Sodium Oxybate in Schizophrenia With Insomnia

• Sponsor: Nathan Kline Institute for Psychiatric Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00594256
• Collaborator: Jazz Pharmaceuticals (Industry)
• Enrollment: 8
• Location: 1
• Arm: 1
• Duration (Months): 11
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The present protocol proposes study of the recently approved compound sodium oxybate (Xyrem), a gamma-aminobutyric acid type b (GABAB) and a g-hydroxybutyric acid (GHB) receptor agonist, for the study of persistent symptoms of schizophrenia. Sodium oxybate is a central nervous system depressant currently approved for treatment of narcolepsy associated with cataplexy and excessive daytime sleepiness. In addition to evaluating effects on sodium oxybate on persistent symptoms and neurocognitive deficits in schizophrenia, the study will test the hypothesis that this medication may be particularly effective in combating Insomnia Related to Schizophrenia, and in normalizing symptomatic and polysomnographic manifestations of sleep-related brain dysfunction in schizophrenia.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Insomnia Related to Schizophrenia (307.42)	Drug: Sodium Oxybate	Phase 2

Detailed Description

Rationale/Study Hypothesis:

Rationale for study of sodium oxybate is twofold: first, sleep dysfunction is an important and overlooked aspect of schizophrenia intrinsically linked to cognitive and functional impairments, and, second, GABAB receptors regulate dopaminergic and glutamatergic systems in vivo, suggesting that GABAB agonists may be therapeutically beneficial in schizophrenia.

We are aware of three previous trials of GHB in schizophrenia, two of which did not show any overall benefit in psychopathology. We noted multiple limitations in the controlled trials, including:

1. requirement of cumbersome dosing patterns (up to six times a day) that could have led to incomplete compliance,

2. lack of objective measures of subjective sleep or sleep architecture,

3. lack of objective cognitive testing,

4. use of GHB as monotherapy or only in conjunction with only low dose antipsychotics,

5. short trial duration (less than 4 weeks),

6. relatively low overall night-time dose of GHB, and

7. a heterogeneous, small sample.

We propose an open label, proof of concept study evaluating the effect of sodium oxybate on insomnia in schizophrenia. The primary hypothesis of the study is that patients treated with sodium oxybate will show improved subjective sleep as measured by the overall Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index. Secondarily, we expect superior reduction in total psychopathology and PANSS factor scales (PANSS), polysomnographic measures, and neurocognition (MATRICS).

Design and dosage schedule:

We plan to enroll eight hospitalized patients with diagnostic & statistical manual text revision (DSM-IV-TR) schizophrenia and insomnia related to schizophrenia. The study will include: a one-week evaluation period, which will include tapering of any hypnotics, baseline diagnostic, psychopathology, neurocognitive, electrophysiological and polysomnographic measurements. Patients will then begin a four-week trial of adjunctive sodium oxybate, with a three-week taper of sodium oxybate to follow. Hypnotic/sodium oxybate taper may be extended or abbreviated, depending on clinical judgment.

Patients entering the study will be permitted to receive both typical and atypical antipsychotics. Treating psychiatrists will be encouraged to maintain fixed doses of all psychotropic medication throughout the study.

Other than haloperidol and benztropine prn (up to 10 mg/day of haloperidol), the prescription of a new psychotropic will not be permitted. After the second week of study medication, any subject requiring more than 4 doses of haloperidol in one week will be considered to have relapsed, and will be withdrawn from the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label, Pilot Study of Adjunctive Xyrem (Sodium Oxybate) for the Treatment of Schizophrenia and Associated Sleep Disturbances
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Sodium oxybate Active treatment

Drug: Sodium Oxybate; Patients will undergo a one-week evaluation period, which will include a taper and discontinuation of any currently prescribed sedative/hypnotics, as well as baseline diagnostic, psychopathology, neurocognitive and polysomnographic measurements (see below for details). Hypnotic taper may be extended or abbreviated, depending on clinical judgment. Patients will then begin a 4-week trial of adjunctive Xyrem (sodium oxybate). Patients will begin at 4.5 g/night (in divided doses of 2.25 g, with 1st dose at bedtime and then 2nd dose four hours later). Dosage will increase by 1.5 g/day every week, until a dose of 9 g nightly is reached, or a patient cannot tolerate further dose escalations. Medication will be administered in divided dosage for the duration of the study. A three-week taper (by 3 g/day weekly) of sodium oxybate will follow the four-week trial of sodium oxybate.; Other Names: Xyrem

Outcome Measures

Primary Outcome Measures

1. Pittsburgh Sleep Quality Index [1 month]

   This rating scale generates a global sleep-quality score, as well as scores on 7 components of sleep quality: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The 19 items are combined to form seven "component" scores, each of which has a range of O-3 points. The seven component scores are then added to yield one "global" score, with a range of O-21 points, "0" indicating no difficulty and "21" indicating severe difficulties in all areas.

2. Epworth Sleepiness Scale [1 month]

   Designed to measure daytime sleepiness. 8 items rated 0-3, with higher scores associated with a greater daytime sleepiness. overall score rated 0-24, with scores greater than 10 indicating significant daytime sleepiness.

Secondary Outcome Measures

1. Positive and Negative Syndrome Scale (PANSS) Negative Factor [1 month]

   The PANSS Negative factor is a 7-item rating scale widely used in the assessment of schizophrenia. Range is 7-49 with higher scores worse

2. MATRICS Neurocognitive Battery Composite [1 month]

   This is a series of neurocognitive tests developed by the National Institute of Mental Health to evaluate medications targeting cognition in an efficient and reliable manner. It will be modified by the deletion of the social competence domain. The six domains include speed of processing, attention/vigilance, working memory, verbal learning, visual learning and reasoning/problem solving. The primary outcome will be the mean T-score (mean of six domains).

3. Slow Wave Sleep Minutes [1 month]

   Overnight sleep study: Subjects will undergo polysomnography four times during this study, on consecutive nights during the observation week and on consecutive nights at the end. Polysomnography will be performed in a modified seclusion room on the in patient unit. The first of the consecutive nights will be used for adaptation to the study conditions. Sleep was recorded between lights off (10 pm) and lights on (at 6:45 am). We aim for conditions for falling asleep as comfortable as possible under the experimental condition.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients aged 18-45 with a DSM-IV diagnosis of schizophrenia and insomnia related to schizophrenia, confirmed by a structured interview (SCID).

Exclusion Criteria:

• Lack of capacity to give informed consent (capacity is determined by a licensed member of the treatment team).

• Unstable medical illness.

• Diagnosis of restless leg syndrome, a seizure disorder, uncontrolled hypertension, unstable cardiac illness, or obstructive sleep apnea.

• Pregnancy or lack of adequate birth control.

• History of substance dependence disorder.

• Current treatment with valproic acid.

• Succinic semialdehyde dehydrogenase deficiency (SSADH).

• Persistent need for treatment with benzodiazepines, barbiturates, opiates or other sedative hypnotics.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nathan Kline Insitute for Psychiatric Research	Orangeburg	New York	United States	10962

Sponsors and Collaborators

• Nathan Kline Institute for Psychiatric Research
• Jazz Pharmaceuticals

Investigators

• Principal Investigator: Daniel C Javitt, MD PhD, Nathan Kline Institute for Psychiatric Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daniel C. Javitt, MD, PhD, Director, Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research
• ClinicalTrials.gov Identifier: NCT00594256
• Other Study ID Numbers: 07I/C36-0
• First Posted: Jan 15, 2008
• Last Update Posted: Feb 8, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Daniel C. Javitt, MD, PhD, Director, Schizophrenia Research Center, Nathan Kline Institute for Psychiatric Research: Schizophrenia; Sleep Architecture; Sodium Oxybate; Insomnia; Cognition
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Schizophrenia; Sodium Oxybate

Study Results

Participant Flow

Recruitment Details	Rockland Psychiatric Center

Arm/Group Title	Sodium Oxybate (Open Label)
Arm/Group Description	open label sodium oxybate treatment, beginning at 4.5 g/night and increasing weekly to a final dose of 9 g/night. Given in divided dose, half at bedtime and half 4 hours later (subjects were woken up)
Period Title: Overall Study
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Sodium Oxybate (Open Label)
Arm/Group Description	open label sodium oxybate treatment, beginning at 4.5 g/night and increasing weekly to a final dose of 9 g/night. Given in divided dose, half at bedtime and half 4 hours later (subjects were woken up)
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.8 (10)
Sex: Female, Male (Count of Participants)
Female	1 12.5%
Male	7 87.5%
Region of Enrollment (participants) [Number]
United States	8 100%

Outcome Measures

1. Primary Outcome

Title	Pittsburgh Sleep Quality Index
Description	This rating scale generates a global sleep-quality score, as well as scores on 7 components of sleep quality: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The 19 items are combined to form seven "component" scores, each of which has a range of O-3 points. The seven component scores are then added to yield one "global" score, with a range of O-21 points, "0" indicating no difficulty and "21" indicating severe difficulties in all areas.
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Sodium Oxybate
Arm/Group Description
Measure Participants	8
Mean (Standard Deviation) [global score]	6.1 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sodium Oxybate
	Comments	Open label baseline final paired t test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.002
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Epworth Sleepiness Scale
Description	Designed to measure daytime sleepiness. 8 items rated 0-3, with higher scores associated with a greater daytime sleepiness. overall score rated 0-24, with scores greater than 10 indicating significant daytime sleepiness.
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sodium Oxybate
Arm/Group Description
Measure Participants	8
Mean (Standard Deviation) [global score]	4.8 (4.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sodium Oxybate
	Comments	Open label baseline final paired t test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Positive and Negative Syndrome Scale (PANSS) Negative Factor
Description	The PANSS Negative factor is a 7-item rating scale widely used in the assessment of schizophrenia. Range is 7-49 with higher scores worse
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

Paired t test of baseline and final values

Arm/Group Title	Sodiumn Oxybate
Arm/Group Description
Measure Participants	8
Mean (Standard Deviation) [mean decrease in negative subscale]	2.8 (3.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sodium Oxybate
	Comments	Open label baseline final paired t test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	MATRICS Neurocognitive Battery Composite
Description	This is a series of neurocognitive tests developed by the National Institute of Mental Health to evaluate medications targeting cognition in an efficient and reliable manner. It will be modified by the deletion of the social competence domain. The six domains include speed of processing, attention/vigilance, working memory, verbal learning, visual learning and reasoning/problem solving. The primary outcome will be the mean T-score (mean of six domains).
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sodium Oxybate
Arm/Group Description
Measure Participants	8
Mean (Standard Deviation) [Composite T-score]	-.26 (3.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sodium Oxybate
	Comments	Open label baseline final paired t test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Slow Wave Sleep Minutes
Description	Overnight sleep study: Subjects will undergo polysomnography four times during this study, on consecutive nights during the observation week and on consecutive nights at the end. Polysomnography will be performed in a modified seclusion room on the in patient unit. The first of the consecutive nights will be used for adaptation to the study conditions. Sleep was recorded between lights off (10 pm) and lights on (at 6:45 am). We aim for conditions for falling asleep as comfortable as possible under the experimental condition.
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

4 pre post

Arm/Group Title	Sodium Oxybate
Arm/Group Description
Measure Participants	4
Mean (Standard Deviation) [minutes]	34.1 (26.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sodium Oxybate
	Comments	Open label baseline final paired t test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	t-test, 1 sided
	Comments

Adverse Events

Arm/Group Title	Sodium Oxybate (Open Label)
Arm/Group Description	open label sodium oxybate treatment, beginning at 4.5 g/night and increasing weekly to a final dose of 9 g/night. Given in divided dose, half at bedtime and half 4 hours later (subjects were woken up)
All Cause Mortality
	Sodium Oxybate (Open Label)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sodium Oxybate (Open Label)
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	Sodium Oxybate (Open Label)
	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)
Gastrointestinal disorders
nausea	2/8 (25%)	2
Psychiatric disorders
agitation	1/8 (12.5%)	1
Renal and urinary disorders
nocturnal enuresis	2/8 (25%)	2

Limitations/Caveats

Open Label Small sample

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.