Trial of Effects of Oral Xyrem and Zolpidem on Sleep-Disordered Breathing in Obstructive Sleep Apnea Patients

Randomized, Placebo-Controlled Multicenter Trial of the Effects of Orally Administered Xyrem (Sodium Oxybate) and Zolpidem on Sleep-Disordered Breathing in Obstructive Sleep Apnea Patients

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).

Study Overview

• Status: Completed
• Conditions: Obstructive Sleep Apnea Syndrome
• Intervention / Treatment: Drug: Xyrem (X); Drug: Zolpidem (Z); Drug: Placebo (P); Drug: Modafinil (M)

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).

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 4G5
      • London Health Sciences Centre, Victoria Campus
• United States
  • Florida
    • St. Petersburg, Florida, United States, 33707
      • Clinical Research Group of St. Petersburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Xyrem 9 grams given in a divided dose: 4.5 g at bedtime and 4.5 g given 2.5 to 4 hours later	Drug: Xyrem (X); Xyrem (Sodium Oxybate) Oral Solution
Active Comparator: 2; Zolpidem 10 mg + placebo were given at bedtime and placebo given 2.5 to 4 hours later.	Drug: Zolpidem (Z); Zolpidem 10 mg oral tablets; Other Names: Ambien; Drug: Placebo (P); Placebo Oral Solution
Experimental: 3; 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).	Drug: Xyrem (X); Xyrem (Sodium Oxybate) Oral Solution; Drug: Modafinil (M); Modafinil Oral Tablets; Other Names: Provigil
Placebo Comparator: 4; Placebo was given at bedtime and again 2.5 to 4 hours later.	Drug: Placebo (P); Placebo Oral Solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	One night of PSG during one night of treatment each per arm.

Collaborators and Investigators

• Sponsor: Jazz Pharmaceuticals
• Investigators: Study Director: Yanping Zheng, MD, Jazz Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002 Feb 1;25(1):42-9.
• A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep. 2003 Feb 1;26(1):31-5.
• U.S. Xyrem Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med. 2004 Mar;5(2):119-23. doi: 10.1016/j.sleep.2003.11.002.
• The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol. 2003;41(2):131-5. doi: 10.1081/clt-120019128.

Study record dates

Study Major Dates

• Study Start: November 1, 2003
• Primary Completion (Actual): June 1, 2005
• Study Completion (Actual): November 1, 2005

Study Registration Dates

• First Submitted: June 29, 2004
• First Submitted That Met QC Criteria: June 30, 2004
• First Posted (Estimate): July 1, 2004

Study Record Updates

• Last Update Posted (Estimate): February 24, 2012
• Last Update Submitted That Met QC Criteria: January 20, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Sleep-disordered breathing; Obstructive sleep apnea syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Respiratory Aspiration; Apnea; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hypnotics and Sedatives; GABA Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Sleep Aids, Pharmaceutical; Central Nervous System Stimulants; GABA-A Receptor Agonists; GABA Agonists; Wakefulness-Promoting Agents; Zolpidem; Modafinil
• Other Study ID Numbers: OMC-SXB-23