Trial Comparing Effects of Xyrem Taken Orally and Modafinil With Placebo in Treating Daytime Sleepiness in Narcolepsy

Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel-Group, Multi-Center Trial Comparing the Effects of Orally Administered Xyrem (Sodium Oxybate) and Modafinil With Placebo in Treatment of Daytime Sleepiness in Narcolepsy

This study will be conducted as a randomized, double blind, double-dummy, placebo-controlled, parallel-group trial in patients diagnosed with narcolepsy. Volunteers for this trial will be required to make 5 visits over up to 14 weeks to a participating expert physician practitioner for various sleep and narcolepsy evaluations and diaries will also be collected. Participants will take assigned medications during the course of the trial. Subjects will have a 25% probability of receiving placebo for both drugs (modafinil and Xyrem). All subject volunteers must meet criteria for narcolepsy and have evidence of daytime sleepiness. Patients will not incur any personal medical expenses due to participation in this trial. The sponsor is covering all visit costs not covered by insurance and there are some funds for patient expenses such as travel.

Study Overview

• Status: Completed
• Conditions: Narcolepsy
• Intervention / Treatment: Drug: Xyrem; Drug: Modafinil (Placebo); Drug: Xyrem Placebo; Drug: Modafinil at established dose

• Study Type: Interventional
• Enrollment (Actual): 231
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Cedex 13
    • Paris, Cedex 13, France, 75651
      • Hopital Pitie Salpetriere -- Federation des Pathologies du sommeil
  • Cedex 5
    • Montpellier, Cedex 5, France, 34295
      • Centre du sommeil -- Hopital Gui de Chauliac
• Germany
  • Regensburg, Germany, 93042
    • Psychiatrische Universitätsklinik
• Switzerland
  • Zurich, Switzerland, CH-8091
    • Neurologische Poliklinik -- Universitats Spital Zurich
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Pulmonary Associates, PA
  • California
    • Fullerton, California, United States, 92835
      • St. Jude Medical Center -- Sleep Disorders Institute
    • Los Angeles, California, United States, 90048
      • Pacific Sleep Medicine Services, Inc.
    • Pasadena, California, United States, 91105
      • Neuro-Therapeutics, Inc.
    • San Diego, California, United States, 92121
      • Pacific Sleep Medicine Services, Inc.
    • Stanford, California, United States, 94305
      • Stanford Sleep Disorders Clinic
  • Florida
    • St. Petersburg, Florida, United States, 33707
      • Clinical Research Group of St. Petersburg, Inc.
  • Illinois
    • Peoria, Illinois, United States, 61603
      • Peoria Pulmonary Associates, LTD
  • Indiana
    • Danville, Indiana, United States, 46122
      • The Center for Sleep and Wake Disorders/Midwest Neurology
  • Kentucky
    • Bowling Green, Kentucky, United States, 42101
      • Graves Gilbert Clinic
    • Crestview Hills, Kentucky, United States, 41017
      • Community Research & Sleep Management Institute
    • Louisville, Kentucky, United States, 40217
      • Chest Medicine Associates DBA -- Sleep Medicine Specialists
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • The Center for Sleep & Wake Disorders
    • Elkton, Maryland, United States, 21921
      • Sleep Disorders Center -- Union Hospital of Cecil County
    • Towson, Maryland, United States, 21204
      • Sleep Medicine Associates of Maryland
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Missouri
    • St Louis, Missouri, United States, 63108
      • Washington University Sleep Center
  • New Jersey
    • Edison, New Jersey, United States, 08818
      • New Jersey Neuroscience Institute at JFK Medical Center
  • New York
    • Rochester, New York, United States, 14618
      • Sleep Disorders Center of Rochester
    • Rochester, New York, United States, 14618
      • Strong Sleep Disorders Center
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Raleigh Neurology Associates
    • Winston-Salem, North Carolina, United States, 27103
      • ALL-TRIALS Clinical Research, LLC -- Summit Sleep Disorder
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Cincinnati Clinic & Sleep Management Institute
    • Cincinnati, Ohio, United States, 45219
      • Community Research Management Associates,Inc.
    • Grove City, Ohio, United States, 43123
      • CSC Research -- Grove City Sleep Diagnostic Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • Lehigh Valley Hospital Sleep Disorders Center
    • Carlisle, Pennsylvania, United States, 17013
      • Capital Region Sleep Disorder Center
    • Lafayette Hill, Pennsylvania, United States, 19444
      • Center for Sleep Medicine
  • South Carolina
    • Charleston, South Carolina, United States, 29406-7108
      • Lowcountry Lung and Critical Care, PA
    • Columbia, South Carolina, United States, 29220
      • SleepMed of South Carolina
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • SDHRF Clinical Research Center
    • Sioux Falls, South Dakota, United States, 57105
      • Sioux Valley Clinic -- Pulmonary
    • Sioux Falls, South Dakota, United States, 57105
      • Sleep Disorders Center
  • Texas
    • Lubbock, Texas, United States, 79410
      • Bhupesh Dihenia, MD
    • San Antonio, Texas, United States, 78229
      • SLEEP WALKER -- Sleep Disorders Center & Neurodiagnostics--Lung Diagnostics, Ltd.
  • Vermont
    • Essex Junction, Vermont, United States, 05452
      • Vermont Medical Sleep Disorders Center, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA

Patients will be included in the trial if they:

• Have signed and dated an informed consent prior to beginning protocol required procedures.
• Are willing and able to complete the entire trial as described in the protocol.
• Are 18 years of age or older.
• Fulfill the International Classification of Sleep Disorders criteria for the diagnosis of narcolepsy.
• Are taking stable doses of modafinil (200 to 600 mg/day) for the treatment of daytime sleepiness for a period of three months or greater and the modafinil dose has been stable for at least 1 month prior to entering this trial
• 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

Patients will be excluded from the trial if they:

• Have received gamma-hydroxybutyrate in the last 30 days.
• Have taken any investigational therapy within the 30-day period prior to the initial screening visit (Visit 1) for this trial.
• Have sleep apnea syndrome, defined as an Apnea Index > 10 per hour or an AHI (Apnea Hypopnea Index) greater than 15 per hour, or have any other cause of daytime sleepiness, and have any other disorder(s) that can be considered a primary cause of excessive daytime sleepiness (e.g., severe periodic leg movement syndrome as determined by the investigator, sleep apnea, sleep deprivation).
• Are taking hypnotics, tranquilizers, antihistamines (except for non-sedating antihistamines), benzodiazepines or clonidine at the start of the baseline period. Patients taking anticonvulsants are not eligible to participate event if they are willing to washout anticonvulsants for the trial.
• Are experiencing any major illness, including unstable cardiovascular, endocrine, neoplastic, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurological (other than narcolepsy/cataplexy), 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: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1.; Xyrem + Modafinil Placebo	Drug: Xyrem; Xyrem oral solution at 6 g/day for 4 weeks and 9 g/day for another 4 weeks.; Other Names: Sodium Oxybate; Drug: Modafinil (Placebo); Modafinil Placebo oral capsules 1 to 3 capsules per day for 8 weeks.; Other Names: Provigil Placebo
Placebo Comparator: Group 2: Xyrem Placebo + Modafinil Placebo	Drug: Modafinil (Placebo); Modafinil Placebo oral capsules 1 to 3 capsules per day for 8 weeks.; Other Names: Provigil Placebo; Drug: Xyrem Placebo; Xyrem Placebo oral solution 12 ml per day for 4 weeks and 18 ml per day for another 4 weeks.; Other Names: Sodium Oxybate Placebo
Active Comparator: Group 3; Xyrem Placebo + Modafinil at established dose	Drug: Xyrem Placebo; Xyrem Placebo oral solution 12 ml per day for 4 weeks and 18 ml per day for another 4 weeks.; Other Names: Sodium Oxybate Placebo; Drug: Modafinil at established dose; Modafinil oral capsules at 200 to 600 mg per day for 8 weeks.; Other Names: Provigil
Experimental: Group 4: Xyrem + Modafinil at established dose	Drug: Xyrem; Xyrem oral solution at 6 g/day for 4 weeks and 9 g/day for another 4 weeks.; Other Names: Sodium Oxybate; Drug: Modafinil at established dose; Modafinil oral capsules at 200 to 600 mg per day for 8 weeks.; Other Names: Provigil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daytime Sleep Latency as Measured by the Maintenance of Wakefulness Test (MWT)	The Maintenance of Wakefulness Test consisted of four 20 minute tests of the patient's ability to remain awake in soporific conditions. The Mean change from baseline to week 8 in the average MWT number of minutes until sleep onset was the primary endpoint.	Baseline to Week 8

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.
• Scrima L, Hartman PG, Johnson FH Jr, Thomas EE, Hiller FC. The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study. Sleep. 1990 Dec;13(6):479-90. doi: 10.1093/sleep/13.6.479.
• Lammers GJ, Arends J, Declerck AC, Ferrari MD, Schouwink G, Troost J. Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep. 1993 Apr;16(3):216-20. doi: 10.1093/sleep/16.3.216.
• 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.
• Husain AM, Bujanover S, Ryan R, Scheckner B, Black J, Profant J. Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy. J Clin Sleep Med. 2020 Sep 15;16(9):1469-1474. doi: 10.5664/jcsm.8530.
• Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep. 2006 Jul;29(7):939-46. doi: 10.1093/sleep/29.7.939.
• Black J, Pardi D, Hornfeldt CS, Inhaber N. The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy. J Clin Sleep Med. 2010 Dec 15;6(6):596-602.
• Dauvilliers Y, Roth T, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate, modafinil, and their combination on disrupted nighttime sleep in narcolepsy. Sleep Med. 2017 Dec;40:53-57. doi: 10.1016/j.sleep.2017.07.030. Epub 2017 Oct 7.

Helpful Links

• Xyrem Informational website with the package insert

Study record dates

Study Major Dates

• Study Start: April 1, 2003
• Primary Completion (Actual): July 1, 2004
• Study Completion (Actual): November 1, 2004

Study Registration Dates

• First Submitted: August 4, 2003
• First Submitted That Met QC Criteria: August 5, 2003
• First Posted (Estimate): August 6, 2003

Study Record Updates

• Last Update Posted (Estimate): December 29, 2011
• Last Update Submitted That Met QC Criteria: December 21, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: Narcolepsy; Daytime Sleepiness; Daytime sleepiness in narcolepsy
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Disorders of Excessive Somnolence; Sleepiness; Narcolepsy; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Adjuvants, Anesthesia; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Central Nervous System Stimulants; Wakefulness-Promoting Agents; Modafinil; Sodium Oxybate
• Other Study ID Numbers: OMC-SXB-22