Sleep and Breathing in the General Population - Chemical Stimuli

• Sponsor: Wayne State University (Other)
• Overall Status: Completed
• CT.gov ID: NCT04720547
• Collaborator: National Institutes of Health (NIH) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 14
• Location: 1
• Arms: 2
• Actual Duration (Months): 19.9
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Central sleep apnea (CSA) is a common condition and its treatment remains elusive. The focus of this proposal is to identify the role of the physiologic path involving cortical arousals in CSA by decreasing arousal frequency using the pharmacological agent zolpidem. The goal is to identify the acute effects of administering zolpidem on sleep and respiratory outcomes, and subsequently, its effect on the severity of CSA and propensity to develop CSA. This study will shed light on the mechanisms underlying CSA that involve cortical arousals and will guide future therapeutic interventions for CSA.

Condition or Disease	Intervention/Treatment	Phase
Sleep-disordered Breathing	Drug: Zolpidem; Other: No Treatment	Phase 4

Detailed Description

The literature suggests that zolpidem may be effective in the treatment of central sleep apnea (CSA). However, evidence regarding the efficacy of zolpidem and the underlying mechanisms involved in its effect on CSA are not well-studied. Furthermore, respiratory-related arousals are hypothesized to contribute CSA symptoms and severity. The aim of the study is to determine the effect of decreasing respiratory-related arousals on the propensity to develop central apnea. The investigators hypothesize that administration of the nonbenzodiazepine hypnotic zolpidem will decrease the frequency of respiratory-related arousals, lower the central apnea-hypopnea index, and widen the CO2 reserve during sleep in patients with CSA compared to no treatment. Participants will complete a night study on a low dose of zolpidem and another night study without zolpidem in a crossover manner. The order of night studies is randomized. The results will help unveil the role of arousals in CSA and the acute effect of zolpidem on CSA severity and the propensity to CSA.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: After an initial assessment to determine eligibility, participant complete two in-lab night studies in a randomized manner including one night with the administration of zolpidem and another without zolpidem.After an initial assessment to determine eligibility, participant complete two in-lab night studies in a randomized manner including one night with the administration of zolpidem and another without zolpidem.
• Masking: Single (Outcomes Assessor)
• Masking Description: Personnel conducting assessment of outcomes and data analysis are blinded to treatment.
• Primary Purpose: Treatment
• Official Title: Sleep and Breathing in Health and Disease (Part 2A - Chemical Stimuli, Sleep and Breathing in the General Population)
• Actual Study Start Date: Jul 3, 2018
• Actual Primary Completion Date: Feb 29, 2020
• Actual Study Completion Date: Feb 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zolpidem, then No Treatment Participants will be administered zolpidem for the first night study, and No Treatment during the second night study.	Drug: Zolpidem; A nonbenzodiazepine hypnotic; Other Names: Ambien ; Other: No Treatment; The Control condition in which participants do not receive medication.
Experimental: No Treatment, then Zolpidem Participants will be administered zolpidem for the second night study, and No Treatment during the first night study.	Drug: Zolpidem; A nonbenzodiazepine hypnotic; Other Names: Ambien ; Other: No Treatment; The Control condition in which participants do not receive medication.

Outcome Measures

Primary Outcome Measures

1. The Central Apnea-hypopnea Index [one night]

   The number of central apneas and hypopneas per hour of sleep was obtained from polysomnography studies.

2. Respiratory Arousal Index [one night]

   A measure of the frequency of respiratory-related arousals during sleep

Secondary Outcome Measures

1. CO2 Reserve [one night]

   CO2 reserve is the requisite change to induce central apnea is referred to as the CO2 reserve, which can be positive or negative. CO2 reserve is defined as the difference between the eupneic end-tidal CO2 pressure and the end-tidal CO2 pressure induced by the ventilation protocol that is sufficient to trigger a central apnea as defined by the American Academy of Sleep Medicine.

2. Controller Gain [one night]

   Controller gain is a ventilatory response to changes in end-tidal PCO2. Controller gain was calculated by dividing the difference in minute ventilation between the post-mechanical ventilation induced by the ventilation protocol and steady-state respiration by the difference in the end-tidal CO2 pressure between the mechanical ventilation and steady-state respiration.

3. Stead-State Plant Gain (mmHg [one night]

   Plant gain is a blood gas response to a change in ventilation. This measure represents the effectiveness of the "plant" in eliminating CO2. Steady-state plant gain was calculated from the ratio of end-tidal CO2 to minute ventilation during stable respiration.

4. Respiratory Arousal Threshold [one night]

   The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Men and women Veterans with central sleep apnea, defined as Apnea Hypopnea Index (AHI)>15/hour with CAHI>5/hour, will be included in the experiments.

Exclusion Criteria:

• less than 18 years old

• pregnant or breastfeeding female

• have severe respiratory disease that require to be on oxygen

• recent health event that may affect the ability to participate in the study,

• Body Mass Index (BMI) is >40 kg/m2

• significant insomnia

• mental instability

• recent health event that may affect sleep

• if at any time the principal investigator (PI) identifies that a certain drug is not suitable, or are unable to use the device that is used to treat sleep apnea, will be not be allowed to participate in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	John D. Dingell VA Medical Center	Detroit	Michigan	United States	48201

Sponsors and Collaborators

• Wayne State University
• National Institutes of Health (NIH)
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: M Safwan Badr, MD, MBA, John D. Dingell VA Medical Center, Detroit, MI

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 6, 2019

More Information

Publications

None provided.

• Responsible Party: M Safwan Badr, Chair of Internal Medicine, Wayne State University
• ClinicalTrials.gov Identifier: NCT04720547
• Other Study ID Numbers: 1203010749; 5R01HL130552-05
• First Posted: Jan 22, 2021
• Last Update Posted: Apr 28, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by M Safwan Badr, Chair of Internal Medicine, Wayne State University: Sleep-disordered Breathing; central sleep apnea
• Additional relevant MeSH terms: Respiratory Aspiration; Sleep Apnea Syndromes; Zolpidem

Study Results

Participant Flow

Arm/Group Title	Experimental: Zolpidem, Then No Treatment	Experimental: No Treatment, Then Zolpidem
Arm/Group Description	Participants will be administered zolpidem for the first night study, and No Treatment during the second night study. Zolpidem: A nonbenzodiazepine hypnotic	Participants will be administered zolpidem for the second night study, and No Treatment during the first night study.
Period Title: Overall Study
STARTED	6	8
COMPLETED	6	5
NOT COMPLETED	0	3

Baseline Characteristics

Arm/Group Title	Zolpidem, Then No Treatment	No Treatment, Then Zolpidem	Total
Arm/Group Description	Participants will be administered zolpidem for the first night study, and No Treatment during the second night study. Zolpidem: A nonbenzodiazepine hypnotic No Treatment: The Control condition in which participants do not receive medication.	Participants will be administered zolpidem for the second night study, and No Treatment during the first night study. Zolpidem: A nonbenzodiazepine hypnotic No Treatment: The Control condition in which participants do not receive medication.	Total of all reporting groups
Overall Participants	6	5	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.7 (12.7)	70.4 (4.3)	62.9 (11.8)
Sex: Female, Male (Count of Participants)
Female	2 33.3%	0 0%	2 18.2%
Male	4 66.7%	5 100%	9 81.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	6 100%	5 100%	11 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 50%	4 80%	7 63.6%
White	3 50%	1 20%	4 36.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%	5 100%	11 100%
Veteran Status: Yes (Count of Participants)
Count of Participants [Participants]	5 83.3%	5 100%	10 90.9%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.6 (5.6)	32.2 (4.8)	30.8 (5.3)
Neck Girth (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	38.9 (6.2)	41.4 (3.5)	40.0 (5.1)

Outcome Measures

1. Primary Outcome

Title	The Central Apnea-hypopnea Index
Description	The number of central apneas and hypopneas per hour of sleep was obtained from polysomnography studies.
Time Frame	one night

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zolpidem	No Treatment
Arm/Group Description	Outcomes from the Zolpidem night for participants in both sequences	Outcomes from the No Treatment night for participants in both sequences
Measure Participants	10	10
Mean (Standard Error) [events per hour]	14.1 (4.4)	29.9 (7.6)

2. Primary Outcome

Title	Respiratory Arousal Index
Description	A measure of the frequency of respiratory-related arousals during sleep
Time Frame	one night

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zolpidem	No Treatment
Arm/Group Description	Outcomes from the Zolpidem night for participants in both sequences	Outcomes from the No Treatment night for participants in both sequences
Measure Participants	10	10
Mean (Standard Error) [events per hour]	23.3 (4.4)	39.7 (7.7)

3. Secondary Outcome

Title	CO2 Reserve
Description	CO2 reserve is the requisite change to induce central apnea is referred to as the CO2 reserve, which can be positive or negative. CO2 reserve is defined as the difference between the eupneic end-tidal CO2 pressure and the end-tidal CO2 pressure induced by the ventilation protocol that is sufficient to trigger a central apnea as defined by the American Academy of Sleep Medicine.
Time Frame	one night

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zolpidem	No Treatment
Arm/Group Description	Outcomes from the Zolpidem night for participants in both sequences	Outcomes from the No Treatment night for participants in both sequences
Measure Participants	8	8
Mean (Standard Error) [mmHg]	-0.63 (2.42)	-0.44 (4.17)

4. Secondary Outcome

Title	Controller Gain
Description	Controller gain is a ventilatory response to changes in end-tidal PCO2. Controller gain was calculated by dividing the difference in minute ventilation between the post-mechanical ventilation induced by the ventilation protocol and steady-state respiration by the difference in the end-tidal CO2 pressure between the mechanical ventilation and steady-state respiration.
Time Frame	one night

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zolpidem	No Treatment
Arm/Group Description	Outcomes from the Zolpidem night for participants in both sequences	Outcomes from the No Treatment night for participants in both sequences
Measure Participants	5	5
Mean (Standard Error) [L/min*mmHg]	2.39 (1.10)	3.95 (2.34)

5. Secondary Outcome

Title	Stead-State Plant Gain (mmHg
Description	Plant gain is a blood gas response to a change in ventilation. This measure represents the effectiveness of the "plant" in eliminating CO2. Steady-state plant gain was calculated from the ratio of end-tidal CO2 to minute ventilation during stable respiration.
Time Frame	one night

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zolpidem	No Treatment
Arm/Group Description	Outcomes from the Zolpidem night for participants in both sequences	Outcomes from the No Treatment night for participants in both sequences
Measure Participants	8	8
Mean (Standard Error) [mmHg*L/min]	4.78 (0.79)	5.27 (1.0)

6. Secondary Outcome

Title	Respiratory Arousal Threshold
Description	The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal
Time Frame	one night

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zolpidem	No Treatment
Arm/Group Description	Outcomes from the Zolpidem night for participants in both sequences	Outcomes from the No Treatment night for participants in both sequences
Measure Participants	4	4
Mean (Standard Error) [cmH2O]	-8.72 (4.20)	-8.25 (5.63)

Adverse Events

Time Frame	Adverse effects were recorded for the 24 hours following the administration of the study medication
Arm/Group Title	Zolpidem		No Treatment
Arm/Group Description	Outcomes from the Zolpidem night for participants in both sequences		Outcomes from the No Treatment night for participants in both sequences
All Cause Mortality
	Zolpidem		No Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)
Serious Adverse Events
	Zolpidem		No Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Zolpidem		No Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.