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| ID | Type | Description | Link |
|---|---|---|---|
| 5R01HL130552-05 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Zolpidem, then No Treatment | Experimental | Participants will be administered zolpidem for the first night study, and No Treatment during the second night study. |
|
| No Treatment, then Zolpidem | Experimental | Participants will be administered zolpidem for the second night study, and No Treatment during the first night study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Zolpidem | Drug | A nonbenzodiazepine hypnotic |
|
| Measure | Description | Time Frame |
|---|---|---|
| The Central Apnea-hypopnea Index | The number of central apneas and hypopneas per hour of sleep was obtained from polysomnography studies. | one night |
| Respiratory Arousal Index | A measure of the frequency of respiratory-related arousals during sleep | one night |
| Measure | Description | Time Frame |
|---|---|---|
| CO2 Reserve | 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. | one night |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| M Safwan Badr, MD, MBA | John D. Dingell VA Medical Center, Detroit, MI | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| John D. Dingell VA Medical Center | Detroit | Michigan | 48201 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35286569 | Derived | Ahmad B, Sankari A, Eshraghi M, Aldwaikat A, Yarandi H, Zeineddine S, Salloum A, Badr MS. Effect of Zolpidem on nocturnal arousals and susceptibility to central sleep apnea. Sleep Breath. 2023 Mar;27(1):173-180. doi: 10.1007/s11325-022-02593-3. Epub 2022 Mar 14. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Experimental: Zolpidem, Then No Treatment | Participants will be administered zolpidem for the first night study, and No Treatment during the second night study. Zolpidem: A nonbenzodiazepine hypnotic |
| FG001 | Experimental: No Treatment, Then Zolpidem | Participants will be administered zolpidem for the second night study, and No Treatment during the first night study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Zolpidem, Then No Treatment | 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. |
| BG001 | No Treatment, Then Zolpidem |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | The year of birth was acquired from the participant's medical record and the participant's age at the start of the study was calculated and included in the baseline measure. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | The Central Apnea-hypopnea Index | The number of central apneas and hypopneas per hour of sleep was obtained from polysomnography studies. | Posted | Mean | Standard Error | events per hour | one night |
|
|
Adverse effects were recorded for the 24 hours following the administration of the study medication
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Zolpidem | Outcomes from the Zolpidem night for participants in both sequences |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Abdulghani Sankari | Wayne State University | 313-576-3548 | atarbich@med.wayne.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 6, 2019 | Mar 8, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012891 | Sleep Apnea Syndromes |
| D020182 | Sleep Apnea, Central |
| ID | Term |
|---|---|
| D001049 | Apnea |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
| D020919 | Sleep Disorders, Intrinsic |
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| ID | Term |
|---|---|
| D000077334 | Zolpidem |
| ID | Term |
|---|---|
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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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.
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Personnel conducting assessment of outcomes and data analysis are blinded to treatment.
| No Treatment | Other | The Control condition in which participants do not receive medication. |
|
| Controller Gain | 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. | one night |
| Stead-State Plant Gain (mmHg | 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. | one night |
| Respiratory Arousal Threshold | The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal | one night |
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. |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | The sex of participants was acquired from their medical records and confirmed with them through a baseline questionnaire before the beginning of the study. | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | The ethnicity of participants was acquired through a baseline questionnaire before the beginning of the study. Participants indicated whether they identified as Hispanic/Latino, or non-Hispanic/latino, and were given the option to leave it blank. | Count of Participants | Participants |
|
| Race (NIH/OMB) | The race of participants was acquired through a baseline questionnaire before the beginning of the study. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Veteran Status: Yes | This variable indicates whether the participant is an Army Veteran. Veteran status was determined from the participant's medical record and verified with the participant through a baseline questionnaire at the beginning of the study. | Count of Participants | Participants |
|
| BMI | The body mass index was measured through a baseline questionnaire or acquired from the medical records and verified with participants. | Mean | Standard Deviation | kg/m^2 |
|
| Neck Girth | Neck girth was measured at baseline. | Mean | Standard Deviation | cm |
|
| Participants |
|
|
| Primary | Respiratory Arousal Index | A measure of the frequency of respiratory-related arousals during sleep | Posted | Mean | Standard Error | events per hour | one night |
|
|
|
| Secondary | CO2 Reserve | 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. | Posted | Mean | Standard Error | mmHg | one night |
|
|
|
| Secondary | Controller Gain | 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. | Posted | Mean | Standard Error | L/min*mmHg | one night |
|
|
|
| Secondary | Stead-State Plant Gain (mmHg | 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. | Posted | Mean | Standard Error | mmHg*L/min | one night |
|
|
|
| Secondary | Respiratory Arousal Threshold | The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal | Posted | Mean | Standard Error | cmH2O | one night |
|
|
|
| 0 |
| 14 |
| 0 |
| 14 |
| 0 |
| 14 |
| EG001 | No Treatment | Outcomes from the No Treatment night for participants in both sequences | 0 | 14 | 0 | 14 | 0 | 14 |
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| D020920 |
| Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |