Obstructive Sleep Apnea Syndrome
Conditions
Keywords
Sleep-disordered breathing, Obstructive sleep apnea syndrome
Brief summary
To study the effect of Xyrem (9 g), Xyrem (9 g) plus modafinil 200 mg administered the morning prior to Xyrem, positive control (zolpidem 10 mg), and placebo on the frequency and outcome of events of sleep-disordered breathing in patients with obstructive sleep apnea syndrome (OSAS).
Detailed description
This study will be conducted as a randomized, crossover study of the effect of Xyrem (9 g), Xyrem (9 g) plus modafinil 200 mg administered the morning prior to Xyrem, positive control (zolpidem 10 mg), and placebo on the frequency and outcome of events of sleep-disordered breathing in patients with obstructive sleep apnea syndrome (OSAS).
Interventions
DRUGXyrem (X)
Xyrem (Sodium Oxybate) Oral Solution
DRUGZolpidem (Z)
Zolpidem 10 mg oral tablets
DRUGModafinil (M)
Modafinil Oral Tablets
DRUGPlacebo (P)
Placebo Oral Solution
Sponsors
Jazz Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated an informed consent prior to beginning protocol required procedures. * Willing and able to complete the entire trial as per the protocol including 6 nights in the sleep lab. * 18 years of age or older. * Have a history of obstructive sleep apnea syndrome (as per American Academy of Sleep Medicine \[AASM\] Task Force 1999). * Apnea-Hypopnea Index(AHI): 10 to 40 inclusive, lowest O2 saturation ≥75% (see AASM Task Force 1999 criteria) * Females may be included who are surgically sterile, two years post-menopausal, or if of child-bearing potential, using a medically accepted method of birth control (e.g., barrier method with spermicide, oral contraceptive, or abstinence) and agree to continue use of this method for the duration of the trial. * In the opinion of the investigator have adequate support for the duration of the trial to include transportation to and from the trial site. In addition, if in the investigator's assessment it is clinically indicated, the patient is willing to not operate a car or heavy machinery for the duration of the trial or for as long as the investigator deems clinically indicated.
Exclusion criteria
* Have taken sodium oxybate (GHB) in the last 30 days. * Have taken any investigational therapy within the 30-day period prior to the initial screening visit for this trial. * Are routinely taking any stimulant medications, sedative hypnotics, tranquilizers, antihistamines (except for non-sedating antihistamines), benzodiazepines or clonidine at the start of the study. Patients taking anticonvulsants are not eligible to participate even if they are willing to washout anticonvulsants for the trial. * Regularly consume alcohol and are unwilling or unable to totally abstain from alcohol use for the trial duration. * Are experiencing any major illness, including unstable cardiovascular, endocrine, neoplastic, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurological, pulmonary, and/or renal disease which would place the patient at risk during the trial or compromise the objectives outlined in the protocol. * Have psychiatric disorders, major affective or psychotic disorders, or other problems that, in the investigator's opinion, would preclude the patient's participation and completion of this trial or compromise reliable representation of subjective symptoms. * Have a current or recent (within one year) history of a substance use disorder including alcohol abuse as defined by the DSM-IV. * Have a serum creatinine greater than 2.0 mg/dL, abnormal liver function tests (SGOT \[AST\] or SGPT \[ALT\] more than twice the upper limit of normal), or elevated serum bilirubin (more than 1.5 times the upper limit of normal), or pre-trial ECG results demonstrating clinically significant arrhythmias, greater than a first degree AV block or a history of myocardial infarction within the last six months. * Have an occupation that requires variable shift work or routine night shift. * Have a clinically significant history of seizure disorder either past or present, a history of clinically significant head trauma (i.e., concussion resulting in clinically significant loss of consciousness) or past invasive intracranial surgery, and are taking anticonvulsant medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Efficacy Variable Was the Mean Apnea-Hypopnea Index (AHI). | One night of PSG during one night of treatment each per arm. | The AHI was defined as the incidence(events per hour) of apnea and hypopnea events associated with sleep, determined from the overnight polysomnogram (PSG). An apnea event is characterized by a cessation in airflow lasting \>= 10 seconds, accompanied by oxygen desaturation of \>3% or arousal. An Hyponea event is characterized by a transient reduction in breathing lasting \>= 10 seconds, with clear decrease (\>50%) from baseline in the amplitude of breathing or a decrease \<50% in the amplitude of breathing accompanied by oxygen desaturation of \>3% or arousal. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| P Then X Then Z With P Then X With M Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later; then Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment). | 11 |
| X Then X With M Then P Then Z With P Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment); then Placebo was given at bedtime and again 2.5 to 4 hours later; then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later. | 12 |
| X With M Then Z With P Then X Then P Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment); then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later; then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Placebo was given at bedtime and again 2.5 to 4 hours later. | 8 |
| Z With P Then P Then X With M Then X Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later; then Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment); then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later. | 11 |
| P Then X Then P Then X With M Then Z With P Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment); then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later. | 1 |
| X Then Z With P Then X With M Then P Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later; then Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment); then Placebo was given at bedtime and again 2.5 to 4 hours later. | 3 |
| X Then Z With P Then P Then X With M Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later; then Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment). | 1 |
| X Then X Then P Then Z With P Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Placebo was given at bedtime and again 2.5 to 4 hours later; then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later. | 1 |
| X With M Then X Then P Then Z With P Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment); then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Placebo was given at bedtime and again 2.5 to 4 hours later; then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later. | 2 |
| P Then X Then Z With P Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; then Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later. | 1 |
| Z With P Then P Then X With M Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later; then Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment). | 3 |
| P Then X Placebo was given at bedtime and again 2.5 to 4 hours later; then Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later. | 1 |
| Placebo Placebo was given at bedtime and again 2.5 to 4 hours later | 1 |
| Xyrem Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later. | 1 |
| X With M Xyrem 9 g + modafinil 200 mg (Xyrem 9 g was given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later; modafinil was given at 8 am on the morning of Xyrem treatment). | 3 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 1 | 1 | 2 |
| Phase 1 | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Phase 1 | Serious Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Phase 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | P Then X Then Z With P Then X With M | X Then X With M Then P Then Z With P | X With M Then Z With P Then X Then P | Z With P Then P Then X With M Then X | P Then X Then P Then X With M Then Z With P | X Then Z With P Then X With M Then P | X Then Z With P Then P Then X With M | X Then X Then P Then Z With P | X With M Then X Then P Then Z With P | P Then X Then Z With P | Z With P Then P Then X With M | P Then X | Placebo | Xyrem | X With M |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | 50.2 years STANDARD_DEVIATION 9.59 | 50.9 years STANDARD_DEVIATION 9.63 | 46.3 years STANDARD_DEVIATION 11.39 | 49.4 years STANDARD_DEVIATION 4.44 | 50.5 years STANDARD_DEVIATION 8.45 | 49.0 years STANDARD_DEVIATION 0 | 47.3 years STANDARD_DEVIATION 6.11 | 61.0 years STANDARD_DEVIATION 0 | 42.0 years STANDARD_DEVIATION 0 | 64.0 years STANDARD_DEVIATION 18.38 | 43.0 years STANDARD_DEVIATION 0 | 59.3 years STANDARD_DEVIATION 7.77 | 63.0 years STANDARD_DEVIATION 0 | 61.0 years STANDARD_DEVIATION 0 | 36.0 years STANDARD_DEVIATION 0 | 48.0 years STANDARD_DEVIATION 7 |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 54 Participants | 10 Participants | 10 Participants | 8 Participants | 10 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 14 Participants | 0 Participants | 4 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 46 Participants | 11 Participants | 8 Participants | 5 Participants | 9 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 56 | 18 / 53 | 17 / 55 | 11 / 54 |
| serious Total, serious adverse events | 0 / 56 | 0 / 53 | 1 / 55 | 0 / 54 |
Outcome results
Primary
The Primary Efficacy Variable Was the Mean Apnea-Hypopnea Index (AHI).
The AHI was defined as the incidence(events per hour) of apnea and hypopnea events associated with sleep, determined from the overnight polysomnogram (PSG). An apnea event is characterized by a cessation in airflow lasting \>= 10 seconds, accompanied by oxygen desaturation of \>3% or arousal. An Hyponea event is characterized by a transient reduction in breathing lasting \>= 10 seconds, with clear decrease (\>50%) from baseline in the amplitude of breathing or a decrease \<50% in the amplitude of breathing accompanied by oxygen desaturation of \>3% or arousal.
Time frame: One night of PSG during one night of treatment each per arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Primary Efficacy Variable Was the Mean Apnea-Hypopnea Index (AHI). | 22.33 Apnea + Hypopnea episodes per hour | Standard Deviation 10.836 |
| Xyrem | The Primary Efficacy Variable Was the Mean Apnea-Hypopnea Index (AHI). | 18.18 Apnea + Hypopnea episodes per hour | Standard Deviation 11.28 |
| Xyrem + Modafinil | The Primary Efficacy Variable Was the Mean Apnea-Hypopnea Index (AHI). | 21.10 Apnea + Hypopnea episodes per hour | Standard Deviation 13.463 |
| Zolpidem + Placebo | The Primary Efficacy Variable Was the Mean Apnea-Hypopnea Index (AHI). | 22.71 Apnea + Hypopnea episodes per hour | Standard Deviation 10.618 |
p-value: 0.009ANOVA on ranks
p-value: 0.0244ANOVA on ranks
p-value: 0.0119ANOVA on ranks
p-value: 0.5055ANOVA on ranks
p-value: 0.3132ANOVA on ranks