Sleep Disordered Breathing in Gulf War Illness and the Effect of Nasal CPAP Treatment

• Sponsor: US Department of Veterans Affairs (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00252629
• Collaborator: (none)
• Enrollment: 29
• Location: 1
• Arms: 2
• Duration (Months): 60
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine any sleep disordered breathing in veterans with Gulf War Syndrome (GWS) and compare it to healthy normal asymptomatic Gulf War veterans. This study will also determine the effect of treatment with continuous positive airway pressure on veterans with Gulf War Syndrome.

1. The investigators hypothesize that sleep complaints (insomnia, un-refreshing sleep and daytime fatigue) among GWS patients are related to increased sleep fragmentation secondary to the presence of sleep disordered breathing in GWS patients.

2. The investigators hypothesize that increased collapsibility of the upper airway during sleep with the development of inspiratory flow limitation (IFL) and sleep disordered breathing causes the increased sleep fragmentation in GWS patients.

3. The investigators hypothesize that correction of IFL and sleep disordered breathing in GWS patients will result in an improvement of their sleep quality resulting in an improvement of their sleep complaints and other functional symptoms.

Condition or Disease	Intervention/Treatment	Phase
Apnea, Sleep; Chronic Fatigue Syndrome	Other: Nasal CPAP treatment during sleep	N/A

Detailed Description

Hypothesis 1: To demonstrate that compared to Gulf War Veterans without GWS, GWS patients have decreased total sleep and increased sleep fragmentation due to the presence of sleep disordered breathing

In order to accomplish this goal and subsequent goals, we will assemble two samples of Gulf War veterans. The first will be a sample of male GWS patients and the second will be a sample of male Gulf War veterans without GWS (Gulf War veteran control group).

All of the GWS patients will be registered in the Gulf War Veterans Registry. To avoid referral bias favoring the presence of IFL during sleep and sleep disordered breathing, we will enroll GWS patients by contacting them from the Registry and inviting them to participate. Gulf War veteran controls will be recruited in the same way and by advertisement. Prospective study participants will be screened on several self-report instruments to determine eligibility and assignment to the GWS group or to the Gulf War veteran control group.

Criteria for assignment to the GWS group are scores above the designated clinical cutpoint on each of three instruments measuring , fatigue, pain and cognitive dysfunction.

1. Fatigue during the preceding week will be assessed using the fatigue severity scale, a 10-item instrument measuring the level of disability related to fatigue (increasing disability rated 1-7).

2. Pain during the preceding week will be assessed using a pain visual analog scale (VAS; increasing pain rated 0-10 ).

3. Cognitive dysfunction during the preceding week, increasing difficulty with memory, ability to think, and ability to concentrate will be assessed by VAS (increasing cognitive dysfunction rated 0-10 ).

Conversely, criteria for assignment to the GW Veteran control group will require scores in the non-clinical range on each of those instruments. Every subject will have a full night polysomnogram.

Hypothesis 2: To demonstrate that the presence of IFL and sleep disordered breathing during sleep among GWS patients distinguishes them from Gulf War veterans without GWS

A second sleep study will be used to accomplish this second objective. Using precise methods, we will quantify the prevalence of IFL during sleep in GWS patients and in Gulf War veteran controls. Following completion, each study will be staged using Rechtschaffen and Kales criteria. From each study, 3 three minute periods of continuous NREM sleep (a total of approximately 120 breaths) will be randomly selected and analyzed for the prevalence of flow limited breaths. During the three minute periods, all of the breaths will be analyzed whether they occur during sleep or during brief (< 15 second) arousals.

Hypothesis 3: To demonstrate that relief of IFL during sleep and sleep disordered breathing will result in improvement of the functional symptoms of GWS patients

We will accomplish this utilizing a masked parallel group of sham-control and treatment trial of nasal continuous positive airway pressure (CPAP) in GWS patients. Functional symptoms ( fatigue, pain and cognitive dysfunction) will be assessed using validated, self-report questionnaires and daily ratings of symptoms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Inspiratory Flow Dynamics During Sleep in Gulf War Syndrome (GWS) and the Effect of Continuous Positive Airway Pressure (CPAP)
• Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Therapeutic nasal CPAP Comparing change of veterans reported outcomes before and after 3 weeks treatment of therapeutic nasal CPAP with the change on sham nasal CPAP.	Other: Nasal CPAP treatment during sleep; After documenting sleep disordered breathing, GWS subject gets randomized to receive either a therapeutic nasal CPAP or a sham nasal CPAP treatment during sleep, GWS symptoms ( fatigue, pain, and cognitive dysfunction) were assessed by a baseline questionnaires and at 3 week period whether on sham or therapeutic CPAP. The change of symptoms in each group will be compared.
Sham Comparator: Sham nasal CPAP Comparing change of symptoms and veterans reported outcomes before and after treatment of 3 weeks on sham nasal CPAP with the change on therapeutic nasal CPAP	Other: Nasal CPAP treatment during sleep; After documenting sleep disordered breathing, GWS subject gets randomized to receive either a therapeutic nasal CPAP or a sham nasal CPAP treatment during sleep, GWS symptoms ( fatigue, pain, and cognitive dysfunction) were assessed by a baseline questionnaires and at 3 week period whether on sham or therapeutic CPAP. The change of symptoms in each group will be compared.

Outcome Measures

Primary Outcome Measures

1. Change of Fatigue Symptom [3 weeks treatment with either therapeutic or sham CPAP]

   Fatigue- increasing impact was rated 1-7 using the fatigue severity scale on days 1 and 7 averaged, where 1= no fatigue and 7= severe fatigue.

2. The Prevalence of Inspiratory Flow Limitation (IFL) During Sleep in GWS. [On a full night polysomnogram]

   IFL was determined by plotting inspiratory flow against supra-glottic pressure for each breath sampled during continuous stage 2 sleep on a full night polysomnogram on both veterans with GWS and asymptomatic gulf war veterans. We expressed the prevalence of inspiratory flow limitations during sleep as the percentage of flow limited breath in the sample of both GWS and asymptomatic gulf was veterans.

Secondary Outcome Measures

1. Change of Pain Complaint [3 weeks of treatment on either therapeutic or sham nasal CPAP]

   Pain- increased level were rated 0-10 by visual analogue scale, where 0= no pain and 10= severe pain. We compared the change of pain symptom before and after treatment of either 3 weeks on therapeutic nasal CPAP or sham nasal CPAP

2. Change of Cognitive Dysfunction [3 weeks treatment with either therapeutic or sham CPAP]

   Cognition dysfunction- increasing difficulty with memory, ability to think, and ability to concentrate was rated 0-10 daily by visual analogue scale, where 0 no problem and 10=severe problems.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 32 Years to 52 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• First Gulf War veterans with and without the syndrome

• Males

• Between 32 and 52 years of age

• No history of current alcoholism nor opiate use

• No history of current active depression nor post-traumatic stress disorder (PTSD)

Exclusion Criteria:

• Females

• History of active alcoholism or opiate drug use

• History of active depression and PTSD

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Medical Center, Northport	Northport	New York	United States	11768

Sponsors and Collaborators

• US Department of Veterans Affairs

Investigators

• Principal Investigator: Mohammad Amin, MD, VA Medical Center, Northport

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: US Department of Veterans Affairs
• ClinicalTrials.gov Identifier: NCT00252629
• Other Study ID Numbers: RCD-001-05S
• First Posted: Nov 11, 2005
• Last Update Posted: Dec 11, 2014
• Last Verified: Dec 1, 2014

• Keywords provided by US Department of Veterans Affairs: Fatigue; Functional Somatic Syndrome; Gulf War Syndrome; Sleep apnea; Upper Airway Resistance Syndrome
• Additional relevant MeSH terms: Fatigue Syndrome, Chronic; Sleep Apnea Syndromes; Syndrome; Fatigue

Study Results

Participant Flow

Recruitment Details	18 male veterans with GWI and Sleep Disordered Breathing recruited by advertisement, they were splitter into a matched two groups: 9 veterans received active nasal CPAP and 9 veterans received sham nasal CPAP. Additionally, we recruited asymptomatic 11 male veterans of Gulf war.

Arm/Group Title	Therapeutic Nasal CPAP	Sham Nasal CPAP	Comparison of IFL During Sleep in GWS and Healthy
Arm/Group Description	Nine participants assigned to receive 3 weeks of treatment during sleep with therapeutic nasal CPAP. Using validated questionnaires, fatigue, pain, and cognitive dysfunction were assessed by self-report before and after the three weeks treatment trial. We compared the change of veterans reported outcomes "symptoms change" before and after 3 weeks treatment period on therapeutic nasal CPAP.	Nine participants assigned to receive 3 weeks of treatment during sleep with sham nasal CPAP. Using validated questionnaires, fatigue, pain, and cognitive dysfunction were assessed by self-report before and after the three weeks treatment trial. We compared the change of veterans reported outcomes "symptoms change" before and after 3 weeks treatment period on sham nasal CPAP.	We recruited 18 male veterans with GWS (same group that were randomized to receive CPAP treatment) and 11 asymptomatic male veterans of the first Gulf war. All veterans had a polysomnography to determine the presence of sleep disordered breathing. We compared the prevalence of Inspiratory Flow Limitation (IFL) during supine stage 2 sleep among both groups.
Period Title: Overall Study
STARTED	9	9	11
COMPLETED	8	9	11
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Therapeutic Nasal CPAP	Sham Nasal CPAP	Healthy Asymptomatic Control	Total
Arm/Group Description	The occurrence of the following 3 symptoms in a Gulf War veteran beginning after 8/90, lasting at least 6 months and present at the time of screening: fatigue that limits usual activity; musculoskeletal pain involving 2 or more regions of the body; and cognitive symptoms (memory, concentration, or attention difficulties). All 3 symptoms must be unexplained by any clearly defined organic illness.	The occurrence of the following 3 symptoms in a Gulf War veteran beginning after 8/90, lasting at least 6 months and present at the time of screening: fatigue that limits usual activity; musculoskeletal pain involving 2 or more regions of the body; and cognitive symptoms (memory, concentration, or attention difficulties). All 3 symptoms must be unexplained by any clearly defined organic illness.	Eleven male veterans of first gulf war were screened for fatigue, pain and cognitive dysfunction by self report instrument. They all score below the clinical thershold and assigned as healthy asymptomatic	Total of all reporting groups
Overall Participants	9	9	11	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.4 (4.1)	42.9 (3.1)	41 (6.6)	42.2 (0.7)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	9 100%	9 100%	11 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Change of Fatigue Symptom
Description	Fatigue- increasing impact was rated 1-7 using the fatigue severity scale on days 1 and 7 averaged, where 1= no fatigue and 7= severe fatigue.
Time Frame	3 weeks treatment with either therapeutic or sham CPAP

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Nasal CPAP	Sham Nasal CPAP
Arm/Group Description	Comparing the change of fatigue complaint before and after 3 weeks treatment of therapeutic nasal CPAP	Comparing the change of fatigue complaint before and after treatment of 3 weeks on sham nasal CPAP
Measure Participants	8	9
Mean (Standard Error) [units on a scale]	2.1 (0.9)	0.2 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Therapeutic Nasal CPAP, Sham Nasal CPAP
	Comments	The change of fatigue complaint from baseline (before treatment) to post treatment ( after 3 weeks treatment) on either therapeutic CPAP or sham CPAP was compared with student t-test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Change of Pain Complaint
Description	Pain- increased level were rated 0-10 by visual analogue scale, where 0= no pain and 10= severe pain. We compared the change of pain symptom before and after treatment of either 3 weeks on therapeutic nasal CPAP or sham nasal CPAP
Time Frame	3 weeks of treatment on either therapeutic or sham nasal CPAP

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Nasal CPAP	Sham Nasal CPAP
Arm/Group Description	Comparing the change of pain complaint before and after 3 weeks treatment of therapeutic nasal CPAP	Comparing the change of pain complaint before and after treatment of 3 weeks on sham nasal CPAP
Measure Participants	8	9
Mean (Standard Deviation) [units on a scale]	2.0 (0.9)	0.4 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Therapeutic Nasal CPAP, Sham Nasal CPAP
	Comments	The change of pain symptom from baseline (before treatment) to post treatment ( after 3 weeks treatment) on either therapeutic CPAP or sham CPAP was compared with student t-test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0008
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Change of Cognitive Dysfunction
Description	Cognition dysfunction- increasing difficulty with memory, ability to think, and ability to concentrate was rated 0-10 daily by visual analogue scale, where 0 no problem and 10=severe problems.
Time Frame	3 weeks treatment with either therapeutic or sham CPAP

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Therapeutic Nasal CPAP	Sham Nasal CPAP
Arm/Group Description	Comparing the change of cognitive dysfunction ( increasing difficulty with memory, ability to think, and ability to concentrate) complaints before and after 3 weeks treatment of therapeutic nasal CPAP	Comparing the change of cognitive dysfunction ( increasing difficulty with memory, ability to think, and ability to concentrate) complaints before and after 3 weeks treatment on sham nasal CPAP
Measure Participants	8	9
Mean (Standard Deviation) [units on a scale]	2.0 (1.7)	0.4 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Therapeutic Nasal CPAP, Sham Nasal CPAP
	Comments	The change of cognitive dysfunction complaint from baseline (before treatment) to post treatment ( after 3 weeks treatment) on either therapeutic CPAP or sham CPAP was compared with student t-test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	t-test, 2 sided
	Comments

4. Primary Outcome

Title	The Prevalence of Inspiratory Flow Limitation (IFL) During Sleep in GWS.
Description	IFL was determined by plotting inspiratory flow against supra-glottic pressure for each breath sampled during continuous stage 2 sleep on a full night polysomnogram on both veterans with GWS and asymptomatic gulf war veterans. We expressed the prevalence of inspiratory flow limitations during sleep as the percentage of flow limited breath in the sample of both GWS and asymptomatic gulf was veterans.
Time Frame	On a full night polysomnogram

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GWS Male Group	Asymptomatic Male Veterans of Gulf War.
Arm/Group Description	A group of18 male veterans with GWS were examined. Each participant underwent full night polysomnogram while sleeping supine using a standard clinical monitoring for sleep and breathing. Inspiratory flow was measured using pneumotachograph and respiratory effort measured with supra-glottis catheter. Sampling of flow and effort during continuous stage 2 sleep was obtained and compared among both groups. Inspiratory flow was plotted against effort for each breath. IFL was defined as a 1 cm H2O or greater decrease in supraglotic pressure without a corresponding increase in airflow of at least 5 ml/second. The percentage of flow limited breath was calculated as the total number of flow limited breaths divided by the total breaths in all the samples.	A group of 11 asymptomatic male veterans of gulf war were examined. Each participant underwent full night polysomnogram while sleeping supine using a standard clinical monitoring for sleep and breathing. Inspiratory flow was measured using pneumotachograph and respiratory effort measured with supra-glottis catheter. Sampling of flow and effort during continuous stage 2 sleep was obtained and compared among both groups. Inspiratory flow was plotted against effort for each breath. IFL was defined as a 1 cm H2O or greater decrease in supraglotic pressure without a corresponding increase in airflow of at least 5 ml/second. The percentage of flow limited breath was calculated as the total number of flow limited breaths divided by the total breaths in all the samples.
Measure Participants	18	11
Mean (Standard Deviation) [percentage of flow limited breaths]	96 (5)	36 (25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Therapeutic Nasal CPAP
	Comments	The p value was based on t-test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Therapeutic Nasal CPAP		Sham Nasal CPAP		Comparison of IFL During Sleep in GWS and Healthy
Arm/Group Description	Comparing change of veterans reported outcomes ( fatigue, pain and cognitive dysfunction) before and after 3 weeks treatment on therapeutic nasal CPAP with change of symptoms on sham nasal CPAP		Comparing change of veterans reported outcomes ( fatigue, pain and cognitive dysfunction) before and after 3 weeks treatment on sham nasal CPAP with change of symptoms on therapeutic nasal CPAP		We recruited 11 asymptomatic male veterans of the first Gulf war. In addition to our 18 male veterans with GWS (same group that were randomized to receive CPAP treatment). All veterans had a polysomnography to determine the presence of sleep disordered breathing. We compared the prevalence of Inspiratory Flow Limitation (IFL) during supine stage 2 sleep among both groups.
All Cause Mortality
	Therapeutic Nasal CPAP		Sham Nasal CPAP		Comparison of IFL During Sleep in GWS and Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Therapeutic Nasal CPAP		Sham Nasal CPAP		Comparison of IFL During Sleep in GWS and Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Therapeutic Nasal CPAP		Sham Nasal CPAP		Comparison of IFL During Sleep in GWS and Healthy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)		0/11 (0%)

Limitations/Caveats

[Not Specified]

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.