Mild Intermittent Hypoxia for Obstructive Sleep Apnea

Recruiting in Palo Alto (17 mi)

Overseen by Jason H Mateika, PhD MS BS

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: VA Office of Research and Development

Must not be taking: Sleep supplements, others

Disqualifiers: High blood pressure, pulmonary hypertension, others

Stay on Your Current Meds

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The prevalence of obstructive sleep apnea (OSA) is high in the United States and is a major health concern. This disorder is linked to numerous heart, blood vessel and nervous system abnormalities, along with increased tiredness while performing exercise likely because of a reduced blood supply to skeletal muscles. The gold standard treatment of OSA with continuous positive airway pressure (CPAP) in many cases does not lead to significant improvements in health outcomes because the recommended number of hours of treatment per night is often not achieved. Thus, development of novel treatments to eliminate apnea and lessen the occurrence of associated health conditions is important. The investigators will address this mandate by determining if repeated exposure to mild intermittent hypoxia (MIH) reduces heart and blood vessel dysfunction and tiredness/ fatigue experienced while exercise performance. The investigators propose that exposure to MIH has a multipart effect. MIH directly targets heart and blood vessel associated conditions, while simultaneously increasing upper airway stability and improving sleep quality. These modifications may serve to directly decrease breathing episodes and may also serve to improve usage of CPAP. Independent of its effect, MIH may serve as an adjunctive therapy which provides another path to reducing heart and blood vessel abnormalities that might ultimately result in improvements in exercise capacity and reverse performance fatigue in individuals with OSA.

Will I have to stop taking my current medications?

Yes, participants must stop taking their current medications, except for a single prescribed medication for hypertension.

What data supports the effectiveness of the treatment Mild Intermittent Hypoxia for Obstructive Sleep Apnea?

Research suggests that mild intermittent hypoxia (IH) can lead to beneficial outcomes, such as increased stability of the upper airway, which may help reduce the severity of obstructive sleep apnea (OSA). A study found that acute intermittent hypoxia significantly decreased the apnea-hypopnea index, indicating fewer breathing interruptions during sleep, compared to normoxia and continuous hypoxia. ^{1 2 3 4 5}

How does the treatment Mild Intermittent Hypoxia differ from other treatments for obstructive sleep apnea?

Mild Intermittent Hypoxia (MIH) is unique because it involves controlled exposure to low oxygen levels followed by normal oxygen levels, which can enhance respiratory plasticity and stabilize the upper airway, potentially reducing the need for continuous positive airway pressure (CPAP) therapy. This approach may improve treatment compliance and address overlapping conditions like asthma and chronic obstructive pulmonary disease, offering a multipronged therapeutic effect not seen with standard treatments. ^{2 3 4 6 7}

Research Team

Jason H Mateika, PhD MS BS

Principal Investigator

John D. Dingell VA Medical Center, Detroit, MI

Eligibility Criteria

This trial is for adults aged 30-60 with a BMI under 40, newly diagnosed obstructive sleep apnea (OSA), and hypertension. They must have normal lung function, EKG readings, controlled alcohol intake, and not be on CPAP treatment or multiple medications. Pre-diabetic individuals with specific cholesterol levels can join too.

Inclusion Criteria

My lung function is normal, my heart's electrical activity is normal, and I drink less than 2 oz of alcohol per night.

My lungs work normally, my heart's electrical activity is normal, and I drink less than 2 oz of alcohol nightly.

I have never used a CPAP machine before.

Exclusion Criteria

I have a known disease such as pulmonary hypertension.

I am only on one medication for high blood pressure that's hard to control.

Pregnant females

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mild intermittent hypoxia (MIH) or sham MIH treatment to assess its effects on sleep apnea and associated comorbidities

8 weeks

Daily visits (in-person) for MIH administration

Follow-up

Participants are monitored for changes in blood pressure, microvascular function, and other health outcomes after treatment

8 weeks

Regular follow-up visits (in-person and virtual)

Treatment Details

Interventions

• Mild Intermittent Hypoxia (Behavioural Intervention)
• Sham MIH (Behavioural Intervention)

Trial Overview The study tests whether mild intermittent hypoxia (MIH) can improve heart health and reduce fatigue during exercise in OSA patients by increasing airway stability and enhancing sleep quality. It compares MIH to a sham procedure to see if it's an effective standalone or adjunct therapy.

Participant Groups

Group I: Mild Intermittent Hypoxia (MIH) Experimental Treatment 1 Intervention

This arm of the protocol will receive mild intermittent hypoxia (8% oxygen) with end-tidal carbon dioxide maintained 2 millimeters of mercury above baseline, while in the laboratory.

Group II: Sham Mild Intermittent Hypoxia (Sham MIH) Placebo Group 1 Intervention

This arm of the protocol will receive sham MIH (the equivalent of room air), while in the laboratory.

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Dr. Grant Huang

VA Office of Research and Development

Acting Chief Research and Development Officer

PhD in Medical Psychology and Master of Public Health from the Uniformed Services University of Health Sciences

Dr. Erica M. Scavella

VA Office of Research and Development

Chief Medical Officer since 2022

MD from University of Massachusetts School of Medicine

John D. Dingell VA Medical Center

Collaborator

Trials

10

Recruited

1,100+

Findings from Research

Both intermittent hypoxia/normoxia training (IHT) and intermittent hypoxia/hyperoxia training (IHHT) significantly reduced fasting glucose and cholesterol levels in prediabetic patients, with effects lasting up to one month after training ended.

IHHT may offer advantages over IHT by potentially reducing session duration due to shorter reoxygenation periods, making it a more efficient training method for improving metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent Hypoxia/Hyperoxia Versus Intermittent Hypoxia/Normoxia: Comparative Study in Prediabetes. Serebrovska, TV., Grib, ON., Portnichenko, VI., et al.[2020]

Intermittent hypoxia (IH) may have beneficial effects, particularly in promoting respiratory plasticity that could help mitigate obstructive sleep apnea (OSA) when used alongside continuous positive airway pressure (CPAP) therapy.

Mild forms of IH could enhance the stability of the upper airway, potentially reducing the amount of CPAP needed, which may improve patient compliance and overall treatment outcomes for OSA and related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent hypoxia initiated plasticity in humans: A multipronged therapeutic approach to treat sleep apnea and overlapping co-morbidities. Mateika, JH., Komnenov, D.[2019]

Intermittent hypoxia (IH) negatively impacts the human nasal mucosa by decreasing ciliary beat frequency (CBF) and increasing inflammatory cytokines, which can lead to airway inflammation.

In a study comparing normoxic conditions to IH over 72 hours, the IH group exhibited significant changes in CBF and cytokine levels, but there was no difference in cell survival rates, suggesting that while IH affects mucosal function, it does not directly cause cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of intermittent hypoxia on human nasal mucosa. In, SM., Park, DY., Lee, KI., et al.[2021]

In a study of 16 patients with mild to moderate obstructive sleep apnea, acute intermittent hypoxia significantly reduced the apnea-hypopnea index by an average of 8.9 events per hour compared to normoxia, indicating its potential efficacy as a treatment.

Acute intermittent hypoxia also led to a significant decrease in the oxygen desaturation index, with 11 out of 16 participants responding positively, suggesting it may be a safe and effective therapeutic approach for managing obstructive sleep apnea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized controlled crossover trial of acute intermittent and continuous hypoxia exposure in mild-moderate obstructive sleep apnea: A feasibility study. Zha, S., Liu, X., Chen, H., et al.[2023]

Intermittent hypoxia (IH) from obstructive sleep apnea (OSA) leads to significant systemic and vascular inflammation in mice, which contributes to cardiovascular complications, highlighting the need for better understanding of OSA's pathophysiology.

Blocking the RANTES/CCL5 signaling pathway during IH exposure prevented vascular inflammation and structural changes, suggesting that targeting this inflammatory response could be a potential treatment strategy for mitigating the cardiovascular risks associated with OSA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. Arnaud, C., Beguin, PC., Lantuejoul, S., et al.[2021]

Exposure to mild intermittent hypoxia significantly reduced the therapeutic continuous positive airway pressure (CPAP) needed to eliminate breathing events in 10 male participants, suggesting a potential improvement in treatment compliance for sleep apnea.

Unlike the sham protocol, which resulted in flow limitation and increased upper airway resistance, the intermittent hypoxia protocol maintained airway stability, indicating that this approach may enhance upper airway muscle activity and provide additional therapeutic benefits for sleep apnea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exposure to intermittent hypoxia and sustained hypercapnia reduces therapeutic CPAP in participants with obstructive sleep apnea. El-Chami, M., Sudan, S., Lin, HS., et al.[2019]

Obstructive sleep apnea (OSA) involves frequent episodes of upper airway obstruction and hypoxia during sleep, leading to significant health issues and making it a major socio-sanitary concern, especially in adults over 35.

Carotid body chemoreceptors play a crucial role in the pathophysiology of OSA, suggesting that targeted research on these receptors could lead to better understanding and treatment strategies for the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Some reflections on intermittent hypoxia. Does it constitute the translational niche for carotid body chemoreceptor researchers? Gonzalez, C., Yubero, S., Gomez-Niño, MA., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Intermittent Hypoxia/Hyperoxia Versus Intermittent Hypoxia/Normoxia: Comparative Study in Prediabetes. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Intermittent hypoxia initiated plasticity in humans: A multipronged therapeutic approach to treat sleep apnea and overlapping co-morbidities. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

The effects of intermittent hypoxia on human nasal mucosa. [2021]

4. England pubmed.ncbi.nlm.nih.gov

A randomized controlled crossover trial of acute intermittent and continuous hypoxia exposure in mild-moderate obstructive sleep apnea: A feasibility study. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Exposure to intermittent hypoxia and sustained hypercapnia reduces therapeutic CPAP in participants with obstructive sleep apnea. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Some reflections on intermittent hypoxia. Does it constitute the translational niche for carotid body chemoreceptor researchers? [2021]