Hypopnea, Obstructive Sleep Apnea
Conditions
Keywords
Excessive Sleepiness, Obstructive Sleep Apnea, Obstructive Sleep Hypopnea, nCPAP, Cephalon, Cephalon, Inc, NUVIGIL
Brief summary
The primary objective of this study is to determine whether treatment with Armodafinil (CEP-10953) is more effective than placebo treatment for patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (OSAHS) by measuring mean sleep latency from the Maintenance of Wakefulness Test (MWT) (30-minute version) (average of 4 naps at 0900, 1100, 1300, and 1500) and by Clinical Global Impression of Change (CGI-C) ratings (as related to general condition) at week 12, or last post-baseline visit.
Interventions
DRUGArmodafinil 250 mg/day
Armodafinil 250 mg once daily in the morning
Armodafinil 150 mg once daily in the morning
DRUGPlacebo
Matching placebo tablets once daily in the morning
Sponsors
Cephalon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Patients are included in the study if all of the following criteria are met: 1. Written informed consent is obtained. 2. The patient is an outpatient, man or woman of any ethnic origin, 18 to 65 years of age (inclusive). 3. The patient has a complaint of excessive sleepiness despite nCPAP therapy being effective and being a regular user of nCPAP therapy. 4. The patient has a current diagnosis of OSAHS according to International Classification of Sleep Disorders (ICSD) criteria. 5. The patient meets the following nCPAP therapy requirements: * Adequate education and intervention efforts to encourage nCPAP therapy use must be documented. * A patient's nCPAP therapy regimen must be stable for at least 4 weeks. * nCPAP therapy is shown to be effective, with effectiveness defined as having an apnea-hypopnea index (AHI) of 10 or less during nocturnal PSG, and, in the opinion of the investigator, nCPAP is effective therapy. * Following demonstration of effectiveness, evidence of regular nCPAP usage must be shown during a 2-week evaluation period (ie, nCPAP usage for at least 4 hours/night on at least 70% of the nights). 6. The patient is in good health as determined by a medical and psychiatric history, physical examination, ECG, and serum chemistry and hematology. 7. Women must be surgically sterile, 2 years postmenopausal, or, if of child-bearing potential, using a medically accepted method of birth control (ie, barrier method with spermicide, steroidal contraceptive \[oral, implanted, and Depo-Provera contraceptives must be used in conjunction with a barrier method\], or intrauterine device \[IUD\]) and agree to continued use of this method for the duration of the study. 8. The patient has a Clinical Global Impression of Severity of Illness (CGI-S) rating of 4 or more. 9. The patient has an ESS score of 10 or more. 10. The patient does not have any medical or psychiatric disorders that could account for the excessive sleepiness. 11. The patient is able to complete self rating scales and computer-based testing. 12. The patient is willing and able to comply with study restrictions and to attend regularly scheduled clinic visits as specified in this protocol.
Exclusion criteria
Patients are excluded from participating in this study if 1 or more of the following criteria are met: 1. has any clinically significant, uncontrolled medical or psychiatric conditions (treated or untreated) 2. has a probable diagnosis of a current sleep disorder other than OSAHS 3. consumes caffeine including coffee, tea and/or other caffeine containing beverages or food averaging more than 600 mg of caffeine per day 4. used any prescription drugs disallowed by the protocol or clinically significant use of over the-counter (OTC) drugs within 7 days before the second screening visit 5. has a history of alcohol, narcotic, or any other drug abuse as defined by the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, 4th Edition (DSM IV) 6. has a positive urine drug screen (UDS) 7. has a clinically significant deviation from normal in the physical examination 8. is a pregnant or lactating woman. (Any woman becoming pregnant during the study will be withdrawn from the study.) 9. has used an investigational drug within 1 month before the initial screening visit 10. has any disorder that may interfere with drug absorption, distribution, metabolism, or excretion (including gastrointestinal surgery) 11. has a known clinically significant drug sensitivity to stimulants or modafinil
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maintenance of Wakefulness Test (MWT) | change from baseline at 12 weeks | The MWT is an objective assessment of sleepiness that measures the ability of a subject to remain awake. Long latencies to sleep are indicative of a patient's ability to remain awake. The primary variable was the 30 minute MWT (average of 4 naps at 0900, 1100, 1300, and 1500) assessed at the last postbaseline observation. |
| Clinical Global Impression of Change (CGI-C) | change from baseline at 12 weeks | The CGI-C represents a subjective measure of the patient's global health (clinician's rating of disease severity as compared with a pretreatment evaluation as assessed by the CGI-S). The CGI-C scale (change from baseline)categories include:1=Very much improved; 2=Much improved; 3=Minimally improved; 4=No change; 5=Minimally worse; 6=Much worse; and 7=Very much worse. Severity of illness (CGI-S) was assessed at baseline includes categories: 1=Normal; 2=Borderline ill; 3=Mildly (Slightly) ill; 4=Moderately ill; 5=Markedly ill; 6=Severely ill; and 7=Among the most extremely ill patients. |
Participant flow
Recruitment details
37 centers in the US and Canada. First patient enrolled: 19 February 2004/ Last patient last visit: 6 November 2004
Pre-assignment details
3 female patients withdrew after randomization but prior to receiving study drug (1 had a protocol violation and 2 were lost to follow-up)
Participants by arm
| Arm | Count |
|---|---|
| Armodafinil 250 mg/Day Armodafinil 250 mg once daily in the morning | 131 |
| Armodafinil 150 mg/Day Armodafinil 150 mg once daily in the morning | 131 |
| Placebo Matching placebo tablets once daily | 130 |
| Total | 392 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 15 | 10 | 5 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 |
| Overall Study | Miscellaneous | 1 | 1 | 1 |
| Overall Study | Physician Decision | 2 | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 5 | 3 |
Baseline characteristics
| Characteristic | Armodafinil 250 mg/Day | Armodafinil 150 mg/Day | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 130 Participants | 131 Participants | 129 Participants | 390 Participants |
| Age Continuous | 49.1 years STANDARD_DEVIATION 8.74 | 49.3 years STANDARD_DEVIATION 9.17 | 50.1 years STANDARD_DEVIATION 9.43 | 49.5 years STANDARD_DEVIATION 9.1 |
| Region of Enrollment Canada | 14 participants | 14 participants | 14 participants | 42 participants |
| Region of Enrollment United States | 117 participants | 119 participants | 117 participants | 353 participants |
| Sex: Female, Male Female | 42 Participants | 34 Participants | 40 Participants | 116 Participants |
| Sex: Female, Male Male | 89 Participants | 97 Participants | 90 Participants | 276 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 52 / 131 | 32 / 131 | 19 / 130 |
| serious Total, serious adverse events | 1 / 131 | 3 / 131 | 0 / 130 |
Outcome results
Primary
Clinical Global Impression of Change (CGI-C)
The CGI-C represents a subjective measure of the patient's global health (clinician's rating of disease severity as compared with a pretreatment evaluation as assessed by the CGI-S). The CGI-C scale (change from baseline)categories include:1=Very much improved; 2=Much improved; 3=Minimally improved; 4=No change; 5=Minimally worse; 6=Much worse; and 7=Very much worse. Severity of illness (CGI-S) was assessed at baseline includes categories: 1=Normal; 2=Borderline ill; 3=Mildly (Slightly) ill; 4=Moderately ill; 5=Markedly ill; 6=Severely ill; and 7=Among the most extremely ill patients.
Time frame: change from baseline at 12 weeks
Population: Safety Analysis set of 392 total patients (ITT): 3 patients withdrew after randomization but prior to receiving study drug (1 had a protocol violation and 2 were lost to follow-up)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Armodafinil 250 mg/Day | Clinical Global Impression of Change (CGI-C) | 121 Participants |
| Armodafinil 150 mg/Day | Clinical Global Impression of Change (CGI-C) | 120 Participants |
| Placebo | Clinical Global Impression of Change (CGI-C) | 124 Participants |
p-value: <0.0001Cochran-Mantel-Haenszel
p-value: <0.0001Cochran-Mantel-Haenszel
Primary
Maintenance of Wakefulness Test (MWT)
The MWT is an objective assessment of sleepiness that measures the ability of a subject to remain awake. Long latencies to sleep are indicative of a patient's ability to remain awake. The primary variable was the 30 minute MWT (average of 4 naps at 0900, 1100, 1300, and 1500) assessed at the last postbaseline observation.
Time frame: change from baseline at 12 weeks
Population: Safety Analysis set of 392 total patients: 3 patients withdrew after randomization but prior to receiving study drug (1 had a protocol violation and 2 were lost to follow-up)~Full Analysis set of 365 total patients: 27 patients that had withdrawn from the study were non-evaluable for efficacy.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Armodafinil 250 mg/Day | Maintenance of Wakefulness Test (MWT) | 2.2 Minutes | Standard Deviation 8.07 |
| Armodafinil 150 mg/Day | Maintenance of Wakefulness Test (MWT) | 1.7 Minutes | Standard Deviation 6.49 |
| Placebo | Maintenance of Wakefulness Test (MWT) | -1.7 Minutes | Standard Deviation 8.59 |
p-value: 0.0001ANOVA
p-value: 0.0008ANOVA