor}Table 52: Incidence of Selected
Adverse Events Occurring in 5% of PROVIGIL-Treated Patients by Onset
Interval in All Narcolepsy, OSAHS, and SWSD Studies\
(Safety Analysis Set)

+----------------+-------------+-----------+-------------+------------+
| **Adverse      | **Number    |           |             |            |
| event**        | (%) of      |           |             |            |
|                | patients**  |           |             |            |
+----------------+-------------+-----------+-------------+------------+
|                | **Onset     |           |             |            |
|                | interval    |           |             |            |
|                | (months)**  |           |             |            |
+----------------+-------------+-----------+-------------+------------+
|                | **0 to 3**  | **\>3 to  | **\>6 to    | **\>12 to  |
|                |             | 6**       | 12**        | 24**       |
|                | *           |           |             |            |
|                | *(N=2146)** | **(       | *           | *          |
|                |             | N=1336)** | *(N=1024)** | *(N=753)** |
+----------------+-------------+-----------+-------------+------------+
| No. of         | 1366 (64)   | 504 (38)  | 409 (40)    | 305 (41)   |
| patients with  |             |           |             |            |
| at least 1     |             |           |             |            |
| adverse event  |             |           |             |            |
+----------------+-------------+-----------+-------------+------------+
| Headache       | 534 (25)    | 119 (9)   | 81 (8)      | 71 (9)     |
+----------------+-------------+-----------+-------------+------------+
| Nausea         | 182 (8)     | 29 (2)    | 7 (\<1)     | 9 (1)      |
+----------------+-------------+-----------+-------------+------------+
| Nervousness    | 162 (8)     | 28 (2)    | 6 (\<1)     | 13 (2)     |
+----------------+-------------+-----------+-------------+------------+
| Infection      | 157 (7)     | 80 (6)    | 86 (8)      | 71 (9)     |
+----------------+-------------+-----------+-------------+------------+
| Insomnia       | 125 (6)     | 6 (\<1)   | 9 (\<1)     | 11 (1)     |
+----------------+-------------+-----------+-------------+------------+
| Anxiety        | 97 (5)      | 15 (1)    | 11 (1)      | 4 (\<1)    |
+----------------+-------------+-----------+-------------+------------+
| Diarrhea       | 96 (4)      | 15 (1)    | 14 (1)      | 11 (1)     |
+----------------+-------------+-----------+-------------+------------+
| Hypertension   | 47 (2)      | 8 (\<1)   | 9 (\<1)     | 12 (2)     |
+----------------+-------------+-----------+-------------+------------+

OSAHS = obstructive sleep apnea/hypopnea syndrome.

### Adverse Events in the Principal Studies and in the Current PROVIGIL Labeling

Overall, the adverse event profile observed in the 6 principal studies
in the 3 disorders of sleep and wakefulness is no different from that of
the current PROVIGIL labeling for patients with EDS associated with
narcolepsy (Table 53).

[]{#__RefHeading___Toc49234410 .anchor}Table 53: Adverse Events
Occurring in 5% of PROVIGIL-Treated Patients\
Data From the Principal Studies\
Compared With Current PROVIGIL Labeling

  -------------- -------------- -------------- -------------- --------------
  **Adverse      **Number (%)                                 
  event**        of patients**                                

                 **Principal                   **Current      
                 studies**                     PROVIGIL       
                                               labeling**     

                 **PROVIGIL\    **Placebo\     **PROVIGIL\    **Placebo\
                 (N=934)**      (N=567)**      (N=369)**      (N=185)**

  Headache       319 (34)       133 (23)       183 (50)       74 (40)

  Nausea         107 (11)       19 (3)         47 (13)        7 (4)

  Nervousness    69 (7)         19 (3)         30 (8)         12 (6)

  Rhinitis       69 (7)         33 (6)         42 (11)        14 (8)

  Diarrhea       58 (6)         26 (5)         30 (8)         8 (4)

  Back pain      52 (6)         26 (5)         35 (9)         16 (9)

  Insomnia       45 (5)         6 (1)          11 (3)         2 (1)

  Dyspepsia      44 (5)         21 (4)         26 (7)         14 (8)

  Anxiety        44 (5)         5 (\<1)        13 (4)         1 (1)

  Dizziness      43 (5)         20 (4)         17 (5)         7 (4)
  -------------- -------------- -------------- -------------- --------------

## Clinical Laboratory Evaluations

Laboratory data was evaluated for mean changes, shifts (eg, from normal
to high and normal to low) and for clinically significant values, based
on criteria from the Agency (Division of Neuropharmacological Drug
Products memorandum dated 1985 \[see Table 55 and Table 56 for
criteria\]). There were no overall trends in clinical laboratory
evaluations that indicated a clinically meaningful effect of PROVIGIL.

Mean changes from baseline to the last observation for hematologic and
serum chemistry parameters were minimal in both the PROVIGIL and placebo
treatment groups in the 6 principal studies at the final visit. Mean
values for alkaline phosphatase and gamma-glutamyl-transferase (GGT) and
mean changes from baseline showed small increases with increasing
duration of exposure to PROVIGIL (all narcolepsy, OSAHS, and SWSD
studies database) (Table 54). However, these increases were not
accompanied by mean increases in SGOT, SGPT, or total bilirubin.

[]{#__RefHeading___Toc49234411 .anchor}Table 54: Mean (SD) and Mean
Change from Baseline by Time Interval\
for Alkaline Phosphatase and GGT\
(All Studies in Narcolepsy, OSAHS, and SWSD)\
(Safety Analysis Set)

  ------------------- ------------- ------------ ------------ ------------
                      **Time                                  
                      interval                                
                      (months) of                             
                      PROVIGIL                                
                      treatment**                             

  **Variable**        **0 to 3**    **\>3 to 6** **\>6 to     **\>12 to
                                                 12**         24**

  **Alkaline                                                  
  phosphatase (U/L)**                                         

  N                   1476          854          688          472

  Baseline            80.9 (24.44)  79.7 (23.23) 78.8 (21.69) 78.0 (22.11)

  Last value          84.1 (25.92)  85.1 (24.56) 85.1 (23.25) 86.9 (25.03)

  Change from         3.2 (11.95)   5.4 (11.79)  6.3 (12.89)  8.9 (14.63)
  baseline                                                    

  **GGT (U/L)**                                               

  N                   685           496          431          306

  Baseline            29.4 (27.80)  28.2 (24.14) 27.9 (23.26) 27.2 (22.88)

  Last value          35.3 (33.56)  38.0 (38.06) 39.1 (38.85) 39.6 (34.49)

  Change from         5.9 (18.86)   9.8 (26.49)  11.3 (25.93) 12.4 (18.25)
  baseline                                                    
  ------------------- ------------- ------------ ------------ ------------

GGT = gamma-glutamyl-transferase; N = number of patients with both
baseline and postbaseline observation values; OSAHS = obstructive sleep
apnea/hypopnea syndrome; SWSD = shift work sleep disorder.

The numbers of patients with shifts from normal in alkaline phosphatase
values were not notable. Shifts in GGT values from normal (at baseline)
to high were observed more frequently for patients receiving PROVIGIL
(5%, 22 of 447 patients) than for those receiving placebo (1%, 3 of 283
patients) in the 6 principal studies; however, few (5, \<1%) of the
PROVIGIL-treated patients had GGT values that met the criteria for a
clinically significant abnormality. Overall, clinically significant
abnormalities in serum chemistry values were infrequent (\<1%) for all
variables (Table 55).

[]{#__RefHeading___Toc49234412 .anchor}Table 55: Clinically Significant
Abnormal Chemistry Values\
(Principal Studies and All Narcolepsy, OSAHS, and SWSD Studies)\
(Safety Analysis Set)

+---------------+----------+------------+------------+---------------+
|               |          | **Number   |            |               |
|               |          | (%) of     |            |               |
|               |          | patients** |            |               |
+---------------+----------+------------+------------+---------------+
|               |          | **\        |            | **All         |
|               |          | \          |            | narcolepsy,   |
|               |          | Principal  |            | OSAHS, and    |
|               |          | studies**  |            | SWSD          |
|               |          |            |            | studies**     |
+---------------+----------+------------+------------+---------------+
| **Serum       | **Cr     | **         | *          | **PROVIGIL**  |
| chemistry     | iteria** | PROVIGIL** | *Placebo** |               |
| variable**    |          |            |            | **(N=1989)**  |
|               |          | *          | *          |               |
|               |          | *(N=934)** | *(N=567)** |               |
+---------------+----------+------------+------------+---------------+
| BUN (mmol/L)  | 10.71    | 7 (\<1)    | 5 (\<1)    | 19 (\<1)      |
+---------------+----------+------------+------------+---------------+
| Creatinine    | 177      | 0          | 2 (\<1)    | 2 (\<1)       |
| (mol/L)       |          |            |            |               |
+---------------+----------+------------+------------+---------------+
| Uric acid     | 506 (F)  | 7 (\<1)    | 5 (\<1)    | 16 (\<1)      |
| (mol/L)       |          |            |            |               |
+---------------+----------+------------+------------+---------------+
|               | 625 (M)  | 0          | 0          | 2 (\<1)       |
+---------------+----------+------------+------------+---------------+
| SGOT (U/L)    | 3 x UNL  | 2 (\<1)    | 5 (\<1)    | 11 (\<1)      |
+---------------+----------+------------+------------+---------------+
| SGPT (U/L)    | 3 x UNL  | 5 (\<1)    | 3 (\<1)    | 14 (\<1)      |
+---------------+----------+------------+------------+---------------+
| GGT (U/L)     | 3 x UNL  | 5 (\<1)    | 2 (\<1)    | 19 (\<1)      |
+---------------+----------+------------+------------+---------------+
| Total         | 34.2     | 0          | 4 (\<1)    | 2 (\<1)       |
| bilirubin     |          |            |            |               |
| (mol/L)       |          |            |            |               |
+---------------+----------+------------+------------+---------------+

BUN = blood urea nitrogen; GGT = gamma glutamyl transferase; OSAHS =
obstructive sleep apnea/hypopnea syndrome; SGOT = serum glutamic
oxaloacetic transaminase; SGPT = serum glutamate pyruvate transaminase;
SWSD = shift work sleep disorder; UNL = upper limit of normal (range).

Mean changes in hematology values were minimal. Clinically significant
abnormalities in hematology values were also infrequent (Table 56).

[]{#__RefHeading___Toc49234413 .anchor}Table 56: Clinically Significant
Abnormal Hematology Values\
(Principal Studies and All Narcolepsy, OSAHS, and SWSD Studies)\
(Safety Analysis Set)

+--------------+------------+------------+------------+---------------+
|              |            | **Number   |            |               |
|              |            | (%) of     |            |               |
|              |            | patients** |            |               |
+--------------+------------+------------+------------+---------------+
|              |            | **\        |            | **All         |
|              |            | \          |            | narcolepsy,   |
|              |            | Principal  |            | OSAHS, and    |
|              |            | studies**  |            | SWSD          |
|              |            |            |            | studies**     |
+--------------+------------+------------+------------+---------------+
| **Hematology | **         | **         | *          | **PROVIGIL**  |
| variable**   | Criteria** | PROVIGIL** | *Placebo** |               |
|              |            |            |            | **(N=1989)**  |
|              |            | *          | *          |               |
|              |            | *(N=934)** | *(N=567)** |               |
+--------------+------------+------------+------------+---------------+
| WBC (x       | 3.0        | 8 (\<1)    | 3 (\<1)    | 17 (\<1)      |
| 10^9^/L)     |            |            |            |               |
+--------------+------------+------------+------------+---------------+
|              | 20         | 0          | 0          | 0             |
+--------------+------------+------------+------------+---------------+
| Hemoglobin   | 115 (M)    | 3 (\<1)    | 2 (\<1)    | 4 (\<1)       |
| (g/L)        |            |            |            |               |
+--------------+------------+------------+------------+---------------+
|              | 95 (F)     | 0          | 0          | 2 (\<1)       |
+--------------+------------+------------+------------+---------------+
| Hematocrit   | \<0.37 (M) | 5 (\<1)    | 1 (\<1)    | 13 (\<1)      |
| (L/L)        |            |            |            |               |
+--------------+------------+------------+------------+---------------+
|              | \<0.32 (F) | 5 (\<1)    | 1 (\<1)    | 13 (\<1)      |
+--------------+------------+------------+------------+---------------+
| ANC (x       | 1.0        | 5 (\<1)    | 3 (\<1)    | 9 (\<1)       |
| 10^9^/L)     |            |            |            |               |
+--------------+------------+------------+------------+---------------+
| Eosinophils  | 10.0       | 19 (2)     | 10 (2)     | 36 (2)        |
| (%)          |            |            |            |               |
+--------------+------------+------------+------------+---------------+
| Platelets (x | 75         | 0          | 1 (\<1)    | 0             |
| 10^9^/L)     |            |            |            |               |
+--------------+------------+------------+------------+---------------+
|              | 700        | 0          | 1 (\<1)    | 2 (\<1)       |
+--------------+------------+------------+------------+---------------+

ANC = absolute neutrophil count; OSAHS = obstructive sleep
apnea/hypopnea syndrome; SWSD = shift work sleep disorder; WBC = white
blood cell count.

## Vital Signs

### Evaluation of Vital Signs in Patients With Narcolepsy, OSAHS, or SWSD

Mean changes in vital signs values were minimal and there were no marked
differences between the PROVIGIL treatment group and the placebo
treatment group or among the 3 patient populations (narcolepsy, OSAHS,
and SWSD) (Table 57).

[]{#__RefHeading___Toc49234414 .anchor}Table 57: Changes From Baseline
in Vital Signs Values\
(Principal Studies and All Narcolepsy, OSAHS, and SWSD Studies)\
(Safety Analysis Set)

+-----------+-------+-------+-------+-------+-------+-------+-------+
|           |       | **\   |       |       |       | **All |       |
|           |       | Prin  |       |       |       | n     |       |
|           |       | cipal |       |       |       | arcol |       |
|           |       | stud  |       |       |       | epsy, |       |
|           |       | ies** |       |       |       | O     |       |
|           |       |       |       |       |       | SAHS, |       |
|           |       |       |       |       |       | and   |       |
|           |       |       |       |       |       | SWSD  |       |
|           |       |       |       |       |       | stud  |       |
|           |       |       |       |       |       | ies** |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
|           |       | **    |       | *     |       | **    |       |
|           |       | PROVI |       | *Plac |       | PROVI |       |
|           |       | GIL** |       | ebo** |       | GIL** |       |
|           |       |       |       |       |       |       |       |
|           |       | *     |       | *     |       | **    |       |
|           |       | *(N=9 |       | *(N=5 |       | (N=16 |       |
|           |       | 34)** |       | 67)** |       | 13)** |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
| **Vital   | **S   | **    | **C   | **    | **C   | **    | **C   |
| sign      | tatis | Basel | hange | Basel | hange | Basel | hange |
| v         | tic** | ine** | from  | ine** | from  | ine** | from  |
| ariable** |       |       | basel |       | basel |       | basel |
|           |       |       | ine** |       | ine** |       | ine** |
+-----------+-------+-------+-------+-------+-------+-------+-------+
| **Heart   | N     | 902   | 902   | 551   | 551   | 1537  | 1537  |
| rate      |       |       |       |       |       |       |       |
| (bpm)**   |       |       |       |       |       |       |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
|           | Mean  | 73.2  | 0.1   | 71.7  | --0.1 | 73.0  | 1.6   |
|           | (SD)  | 9     | (1    | (1    | (1    | (1    | (1    |
|           |       | (1    | 1.14) | 0.08) | 0.06) | 0.48) | 1.51) |
|           |       | 0.74) |       |       |       |       |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
|           |       |       |       |       |       |       |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
| *         | N     | 902   | 902   | 551   | 551   | 1567  | 1567  |
| *Systolic |       |       |       |       |       |       |       |
| blood**   |       |       |       |       |       |       |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
| *         | Mean  | 123.9 | --0.3 | 124.2 | --1.3 | 123.3 | 1.6   |
| *pressure | (SD)  | (1    | (1    | (1    | (1    | (1    | (1    |
| (mmHg)**  |       | 4.53) | 3.19) | 3.92) | 2.83) | 4.44) | 3.41) |
+-----------+-------+-------+-------+-------+-------+-------+-------+
|           |       |       |       |       |       |       |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
| **        | N     | 902   | 902   | 551   | 551   | 1567  | 1567  |
| Diastolic |       |       |       |       |       |       |       |
| blood**   |       |       |       |       |       |       |       |
+-----------+-------+-------+-------+-------+-------+-------+-------+
| *         | Mean  | 77.8  | --0.4 | 78.3  | --1.0 | 77.6  | 0.9   |
| *pressure | (SD)  | (     | (     | (     | (     | (     | (     |
| (mmHg)**  |       | 9.71) | 9.11) | 9.34) | 9.03) | 9.58) | 9.66) |
+-----------+-------+-------+-------+-------+-------+-------+-------+

bpm = beats per minute; N = number of patients with both baseline and
postbaseline observation values; OSAHS = obstructive sleep
apnea/hypopnea syndrome; rpm = respirations per minute; SWSD = shift
work sleep disorder.

Vital signs measurements, including body weight, were evaluated for
clinically significant changes as determined by the Agency (Division of
Neuropharmacological Drug Products memorandum dated 1985 \[see Table 58
for criteria\]). Except for increases and decreases in body weight,
clinically significant abnormalities in vital signs were infrequent
(Table 58). In the 6 principal studies, clinically significant decreases
in body weight were more frequent in the PROVIGIL treatment group (3%)
than in the placebo treatment group (1%). This trend was most pronounced
in the OSAHS studies (7% PROVIGIL; 1% placebo).

[]{#__RefHeading___Toc49234415 .anchor}Table 58: Clinically Significant
Abnormal Vital Signs Values\
(Principal Studies and All Narcolepsy, OSAHS, and SWSD Studies)\
(Safety Analysis Set)

+--------------+--------------+----------+------------+-------------+
|              |              | **Number |            |             |
|              |              | (%) of   |            |             |
|              |              | pa       |            |             |
|              |              | tients** |            |             |
+--------------+--------------+----------+------------+-------------+
|              |              | **\      |            | **All       |
|              |              | \        |            | narcolepsy, |
|              |              | P        |            | OSAHS, and  |
|              |              | rincipal |            | SWSD        |
|              |              | s        |            | studies**   |
|              |              | tudies** |            |             |
+--------------+--------------+----------+------------+-------------+
| **Variable** | **Criteria** | **PR     | *          | *           |
|              |              | OVIGIL** | *Placebo** | *PROVIGIL** |
|              |              |          |            |             |
|              |              | **(      | *          | *           |
|              |              | N=934)** | *(N=567)** | *(N=1613)** |
+--------------+--------------+----------+------------+-------------+
| **Heart rate | 120 and      | 1 (\<1)  | 1 (\<1)    | 3 (\<1)     |
| (bpm)**      | increase 15  |          |            |             |
+--------------+--------------+----------+------------+-------------+
|              | 50 and       | 4 (\<1)  | 6 (1)      | 21 (1)      |
|              | decrease 15  |          |            |             |
+--------------+--------------+----------+------------+-------------+
|              |              |          |            |             |
+--------------+--------------+----------+------------+-------------+
| **Systolic   | 180 and      | 1 (\<1)  | 0          | 13 (\<1)    |
| BP (mmHg)**  | increase 20  |          |            |             |
+--------------+--------------+----------+------------+-------------+
|              | 90 and       | 9 (\<1)  | 3 (\<1)    | 24 (2)      |
|              | decrease 20  |          |            |             |
+--------------+--------------+----------+------------+-------------+
|              |              |          |            |             |
+--------------+--------------+----------+------------+-------------+
| **Diastolic  | 105 and      | 9 (\<1)  | 0          | 34 (2)      |
| BP (mmHg)**  | increase 15  |          |            |             |
+--------------+--------------+----------+------------+-------------+
|              | 50 and       | 7 (\<1)  | 3 (\<1)    | 19 (1)      |
|              | decrease 15  |          |            |             |
+--------------+--------------+----------+------------+-------------+
|              |              |          |            |             |
+--------------+--------------+----------+------------+-------------+
| **Weight     | Increase 7   | 10 (1)   | 5 (\<1)    | 152 (9)     |
| (kg)**       |              |          |            |             |
+--------------+--------------+----------+------------+-------------+
|              | Decrease 7   | 28 (3)   | 7 (1)      | 184 (11)    |
+--------------+--------------+----------+------------+-------------+

BP = blood pressure; bpm = beats per minute; OSAHS = obstructive sleep
apnea/hypopnea syndrome;\
SWSD = shift work sleep disorder.

### Evaluation of Blood Pressure and Heart Rate in Patients With OSAHS

It has been reported in the literature that having OSAHS is an
independent risk factor for the development of hypertension and
cardiovascular disease; therefore, further analyses of heart rate and
systolic and diastolic blood pressures were undertaken specifically in
patients with OSAHS.

Specifically, in the OSAHS principal studies, there was no clinically
relevant difference in mean systolic or diastolic blood pressure or
heart rate (Table 59).

[]{#__RefHeading___Toc49234416 .anchor}Table 59: Evaluation of Blood
Pressure and Heart Rate in Patients with OSAHS\
(OSAHS Studies 303 and 402)

  ------------------- ----------------- ---------------- -----------------
  **Parameter**       **Treatment                        
                      group**                            

                      **PROVIGIL 200    **PROVIGIL 400   **Placebo**
                      mg\               mg\              
                      (N=109)**         (N=183)**        

  **Systolic BP                                          
  (mmHg)**                                               

  Baseline mean (SD)  127.7 (13.2)      126.4 (12.4)     129.5 (12.3)

  Mean (SD) change    --1.4 (15.1)      0.3 (11.8)       --2.1 (12.8)

  **Diastolic BP                                         
  (mmHg)**                                               

  Baseline mean (SD)  80.4 (8.3)        79.7 (7.9)       80.4 (8.3)

  Mean (SD) change)   --2.0 (10.1)      0.2 (8.7)        --1.6 (8.7)

  **Heart rate                                           
  (bpm)**                                                

  Baseline mean (SD)  71.3 (10.5)       73.0 (9.9)       71.1 (9.9)

  Mean (SD) change    --0.8 (10.0)      0.3 (10.6)       0.2 (10.1)
  ------------------- ----------------- ---------------- -----------------

Mean change = mean change from baseline to the final visit.

OSAHS = obstructive sleep apnea/hypopnea syndrome.

In addition, an evaluation of high systolic and diastolic blood pressure
values based on the World Health Organisation (WHO) definition of
hypertension (SBP ≥140 mmHg and DPB ≥90 mmHg) was made utilizing data
from the 2 principal (studies 303 and 402), and a placebo‑controlled
crossover study (study 407).

The results of this evaluation show that there is no evidence of any
clinically meaningful differences between the PROVIGIL and placebo
treatment groups (Table 60).

[]{#__RefHeading___Toc49234417 .anchor}Table 60: Patients With High
Blood Pressure Values (WHO Criteria) at the Final Visit\
by Treatment Group for Patients With OSAHS\
(OSAHS Studies 303, 402, and 407)

  ------------- ---------------- ------------- ------------- ------------- ------------
  **\           **\              **Number (%)                              
  \             \                of patients**                             
  Parameter**   Criteria**                                                 

                                 **PROVIGIL\   **PROVIGIL\   **PROVIGIL\   **Placebo\
                                 200 mg/day\   400 mg/day\   combined\     (n=218)**
                                 (n=109)**     (n=214)**     (n=323)**     

  SBP (mmHg)    140 to 159       14 (13)       36 (18)       50 (16)       37 (17)
                (inclusive)                                                

                160 to 179       2 (2)         3 (1)         5 (2)         3 (1)
                (inclusive)                                                

                ≥140 and ≥10%    7 (7)         15 (7)        22 (7)        15 (7)
                change from                                                
                baseline                                                   

  DBP\          90 to 99         7 (7)         29 (14)       36 (12)       25 (12)
  (mmHg)        (inclusive)                                                

                100 to 110       1 (\<1)       5 (2)         6 (2)         1 (\<1)
                (inclusive)                                                

                ≥90 and ≥10%     3 (3)         15 (7)        18 (6)        9 (4)
                change from                                                
                baseline                                                   
  ------------- ---------------- ------------- ------------- ------------- ------------

> OSAHS = obstructive sleep apnea/hypopnea syndrome; SBP = systolic
> blood pressure; DBP = diastolic blood pressure; WHO = World Health
> Organization.

## Electrocardiography

There was no difference in the incidence of newly diagnosed
electrocardiography (ECG) findings reported for patients receiving
PROVIGIL (17% \[162 of 934 patients\]) and those receiving placebo (18%
\[102 of 567 patients\]) in the 6 principal studies.

ECG intervals including QTC interval were evaluated in the 6 principal
studies at baseline and the final visit. No trends were seen in changes
in mean interval lengths and no clinically relevant outlier values were
observed.

## Overall Summary of Safety Evaluations

The primary evaluation of the safety of PROVIGIL treatment in patients
with excessive sleepiness associated with disorders of sleep and
wakefulness was made on the basis of the 6 principal studies that
contributed data to the evaluation of efficacy above. A total of 934
patients received PROVIGIL treatment in these studies (477 patients at
200 mg/day, 90 patients at 300 mg/day, and 367 patients at 400 mg/day),
and 567 patients received placebo treatment. Of the 934 patients who
received PROVIGIL, 369 patients had excessive sleepiness associated with
narcolepsy, 292 patients had excessive sleepiness associated with OSAHS,
and 273 patients had excessive sleepiness associated with SWSD.

Supportive safety data are obtained from open-label treatment extensions
of these double-blind studies and additional controlled and uncontrolled
studies in adult patients with narcolepsy or OSAHS (all narcolepsy,
OSAHS, and SWSD studies). Across all narcolepsy, OSAHS, and SWSD studies
combined, a total of 2146 patients received PROVIGIL treatment. The mean
duration of exposure to PROVIGIL in these studies was 349 days (2083
patient-years). Over 700 patients were treated with PROVIGIL for a year
or more and more than 300 patients for more than 2 years.

In adult patients with excessive sleepiness associated with disorders of
sleep and wakefulness, the type and incidence of adverse events reported
were consistent with the known safety profile of PROVIGIL as represented
in the current product labeling. The type and incidence of adverse
events observed for all narcolepsy, OSAHS, and SWSD studies combined,
and for all studies in all indications, were similar to that observed in
the principal studies.

In the principal studies, the type and incidence of adverse events was
similar among the 3 study populations (narcolepsy, OSAHS, and SWSD),
except for headache, which was observed more frequently in patients with
narcolepsy. The overall incidence of adverse events was similar for the
3 PROVIGIL dosage groups (200, 300, and 400 mg/day). There were no clear
dose‑related trends with respect to the frequency of specific adverse
events except for headache. The majority of adverse events were mild to
moderate in severity and occurred within the first month of treatment.
The incidence of adverse events, and headache in particular, was higher
for women compared to men in both the PROVIGIL and placebo treatment
groups. There were no apparent differences in the adverse event profile
of PROVIGIL based on race (white vs nonwhite), age (65 years vs \>65
years), or body mass index (32 vs \>32).

In the principal studies, 8% of patients who received PROVIGIL treatment
and 3% of patients who received placebo treatment had adverse events
leading to withdrawal from study. In the PROVIGIL treatment group, the
most common adverse events leading to withdrawal were headache (16
patients, 2%), nausea, anxiety, dizziness, and insomnia (9 patients
each, \<1%), chest pain (8 patients, \<1%), and nervousness (7 patients,
\<1%). The incidence of serious adverse events was 2% for patients
treated with PROVIGIL and 1% for patients treated with a placebo. Six
(\<1%) patients in the PROVIGIL treatment group had serious adverse
events that were considered related to treatment.

In all narcolepsy, OSAHS, and SWSD studies combined, withdrawal due to
adverse events was reported for 10% of patients and serious adverse
events were reported for 5% of patients. Across all narcolepsy, OSAHS,
and SWSD studies combined, there were 2 patient deaths in an open‑label
extension of one of the principal placebo-controlled narcolepsy studies,
both of which were considered unrelated to study drug.

There were no overall trends in clinical laboratory evaluations of
patients receiving PROVIGIL treatment in either the principal studies or
all narcolepsy, OSAHS, and SWSD studies combined that indicate a
clinically significant effect of PROVIGIL.

In the principal studies, mean changes from baseline to the last
observation for serum chemistry parameters were minimal in both the
PROVIGIL and placebo treatment groups. The only difference between the
treatment groups was a greater mean increase from baseline in alkaline
phosphatase and GGT in the PROVIGIL treatment group compared to the
placebo treatment group. In all narcolepsy, OSAHS, and SWSD studies
combined, including long-term open-label extension periods of
double-blind studies, mean values for alkaline phosphatase and GGT and
mean changes from baseline showed small increases with increasing
duration of exposure to PROVIGIL. In both groups of studies, increases
in alkaline phosphatase and GGT were not accompanied by increases in
SGOT, SGPT, or total bilirubin. In the principal studies, the
distribution of shifts relative to the normal range for serum chemistry
variables was similar in the PROVIGIL and placebo treatment groups, with
the exception of GGT, for which there was a somewhat higher incidence of
patients with values above the normal range both at baseline and the
final visit (ie, high to high) for PROVIGIL (6%, 27 of 447 patients)
compared to placebo (3%, 8 of 283 patients), and of patients whose
values shifted from within the normal range at baseline to above the
normal range at the final visit (ie, normal to high), for which the
incidence was 5% (22 of 447 patients) for PROVIGIL and 1% (3 of 283
patients) for placebo. Five (\<1%) patients who received PROVIGIL in the
principal studies had GGT values that met the criteria for clinically
significant abnormality. Clinically significant abnormalities in serum
chemistry values were infrequent (\<1% for all variables) in both the
principal studies combined and all narcolepsy, OSAHS, and SWSD studies
combined.

In the principal studies, mean changes from baseline to the last
observation for hematology parameters were minimal in both the PROVIGIL
and placebo treatment groups, and the distribution of shifts relative to
the normal range was similar for the 2 treatment groups. Clinically
significant abnormalities in hematology values were infrequent both in
the principal studies and all narcolepsy, OSAHS, and SWSD studies
combined.

There was no evidence of clinically significant effects of PROVIGIL on
vital signs in the principal studies or for all narcolepsy, OSAHS, and
SWSD studies combined. In response to a request made by the Division of
Neuropharmacological Drug Products of the FDA at a pre‑submission
meeting with Cephalon on 9 August 2002, additional evaluations of the
effect of PROVIGIL treatment on blood pressure and heart rate in
patients with excessive sleepiness, and specifically in patients with
OSAHS were performed. The results of these additional analyses
demonstrate that chronic administration of PROVIGIL at 200 to 400 mg/day
is not associated with clinically relevant changes in blood pressure
(SBP or DBP) or HR in patients with excessive sleepiness associated with
OSAHS. No consistent effects or patterns of change in BP or HR were seen
in patients with OSAHS, whether or not the patients had evidence for a
diagnosis of hypertension and/or had elevated BP or HR at baseline.

Though there has been no evidence from postmarketing surveillance to
suggest that PROVIGIL treatment contributes to an alteration of ECG
intervals, a review of the available (electronic) ECG interval data was
undertaken in response to a specific request made by the Division of
Neuropharmacological Drug Products (9 August 2002). In a review of data
from over 90 healthy subjects treated with PROVIGIL who had ECG data
recorded during the time of the expected PROVIGIL C~max~, no evidence
was found that PROVIGIL led to clinically relevant changes in ECG
intervals. In particular, there was no evidence of prolonged ventricular
repolarization, as measured by the QTc interval. PROVIGIL doses 2 to
4 times higher than those used in efficacy studies in patient
populations had no effect on QTc intervals in healthy subjects when ECGs
were done during the time of the expected PROVIGIL C~max~. Similarly, in
patients with SWSD, there was also no evidence that chronic treatment
with PROVIGIL led to clinically relevant changes in ECG intervals.

## Safety Conclusions

The safety of PROVIGIL has been evaluated in more than 4000 healthy
subjects/patients enrolled in clinical studies. Across all studies
conducted in patients with narcolepsy, OSAHS, or SWSD, nearly
700 patients have received PROVIGIL for more than 1 year and more than
300 patients have received PROVIGIL for more than 2 years. The results
of these studies support the following conclusions for this patient
population:

-   PROVIGIL treatment is well tolerated.

-   PROVIGIL's safety profile is similar among the 3 disorders of sleep
    and wakefulness (narcolepsy, OSAHS, and SWSD).

-   PROVIGIL's safety profile for the broader indication under
    consideration is consistent with its known profile, with no new
    trends emerging.

# special considerations

## Effect on Nighttime/Daytime Sleep

Situationally appropriate sleep (ie, nighttime sleep for patients with
narcolepsy or OSAHS, daytime for patients with SWSD) was evaluated
during the double‑blind treatment periods in the principal studies in
narcolepsy (studies 301 and 302), OSAHS (studies 303 and 402), and SWSD
(study 305) using polysomnography (PSG). Results of PSG indicate that
treatment with PROVIGIL did not have an adverse effect on the sleep of
these patients. Assessments of sleep efficiency (percentage of time in
bed spent asleep), arousal index (number of arousals per hour of sleep),
and time spent awake after sleep onset showed no clinically important
difference between the PROVIGIL and placebo treatment groups in any of
the patient populations. There was also no evidence, on the basis of
these data, that PROVIGIL treatment alters the underlying disturbed
sleep.

Furthermore, in SWSD study 305 (Table 61) and study 306 (Table 62),
patient-reported (from sleep logs) sleep efficiency during the days
following the nights worked showed that treatment with PROVIGIL did not
adversely affect daytime sleep in this patient population.

[]{#__RefHeading___Toc49234418 .anchor}Table 61: Patient‑Reported Sleep
Efficiency (%) From Daytime Sleep Logs\
in SWSD Study 305

  --------------- ------------------ ------------------ ------------- ------------------ ------------------ -------------
                  **PROVIGIL\                                         **Placebo**                           
                  200 mg**                                                                                  

  **Statistic**   **Pretreatment**   **On-treatment**   **Change on   **Pretreatment**   **On-treatment**   **Change on
                                                        treatment**                                         treatment**

  n               78                 78                 78            84                 84                 84

  Mean (SD)       80.3 (19.92)       87.5 (14.39)       7.3 (18.55)   78.0 (20.67)       87.5 (14.12)       9.5 (18.32)

  Median          85.5               91.5               2.5           84.9               90.4               5.4

  Min, max        2.7, 100.0         17.4, 99.8         --34.7, 87.2  4.6, 100.0         13.9, 100.0        --26.3, 73.0
  --------------- ------------------ ------------------ ------------- ------------------ ------------------ -------------

Note: Data are for sleep efficiency during days following the night
shift worked.

SWSD = shift work sleep disorder; min = minimum; max = maximum.

[]{#__RefHeading___Toc49234419 .anchor}Table 62: Patient-Reported Sleep
Efficiency (%) From Daytime Sleep Logs in SWSD Study 306

  --------------- ------------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- -------------
                                      **PROVIGIL\                                             **PROVIGIL\                                             **Placebo**                 
                                      200 mg/day**                                            300 mg/day**                                                                        

  **Statistic**   **Pre-treatment**                 **On-\        **Change on   **Pre-\                     **On-\        **Change on   **Pre-\                     **On-\        **Change on
                                                    treatment**   treatment**   treatment**                 treatment**   treatment**   treatment**                 treatment**   treatment**

  n               34                                73            34            33                          69            33            32                          63            31

  Mean (SD)       85.07 (11.50)                     92.35 (5.99)  5.53 (10.30)  87.04 (9.72)                88.13 (12.53) 3.41 (8.16)   89.13 (8.53)                90.29 (7.66)  3.97 (8.71)

  Median          88.21                             93.17         2.15          88.72                       91.71         3.98          89.47                       91.84         2.31

  Min, max        48.7, 100.0                       70.8, 100.0   -6.4, 41.3    51.1, 100.0                 28.6, 100.0   -12.6, 30.9   67.3, 100.0                 68.9, 100.0   -8.9, 30.9
  --------------- ------------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- ------------- -------------

Note: Data are for sleep efficiency during days following the night
shift worked.

> SWSD = shift work sleep disorder; min = minimum; max = maximum.

## Effect on Nasal Continuous Positive Airway Pressure Usage in Patients With OSAHS

In the 2 OSAHS studies 303 and 402, which included 811 patients, the
effect of treatment with PROVIGIL on the usage of nCPAP therapy was
evaluated during both the double‑blind and open‑label treatment periods.
No notable changes in nCPAP therapy usage were observed either within or
between treatment groups from baseline assessments to the end of the
treatment period (ie, for either the double‑blind or open‑label
treatment periods).

In OSAHS study 303, nCPAP usage for the 327 patients (218 treated with
PROVIGIL and 109 treated with a placebo) remained constant during the
double‑blind treatment period for patients in all 3 treatment groups.
The mean pre-treatment nightly nCPAP therapy usage was 5.99 and 5.95
hours for the 200‑ and 400‑mg/day PROVIGIL treatment groups,
respectively, and 5.89 hours for the placebo treatment group. At the end
of treatment, values were 5.90, 6.01, and 5.86 hours, respectively.
During the open‑label extension period, the average nightly use of nCPAP
therapy for all patients at the time of entry was 5.88 hours, and the
average nCPAP use after 12 months of treatment was 5.40 hours. The mean
change in nCPAP usage during the open‑label extension period was
‑0.57 hours, which is above the mean duration of usage reported in the
literature.

Furthermore, in study 303, which was the larger of the 2 OSAHS studies,
assessment of the change from baseline assessments to the final visit in
RDI and oxygen saturation showed that PROVIGIL treatment had no adverse
effect on the effectiveness of the patients' nCPAP therapy (Table 63).

[]{#__RefHeading___Toc49234420 .anchor}Table 63: Mean Change From
Baseline Assessments to the Final Visit in\
Apnea‑Hypopnea Index (AHI) and Oxygen Saturation for Patients\
in OSAHS Study 303

+---------------------+---------------+---------------+--------------+
| **Parameter\        | **PROVIGIL\   | **PROVIGIL\   | **\          |
| Mean (SD)**         | 200 mg/day\   | 400 mg/day\   | Placebo\     |
|                     | (N=99)**      | (N=92)**      | (N=100)**    |
+---------------------+---------------+---------------+--------------+
| **AHI**             |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Baseline          | 4.2 (5.56)    | 4.2 (5.58)    | 5.8 (8.11)   |
+---------------------+---------------+---------------+--------------+
| > Final visit       | 5.2 (11.46)   | 4.3 (7.86)    | 7.0 (10.03)  |
+---------------------+---------------+---------------+--------------+
| > Change from       | 0.7 (11.73)   | 0.2 (4.78)    | 1.1 (9.54)   |
| > baseline          |               |               |              |
+---------------------+---------------+---------------+--------------+
| **Lowest oxygen     |               |               |              |
| saturation**        |               |               |              |
+---------------------+---------------+---------------+--------------+
| > Baseline          | 91.0 (3.70)   | 90.7 (3.46)   | 90.1 (5.53)  |
+---------------------+---------------+---------------+--------------+
| > Final visit       | 89.6 (8.01)   | 89.6 (8.61)   | 89.4 (7.22)  |
+---------------------+---------------+---------------+--------------+
| > Change from       | --1.3 (7.90)  | --1.3 (8.23)  | --0.8 (6.57) |
| > baseline          |               |               |              |
+---------------------+---------------+---------------+--------------+

> AHI = apnea‑hypopnea index.

In OSAHS study 402, nCPAP usage was evaluated for 157 patients
(77 treated with PROVIGIL and 80 treated with a placebo). The mean
pretreatment nightly nCPAP therapy use in the PROVIGIL‑treated group and
the placebo‑treated group was 6.35 and 6.20 hours, respectively. Similar
values were observed at posttreatment, with mean nightly nCPAP therapy
use of 6.15 hours and 6.18 hours in the PROVIGIL‑treated group and the
placebo‑treated groups, respectively. During the open‑label extension
period, the average nightly usage of nCPAP therapy at the time of entry
was 6.28 hours, and the average nCPAP usage at the end of the treatment
period was 5.94 hours (mean change of 0.34 hours).

## Effect on Circadian Phase in Patients With SWSD

In order to assess the effect of PROVIGIL treatment on circadian phase,
in SWSD study 305, saliva samples from participating patients were
collected and melatonin concentrations analyzed. The main variable for
the melatonin analysis was DLMO (dim light melatonin onset), defined as
the time point when salivary melatonin levels rise to and are sustained
above 3 pg/ml in saliva. If the calculation of DLMO was not possible,
DLMOff (dim light melatonin offset), defined as the time point when
salivary melatonin levels decreased to 3 pg/ml, was calculated for that
patient. Melatonin midpoint was derived by adding 6 hours to DLMO or
subtracting 6 hours from DLMOff.

The mean change from baseline to the last postbaseline visit in the DLMO
was 1.0 hours for patients in the PROVIGIL treatment group versus
--0.1 hour for patients in the placebo treatment group. However, the 95%
confidence interval for the difference between the mean change from
baseline was --0.324 to 2.536 indicating a minimal difference in DLMO
phase change between treatment groups. There were also no significant
differences for change based on DLMOff or melatonin midpoint between
treatment groups.

The results of this analysis suggest that treatment with 200 mg of
PROVIGIL in patients with ES associated with SWSD does not affect
circadian adaptation to shift work schedules. These findings support the
conclusion that the ability of PROVIGIL to treat symptoms of ES in
patients with SWSD is a result of improvement in wakefulness, similar to
that demonstrated in other models of sleep and wakefulness and not due
to differentially affecting circadian adaptation.

The finding that some patients had DLMOffs, but not DLMOs, suggests that
there was a small population of patients that showed some degree of
circadian adaptation before treatment with PROVIGIL or placebo. However,
whether or not a patient showed circadian adaptation before treatment
with the study drug, treatment with PROVIGIL did not lead to a
meaningful change in circadian phase from baseline or compared to
placebo.

# Benefit/risk assessment

Excessive sleepiness associated with disorders of sleep and wakefulness
can be disabling. The ES experienced by patients with these disorders
affects their quality of life and their ability to participate in
desired waking activities (e.g., work or school), and may represent a
safety risk, not only for the patient but for society in general. For
these patients, improving wakefulness (or decreasing ES) is important to
allow adequate functioning at home, in the workplace, and while
commuting to and from work.

PROVIGIL treatment improves wakefulness equally in patients with ES
associated with disorders of sleep and wakefulness, regardless of the
underlying disorder. The clinical benefits of PROVIGIL have been
established in multiple clinical studies using multiple measures, both
objective and subjective in nature. Across all disorders and within a
disorder, there were statistically significant improvements with
PROVIGIL treatment in mean sleep latency as measured by either MWT or
MSLT and these improvements were maintained over the course of
treatment. Statistically significant improvements in subjectively
reported sleepiness were seen in all studies, and PROVIGIL-treated
patients showed significant improvement on the basis of clinical
impression (CGI-C). PROVIGIL treatment also improves the behavioral
consequences of ES. The results of the PVT and SCPT demonstrate the
positive effect of PROVIGIL treatment on sustained alertness and
vigilance. The results of the studies also support the conclusion that
PROVIGIL can have a clinically meaningful impact on some aspects of
quality of life for these patients.

Across all disorders of sleep and wakefulness studied, PROVIGIL was
generally well tolerated, and the adverse events seen have been
generally innocuous. The most common adverse events reported in clinical
studies were headache, nervousness, nausea, and insomnia. Most of these
adverse events were mild to moderate in severity and occurred within the
first month of PROVIGIL treatment. PROVIGIL appears to be well tolerated
with long-term use, with no new patterns of adverse events observed.
PROVIGIL tablets have been marketed in the US since 1999, with
approximately 140,000 patient-treatment years of exposure. The safety
profile observed with PROVIGIL in postmarketing surveillance is similar
to that seen in clinical studies, and the safety profile as it applies
to the broader population under consideration appears to be no different
than the safety profile as outlined in the current PROVIGIL labeling.

On the basis of extensive clinical research, the benefits of PROVIGIL
treatment clearly exceed its risks. Furthermore, PROVIGIL treatment is
seen as fulfilling an unmet need for improving wakefulness in patients
with ES associated with disorders of sleep and wakefulness.

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[]{#__RefHeading___Toc49234351 .anchor}Appendix 1\
International Classification of Sleep Disorders\
Classification Outline

**INTERNATIONAL CLASSIFICATION OF SLEEP DISORDERS\
Classification Outline**

1.  DYSSOMNIAS

    A.  Intrinsic Sleep Disorders

```{=html}
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```
1.  Psychophysiologic Insomnia 307.42-0

2.  Sleep State Misperception 307.49-1

3.  Idiopathic Insomnia 780.52-7

4.  Narcolepsy 347

5.  Recurrent Hypersomnia 780.54-2

6.  Idiopathic Hypersomnia 780.54-7

7.  Post-traumatic Hypersomnia 780.54-8

8.  Obstructive Sleep Apnea Syndrome 780.53-0

9.  Central Sleep Apnea Syndrome 780.51-0

10. Central Alveolar Hypoventilation Syndrome 780.51-1

11. Periodic Limb Movement Disorder 780.52-4

12. Restless Legs Syndrome 780.52-5

13. Intrinsic Sleep Disorder NOS 780.52-9

    A.  Extrinsic Sleep Disorders

```{=html}
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```
1.  Inadequate Sleep Hygiene 307.41-1

2.  Environmental Sleep Disorder 780.52-6

3.  Altitude Insomnia 289.0

4.  Adjustment Sleep Disorder 307.41-0

5.  Insufficient Sleep Disorder 307.49-4

6.  Limit-setting Sleep Disorder 307.42-4

7.  Sleep-onset Association Disorder 307.42-5

8.  Food Allergy Insomnia 780.52-2

9.  Nocturnal Eating (Drinking) Syndrome 780.52-8

10. Hypnotic-Dependent Sleep Disorder 780.52-0

11. Stimulant-Dependant Sleep Disorder 780.52-1

12. Alcohol-Dependent Sleep Disorder 780.52-3

13. Toxin-Induced Sleep Disorder 780.54-6

14. Extrinsic Sleep Disorder NOS 780.52-9

    A.  Circadian-Rhythm Sleep Disorders

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1.  Time Zone Change (Jet Lag) Syndrome 307.45-0

2.  Shift Work Sleep Disorder 307.45-1

3.  Irregular Sleep-Wake Pattern 307.45-3

4.  Delayed Sleep-Phase Syndrome 780.55-0

5.  Advanced Sleep-Phase Syndrome 780.55-1

6.  Non-24-Hour Sleep-Wake Disorder 780.55-2

7.  Circadian Rhythm sleep Disorder 780.55-9

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2.  PARASOMNIAS

    A.  Arousal Disorders

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1.  Confusional Arousals 307.46-2

2.  Sleepwalking 307.46-0

3.  Sleep Terrors 307.46-1

    A.  Sleep-Wake Transition Disorders

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1.  Rhythmic movement Disorder 307.3

2.  Sleep Starts 307.47-2

3.  Sleep Talking 307.47-3

4.  Nocturnal Leg Cramps 729.82

    A.  Parasomnias Usually Associated with REM Sleep

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1.  Nightmares 307.47-0

2.  Sleep Paralysis 780.56-2

3.  Impaired Sleep-Related Penile Erections 780.56-3

4.  Sleep-Related Painful Erections 780.56-4

5.  REM Sleep-Related Sinus Arrest 780.56-8

6.  REM Sleep Behavior Disorder 780.59-0

    A.  Other Parasomnias

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1.  Sleep Bruxism 306.8

2.  Sleep Enuresis 788.36-0

3.  Sleep-Related Abnormal Swallowing Syndrome 780.56-6

4.  Nocturnal Paroxysmal Dystonia 780.59-1

5.  Sudden Unexplained Nocturnal Death Syndrome 780.59-3

6.  Primary Snoring 786.09-1

7.  Infant Sleep Apnea 770.80

8.  Congenital Central Hypoventilation Syndrome 770.81

9.  Sudden Infant Death Syndrome 798.0

10. Benign Neonatal Sleep Myoclonus 780.59-5

11. Other Parasomnia NOS 780.59-9

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3.  SLEEP DISORDERS ASSOCIATED WITH MENTAL, NEUROLOGIC, OR OTHER MEDICAL
    DISORDERS

    A.  Associated with Mental Disorders 290-319

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1.  Psychoses 290-299

2.  Mood Disorders 296-301,311

3.  Anxiety Disorders 300,308,309

4.  Panic Disorders 300

5.  Alcoholism 303,305

    A.  Associated with Neurologic Disorders

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1.  Cerebral Degenerative Disorders 320-389

2.  Dementia 330-337

3.  Parkinsonism 331

4.  Fatal Familial Insomnia 332

5.  Sleep-Related Epilepsy 337.9

6.  Electrical Status Epilepticus of Sleep 345.8

7.  Sleep-Related Headaches 346

    A.  Associated with Other Medical Disorders

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1.  Sleeping Sickness 086

2.  Nocturnal Cardiac Ischemia 411-414

3.  Chronic Obstructive Pulmonary Disease 490-496

4.  Sleep-Related Asthma

5.  Sleep-Related Gastroesophageal Reflux

6.  Peptic Ulcer Disease

7.  Fibromyalgia

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4.  PROPOSED SLEEP DISORDERS

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1.  Short Sleeper 307.49-0

2.  Long Sleeper 307.49-2

3.  Subwakefulness Syndrome 307.47-1

4.  Fragmentary Myoclonus 780.59-7

5.  Sleep Hyperhidrosis 780.8

6.  Menstrual-Associated Sleep Disorder 780.54-3

7.  Pregnancy-Associated Sleep Disorder 780.59-6

8.  Terrifying Hypnagogic Hallucinations 307.47-4

9.  Sleep-Related Neurogenic Tachypnea 780.53-2

10. Sleep-Related Laryngospasm 780.59-4

11. Sleep Choking Syndrome 307.42-1

[]{#__RefHeading___Toc49234352 .anchor}Appendix 2\
International Classification of Sleep Disorders\
Diagnostic Criteria

**Diagnostic Criteria**

**Diagnostic Criteria: Narcolepsy (347)**

A.  A patient has a compliant of excessive sleepiness or sudden muscle
    weakness.

B.  Recurrent daytime naps or lapses into sleep occur almost daily for
    at least 3 months.

C.  Sudden bilateral loss of postural muscle tone occurs in association
    with intense emotion (cataplexy).

D.  Associated features include

> 1\. Sleep paralysis
>
> 2\. Hypnagogic hallucinations
>
> 3\. Automatic behaviors
>
> 4\. Disrupted major sleep episode

E.  Polysomnograpy demonstrates 1 or more of the following:

> 1\. Sleep latency less than 10 minutes
>
> 2\. REM sleep latency less than 20 minutes and
>
> 3\. An MSLT that demonstrates a mean sleep latency of less than 5
> minutes
>
> and
>
> 4\. Two or more sleep-onset REM periods

F.  HLA typing demonstrates DQB1\*0602 or DR2 positivity.

G.  No medical or mental disorder accounts for symptoms.

H.  Other sleep disorders (eg, periodic limb movement disorder or
    central sleep apnea syndrome) may be present but are not the primary
    cause of the symptoms.

Minimum Criteria: B plus C, or A plus D plus E plus G.

**Diagnostic Criteria: Obstructive Sleep Apnea/Hypopnea Syndrome
(780.53-0)**

A.  The patient has a complaint of excessive sleepiness or insomnia.
    Occasionally, the patient may be unaware of clinical features that
    are observed by others.

B.  Frequent episodes of obstructed breathing occur during sleep.

C.  Associated features include:

> 1\. Loud snoring
>
> 2\. Morning headaches
>
> 3\. A dry mouth upon awakening
>
> 4\. Chest retraction during sleep in young children

D.  Polysomnographic monitoring demonstrates:

> 1\. More than 5 obstructive apneas, greater than 10 seconds in
> duration, per hour of sleep and 1 or more of the following:
>
> a\. Frequent arousals from sleep associated with apneas
>
> b\. Bradytachycardia
>
> c\. Arterial oxygen desaturation in association with apneic episodes
>
> 2\. MSLT may or may not demonstrate a mean sleep latency of less than
> 10 minutes.

E.  The symptoms can be associated with other medical disorders (eg,
    tonsilar enlargement).

F.  Other sleep disorders can be present (eg, periodic limb movement
    disorder or narcolepsy

*Note:* State and code obstructive sleep apnea syndrome on axis A and
causative disorders on axis C (eg, tonsilar enlargement).

Minimum Criteria: A plus B plus C.

**Diagnostic Criteria: Shift Work Sleep Disorder (307.45-1)**

A.  The patient has a primary complaint of insomnia or excessive
    sleepiness.

B.  The primary complaint is temporally associated with a work period
    (usually night work) that occurs during the habitual sleep phase.

C.  Polysomnography and the MSLT demonstrate loss of a normal sleep-wake
    pattern (ie, disturbed chronobiologic rhythmicity).

D.  No medical or mental disorder accounts for the symptoms.

E.  The symptoms do not meet criteria for any other sleep disorder
    producing insomnia or excessive sleepiness (eg, time-zone change
    \[jet lag\] syndrome).

Minimum Criteria: A plus B.

[^1]: Among the studies that were part of the original ISS database (NDA
    20-717) were 81 studies of PROVIGIL. Among the subjects/patients who
    were enrolled in these studies, some participated in 2 or more
    studies. In the summary of drug exposure for all studies in all
    indications presented in this document, only the number of unique,
    identifiable subjects/patients from the 81 studies are included in
    the denominator. However, in the summaries of adverse events
    presented for all studies in all indications, the denominator
    includes all subject exposures, ie, the number of unique subjects
    (n=3546) plus 198 additional subject-exposures (total of 3744
    subject exposures).