Sleep Apnea SyndromesEarly Phase 1RAP-IHNCT00860743
Respiratory and Autonomic Plasticity Following Intermittent Hypoxia
A Early Phase 1 study testing Antioxidant cocktail in people with Sleep Apnea Syndromes, run by VA Office of Research and Development at 1 site in United States.
Trial summary
The prevalence of obstructive sleep apnea is high in the Veteran population. If not treated promptly, sleep apnea may result in daytime fatigue which may lead to increased prevalence of accidents while driving or in the workplace. Read more about this study
- Who is it for?
- Ages 20 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Sleep Apnea Syndromes
- What is being tested?
- Antioxidant cocktail
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 63 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2009to Sep 2013
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Characteristics of OSA subject population:
- Body mass index < 30 kg/m2.
- 20 to 40 years old.
- Newly diagnosed never-treated mild to moderate sleep apnea (i.e. 50 > apnea/hypopnea index >10 events per hour - average nocturnal oxygen saturation > 90%).
- Not pregnant.
- Free of any other known medical conditions.
Show all 18Show fewer
- Not taking any medication.
- Non-smokers with normal lung function.
- Minimal alcohol consumption (i.e. no more than the equivalent of a glass of wine/day).
- Characteristics of control group population:
- Body mass index < 30 kg/m2.
- 20 to 40 years old.
- Apnea/hypopnea index < 5 events per hour.
- Not pregnant.
- Free of any known medical conditions.
- Not taking any medication.
- Non-smokers with normal lung function.
- Minimal alcohol consumption (i.e. no more than the equivalent of a glass of wine/day).
Who cannot join
- Anything not in inclusion criteria.
Trial locations and contacts
1 site in 1 country.
United States1 site
John D. Dingell VA Medical Center, Detroit
Detroit, Michigan, 48201
About this study
The prevalence of obstructive sleep apnea is high in the Veteran population. If not treated promptly, sleep apnea may result in daytime fatigue which may lead to increased prevalence of accidents while driving or in the workplace. Recent large scale epidemiological studies have shown that the prevalence of excessive daytime sleepiness increases in individuals who suffer from obstructive sleep apnea. Obstructive sleep apnea may also result in the development of hypertension and other cardiovascular disorders. Previous findings have shown that subjects with sleep apnea have a greater risk for developing coronary vascular disease compared to individuals that do not suffer from sleep apnea Thus, a significant amount of evidence suggests that sleep apnea is a major health concern in the Veteran population. Consequently, determining the mechanisms that may impact on the severity of sleep apnea and increase the prevalence of cardiovascular incidents associated with this disorder is important, as is discovering novel treatments.
Read the detailed description
Approximately 8 % of the Veteran population in the United States suffers from sleep apnea. Consequences of untreated sleep apnea include increased daytime fatigue, hypertension and stroke. Thus, sleep apnea is a major health concern. One of the primary hallmarks of sleep apnea is exposure to intermittent hypoxia (IH) which occurs as a consequence of central or obstructive apneas. Exposure to IH may lead to neural plasticity (i.e. a change in system performance based on prior experience) of the respiratory and autonomic nervous system. One adaptation that has been shown to manifest itself in animals following exposure to IH is long-term facilitation (LTF) of ventilation and sympathetic nervous system activity (SNSA). This phenomenon is characterized by a gradual increase in respiratory motor activity and SNSA during successive periods of normoxia that separate hypoxic episodes and by activity that persists above baseline levels for up to 90 minutes following exposure to IH. Although LTF of minute ventilation has been well established in animals it has not been observed consistently in healthy humans or in individuals with obstructive sleep apnea. Similarly, although a few studies have shown that exposure to IH leads to increases in SNSA in healthy individuals the magnitude of the response has varied significantly. Findings from animal studies suggest that the manifestation of LTF in humans might in part be dependent on a variety of factors, including prior exposure to IH, arousal state (wake vs. sleep) and gender. Thus, the initial aim of our proposal will establish whether LTF can be induced in healthy humans and individuals with obstructive sleep apnea and whether the magnitude of the response is dependent on those factors mentioned above. Moreover, the initial aim will explore whether the presence of LTF of minute ventilation promotes or mitigates apnea severity. Animal studies have also indicated that LTF of respiratory and autonomic activity may in part be induced by increases in oxidative stress. Thus, the second objective of our proposal will explore whether administration of an antioxidant cocktail impacts respiratory and autonomic nervous system plasticity during wakefulness and sleep following IH. Likewise, the second aim will explore whether administration of an antioxidant cocktail alters apnea severity following exposure to IH. Establishing whether LTF of minute ventilation exists in individuals with sleep apnea is important since activation of this phenomenon could impact on apnea severity across the night. Similarly, LTF of SNSA activity and possibly long-term depression (LTD) of parasympathetic nervous system activity (PNSA) could ultimately lead to persistent increases in blood pressure and heart rate. Furthermore, given that exposure to IH may lead to long-term plasticity of respiratory and autonomic activity that are physiologically detrimental, exploring mechanisms that ultimately lead to treatments that may mitigate or prevent the manifestation of this phenomenon are important.
- Conditions
- Sleep Apnea Syndromes
- Being tested
- Antioxidant cocktail
- Keywords
- intermittent hypoxia, ventilatory long-term facilitation, autonomic nervous system plasticity
- Medical subject headings
- Sleep Apnea Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Antioxidant cocktailDrug
120 mg of Coenzyme Q10 (orally), 800 mg of Superoxide Dismutase (orally), 400 IU of Vitamin E (orally) before exposure to intermittent hypoxia. Two doses of 1 g of Vitamin C in 50 cc of saline IV (in the vein) before and after exposure to intermittent hypoxia.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | No intervention | We plan to study 10 males and 10 females with moderate obstructive sleep apnea (OSA), and 10 healthy males and 10 healthy females. The males and the females will be matched based on age, race, sex and body mass index. The OSA and control participants will be exposed to intermittent hypoxia and "sham" intermittent hypoxia during wakefulness and sleep. |
| ANTIOXIDANT COCKTAIL | Experimental | We plan to study 10 male participants with moderate obstructive sleep apnea (OSA) and 10 male control participants matched for age, race and body mass index. The OSA and control participants will be exposed to intermittent hypoxia during wakefulness and sleep following administration of an antioxidant or a placebo cocktail that will be presented in a randomized fashion. Receives: Drug: Antioxidant cocktail |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ventilation (Aim 1)
Ventilation was measured before and after exposure to intermittent hypoxia in males and females. Ventilation was measured using a pneumotachograph, which is a flow measuring device.
Measured: Within the same experimental session
Heart Rate Variability (Aim 2)
Heart rate variability (HRV) was measured before and after exposure to intermittent hypoxia following administration of a placebo or antioxidant cocktail. Heart rate variability refers to beat-to-beat alterations in heart rate. Under resting conditions, the electrocardiogram of healthy individuals reveals periodic variation in R-R intervals. To measure HRV, R-R interval data are presented in a graph, in which the y-axis plots the R-R intervals (ms2), and the x-axis the total number of beats. Spectral analysis of the graph transforms the signal from time to frequency on the x-axis (Hz), by representing the signal as a combination of sine and cosine waves, with different amplitudes and frequencies. The approach uses Fourier transforms. The heart rate spectrum contains a high frequency (0.15-0.4 Hz) component, which is synchronous with respiration and a low frequency (0.04 to 0.15 Hz) component that appears to be mediated by both the vagus and cardiac sympathetic nerves.
Measured: Within the same experimental session
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Mar 2009 (estimated)
- Study startSep 2009
- Primary completionSep 2013
- Study completionSep 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Sleep Apnea SyndromesStudies of the same condition, open and under way.
- More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 63 participants (actual)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- Jason H Mateika, PhD MS BS, Principal investigator, John D. Dingell VA Medical Center, Detroit
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00860743
- Sponsor's protocol ID
- PULM-014-08F
- Other IDs
- GRANT00507547
- Acronym
- RAP-IH
- Status last verified
- Sep 2017
- First submitted
- 10 Mar 2009
- Last updated
- 1 Nov 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Mateika JH, Syed Z. Intermittent hypoxia, respiratory plasticity and sleep apnea in humans: present knowledge and future investigations. Respir Physiol Neurobiol. 2013 Sep 15;188(3):289-300. doi: 10.1016/j.resp.2013.04.010. Epub 2013 Apr 12.
PubMed 23587570Syed Z, Lin HS, Mateika JH. The impact of arousal state, sex, and sleep apnea on the magnitude of progressive augmentation and ventilatory long-term facilitation. J Appl Physiol (1985). 2013 Jan 1;114(1):52-65. doi: 10.1152/japplphysiol.00985.2012. Epub 2012 Nov 8.
PubMed 23139361
Study at a glance
From the registry record, last updated by the sponsor on 1 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Respiratory and Autonomic Plasticity Following Intermittent Hypoxia
- ClinicalTrials.gov ID
- NCT00860743
- Acronym / sponsor ID
- RAP-IH / PULM-014-08F
- Conditions
- Sleep Apnea Syndromes
- Keywords
- intermittent hypoxia, ventilatory long-term facilitation, autonomic nervous system plasticity
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 63 participants (actual)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- Sep 2009
- Primary completion
- Sep 2013 (actual)
- Study completion
- Sep 2013 (actual)
- First posted
- 12 Mar 2009 (estimated)
- Results
- Posted 25 Feb 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The prevalence of obstructive sleep apnea is high in the Veteran population. If not treated promptly, sleep apnea may result in daytime fatigue which may lead to increased prevalence of accidents while driving or in the workplace. Recent large scale epidemiological studies have shown that the prevalence of excessive daytime sleepiness increases in individuals who suffer from obstructive sleep apnea. Obstructive sleep apnea may also result in the development of hypertension and other cardiovascular disorders. Previous findings have shown that subjects with sleep apnea have a greater risk for developing coronary vascular disease compared to individuals that do not suffer from sleep apnea Thus, a significant amount of evidence suggests that sleep apnea is a major health concern in the Veteran population. Consequently, determining the mechanisms that may impact on the severity of sleep apnea and increase the prevalence of cardiovascular incidents associated with this disorder is important, as is discovering novel treatments.
Detailed description
Approximately 8 % of the Veteran population in the United States suffers from sleep apnea. Consequences of untreated sleep apnea include increased daytime fatigue, hypertension and stroke. Thus, sleep apnea is a major health concern. One of the primary hallmarks of sleep apnea is exposure to intermittent hypoxia (IH) which occurs as a consequence of central or obstructive apneas. Exposure to IH may lead to neural plasticity (i.e. a change in system performance based on prior experience) of the respiratory and autonomic nervous system. One adaptation that has been shown to manifest itself in animals following exposure to IH is long-term facilitation (LTF) of ventilation and sympathetic nervous system activity (SNSA). This phenomenon is characterized by a gradual increase in respiratory motor activity and SNSA during successive periods of normoxia that separate hypoxic episodes and by activity that persists above baseline levels for up to 90 minutes following exposure to IH. Although LTF of minute ventilation has been well established in animals it has not been observed consistently in healthy humans or in individuals with obstructive sleep apnea. Similarly, although a few studies have shown that exposure to IH leads to increases in SNSA in healthy individuals the magnitude of the response has varied significantly. Findings from animal studies suggest that the manifestation of LTF in humans might in part be dependent on a variety of factors, including prior exposure to IH, arousal state (wake vs. sleep) and gender. Thus, the initial aim of our proposal will establish whether LTF can be induced in healthy humans and individuals with obstructive sleep apnea and whether the magnitude of the response is dependent on those factors mentioned above. Moreover, the initial aim will explore whether the presence of LTF of minute ventilation promotes or mitigates apnea severity. Animal studies have also indicated that LTF of respiratory and autonomic activity may in part be induced by increases in oxidative stress. Thus, the second objective of our proposal will explore whether administration of an antioxidant cocktail impacts respiratory and autonomic nervous system plasticity during wakefulness and sleep following IH. Likewise, the second aim will explore whether administration of an antioxidant cocktail alters apnea severity following exposure to IH. Establishing whether LTF of minute ventilation exists in individuals with sleep apnea is important since activation of this phenomenon could impact on apnea severity across the night. Similarly, LTF of SNSA activity and possibly long-term depression (LTD) of parasympathetic nervous system activity (PNSA) could ultimately lead to persistent increases in blood pressure and heart rate. Furthermore, given that exposure to IH may lead to long-term plasticity of respiratory and autonomic activity that are physiologically detrimental, exploring mechanisms that ultimately lead to treatments that may mitigate or prevent the manifestation of this phenomenon are important.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | No intervention | –We plan to study 10 males and 10 females with moderate obstructive sleep apnea (OSA), and 10 healthy males and 10 healthy females. The males and the females will be matched based on age, race, sex and body mass index. The OSA and control participants will be exposed to intermittent hypoxia and "sham" intermittent hypoxia during wakefulness and sleep. |
| ANTIOXIDANT COCKTAIL | Experimental | Drug: Antioxidant cocktailWe plan to study 10 male participants with moderate obstructive sleep apnea (OSA) and 10 male control participants matched for age, race and body mass index. The OSA and control participants will be exposed to intermittent hypoxia during wakefulness and sleep following administration of an antioxidant or a placebo cocktail that will be presented in a randomized fashion. |
Who may qualify
- Ages
- 20 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (18 listed)
- Body mass index < 30 kg/m2.
- 20 to 40 years old.
- Newly diagnosed never-treated mild to moderate sleep apnea (i.e. 50 > apnea/hypopnea index >10 events per hour - average nocturnal oxygen saturation > 90%).
- Not pregnant.
- Free of any other known medical conditions.
Key exclusion criteria (1 listed)
- Anything not in inclusion criteria.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Antioxidant cocktail120 mg of Coenzyme Q10 (orally), 800 mg of Superoxide Dismutase (orally), 400 IU of Vitamin E (orally) before exposure to intermittent hypoxia. Two doses of 1 g of Vitamin C in 50 cc of saline IV (in the vein) before and after exposure to intermittent hypoxia. | Drug | ANTIOXIDANT COCKTAIL |
Primary outcome
Ventilation (Aim 1)
Time frame: Within the same experimental session
Ventilation was measured before and after exposure to intermittent hypoxia in males and females. Ventilation was measured using a pneumotachograph, which is a flow measuring device.
Heart Rate Variability (Aim 2)
Time frame: Within the same experimental session
Heart rate variability (HRV) was measured before and after exposure to intermittent hypoxia following administration of a placebo or antioxidant cocktail. Heart rate variability refers to beat-to-beat alterations in heart rate. Under resting conditions, the electrocardiogram of healthy individuals reveals periodic variation in R-R intervals. To measure HRV, R-R interval data are presented in a graph, in which the y-axis plots the R-R intervals (ms2), and the x-axis the total number of beats. Spectral analysis of the graph transforms the signal from time to frequency on the x-axis (Hz), by representing the signal as a combination of sine and cosine waves, with different amplitudes and frequencies. The approach uses Fourier transforms. The heart rate spectrum contains a high frequency (0.15-0.4 Hz) component, which is synchronous with respiration and a low frequency (0.04 to 0.15 Hz) component that appears to be mediated by both the vagus and cardiac sympathetic nerves.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Nov 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 23587570Mateika JH, Syed Z. Intermittent hypoxia, respiratory plasticity and sleep apnea in humans: present knowledge and future investigations. Respir Physiol Neurobiol. 2013 Sep 15;188(3):289-300. doi: 10.1016/j.resp.2013.04.010. Epub 2013 Apr 12.
- Results publication: PubMed 23139361Syed Z, Lin HS, Mateika JH. The impact of arousal state, sex, and sleep apnea on the magnitude of progressive augmentation and ventilatory long-term facilitation. J Appl Physiol (1985). 2013 Jan 1;114(1):52-65. doi: 10.1152/japplphysiol.00985.2012. Epub 2012 Nov 8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jason H Mateika, PhD MS BS principal investigator
John D. Dingell VA Medical Center, Detroit
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Antioxidant cocktail in people with Sleep Apnea Syndromes, run by VA Office of Research and Development at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Feb 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ventilation (Aim 1) (time frame: Within the same experimental session). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00860743, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2017.