Intermittent Hypoxia-initiated Plasticity in Humans: A Multi-pronged Therapeutic Approach to Treat Sleep Apnea and Overlapping Co-morbidities

NCT05558501 | Recruiting Phase 1 DMC

• 2 other identifiers: PULM-003-22SCX000125
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Obstructive Sleep Apnea

Keywords

Intermittent Hypoxia; Microvascular Function; Fatigability; Maximal Oxygen Consumption; Sympatho-Vagal Balance; CPAP Adherence; Arousal Threshold

Outcome Measures

Primary Outcomes (3)

• Change in Blood Pressure

  Blood pressure measures over 24 hours will be obtained. Blood pressure will be measured every 20 minutes beginning on Sunday at 6 AM and ending Monday at 6 AM. Participants will wear an actigraph (Actiwatch Spectrum, Respironics) and record their activities in a journal to determine the arousal state (i.e., active wakefulness, quiet wakefulness and sleep) associated with each blood pressure measurement. The data will be separated into active-awake, rest-awake and sleep based on the activity log and corresponding data from an actigraph watch. The average value of blood pressure in a healthy individual is 120/80 mmHg. In their participants with OSA, the investigators expect the blood pressure to be higher at baseline and decrease 15 days after treatment. The investigators also expect that this reduction will be maintained at 4 and 8-weeks following treatment.

  Change at 15 days, 4 and 8- weeks following treatment compared to baseline

• Change in Microvascular Function (Maximal hyperemic Response)

  Microvascular reactivity associated with hyperemia induced by vascular occlusion will be determined by analyzing the maximal hyperemic response (MHR) of tissue saturation index (TSI) signal derived from near-infrared spectroscopy (NIRS) of the lateral gastrocnemius muscle of the non-dominant leg. The average value of TSI MHR of the NIRS signals in healthy individuals is 159±9 %. In their participants with OSA, the investigators expect these values to be lower at baseline and to increase 15 days after treatment. The investigators also expect that the increase will be maintained 4 and 8-weeks following treatment.

  Change at 15 days, 4 and 8- weeks following treatment compared to baseline

• Change in Microvascular Function (Time to reach Maximal Hyperemic Response)

  Microvascular reactivity associated with hyperemia induced by vascular occlusion will be determined by analyzing the time to reach maximal hyperemic response (tM) of tissue saturation index (TSI) signal derived from near-infrared spectroscopy (NIRS) of the lateral gastrocnemius muscle of the non-dominant leg. The average value of tM TSI in healthy individuals is 39±5 s. In their participants with OSA, the investigators expect these values to be higher at baseline and to lower 15 days after treatment. The investigators also expect that the decrease will be maintained 4 and 8-weeks following treatment.

  Change at 15 days, 4 and 8- weeks following treatment compared to baseline

Secondary Outcomes (7)

• Change in Muscle Oxygen Extraction (Time Delay)

  Change at 15 days following treatment compared to baseline

• Change in Muscle Oxygen Extraction (Mean Response Time)

  Change at 15 days following treatment compared to baseline

• Change in Sympatho-Vagal Balance (Blood Pressure Variability)

  Change at 15 days, 4 and 8- weeks following treatment compared to baseline

• Change in Muscle Oxygen Extraction (Tau)

  Change at 15 days following treatment compared to baseline

• Change in Maximal Oxygen Consumption

  Change at 15 days, 4 and 8- weeks following treatment compared to baseline

Other Outcomes (3)

• Change in CPAP Adherence

  Change at 15 days, 4 and 8-weeks following treatment compared to baseline

• Change in Arousal Threshold

  Change at 15 days, 4 and 8- weeks following treatment compared to baseline

• Change in Sleep Apnea Severity

  Change at 15 days, 4 and 8-weeks following treatment compared to baseline

Study Arms (2)

Mild Intermittent Hypoxia (MIH)

EXPERIMENTAL

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.

Other: Mild Intermittent Hypoxia

Sham Mild Intermittent Hypoxia (Sham MIH)

SHAM COMPARATOR

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

Other: Sham MIH

Interventions

Mild Intermittent Hypoxia OTHER

The MIH protocol will be comprised of a 20-minute baseline period followed by exposure to twelve two-minute episodes of hypoxia \[partial pressure of end-tidal oxygen (PETO2)= 50 mmHg\]. Each episode will be interspersed with a 2-minute recovery period under normoxic conditions. The final episode will be followed by a 30-minute end-recovery period. The partial pressure of end-tidal carbon dioxide (PETCO2) will be sustained 2 mmHg above baseline values for the last ten minutes of baseline and throughout the remainder of the protocol. To rapidly induce a PETO2 of 50 mmHg participants will inspire a gas mixture comprised of 8 % oxygen and 92 % nitrogen from a non-diffusible bag. To maintain PETO2 (i.e. 50 mmHg) and PETCO2 (i.e. 2 mmHg above baseline) at the desired levels supplemental oxygen and carbon dioxide will be added to the inspiratory line from the output of a flow meter device that receives inputs from tanks of 100 % oxygen and 100 % carbon dioxide.

Mild Intermittent Hypoxia (MIH)

Sham MIH OTHER

During "sham MIH" the participants will be exposed to compressed air (the equivalent of room air).

Sham Mild Intermittent Hypoxia (Sham MIH)

Eligibility Criteria

• Age: 30 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female of any race, 30-60 years of age with a BMI of less than 40 kg/m2 and a weight to hip ratio of less than 1.3in males and 1.2 in females along with pure or predominantly (i.e., comprised of both a central and obstructive component)OSA (AHI less than or equal to 100 events per hour and an average oxygen desaturation level of 85 % or greater).
• Participants will be newly diagnosed and not previously treated with CPAP.
• Participants will also be diagnosed with hypertension. Participants will either be untreated or will be treated unsuccessfully with a single prescribed medication for hypertension. Hypertension will be classified according to the American Heart Association 2018 criteria which includes an elevated systolic blood pressure in the range of 120-129 and a diastolic pressure less than 80 mmHg in addition to stage I and stage II hypertension defined by a systolic blood pressure greater than 130 mmHg and a diastolic pressure greater than 80 mmHg.
• Participants will also be included if they are pre-diabetic (HbA1C: 5.7 - 6.4 %; fasting blood glucose: 100 - 125 mg/dL) and have cholesterol levels ranging from 200-239 mg/dL.
• All participants will have normal lung function and a normal EKG with no or minimal alcohol consumption (\< 2 oz of alcohol/night).
• Females will be studied at similar points in their menstrual cycle.

You may not qualify if:

• Participants with baseline blood pressure greater than 160/110 will be excluded from participation.
• Participants on any medications, with the exception of a single prescribed medication for individuals with resistant hypertension.
• Participants with any other known disease (e.g. pulmonary hypertension).
• Participants using any sleep promoting supplements including melatonin.
• Night shift workers or participants who recently travelled across time zones.
• Pregnant females.

Sponsors & Collaborators

• VA Office of Research and Development: lead
• John D. Dingell VA Medical Center: collaborator

Study Sites (1)

John D. Dingell VA Medical Center, Detroit, MI

Detroit, Michigan, 48201-1916, United States

RECRUITING

MeSH Terms

Conditions

Sleep Apnea, Obstructive

Condition Hierarchy (Ancestors)

Sleep Apnea Syndromes; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases

Study Officials

• Jason H Mateika, PhD MS BS

  John D. Dingell VA Medical Center, Detroit, MI

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jason H Mateika, PhD MS BS

CONTACT

(313) 576-4481; jmateika@med.wayne.edu

Shipra Puri

CONTACT

(313) 576-1000; shiprapuri@wayne.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: The study participants will be blinded to the composition of the gas mixture. In addition, the research staff that do not administer the treatment (gas mixture) will complete a blind analysis of all the outcome measures.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: The present study utilizes a double blind parallel randomized design using an equal allocation ratio for each arm. Block randomization will be conducted to reduce the probability that a disproportionate number of participants are randomized to one group. Mild intermittent hypoxia and "sham MIH" will be administered during wakefulness each day for 15 days over a 3-week period.

Study Record Dates

• First Submitted: September 19, 2022
• First Posted: September 28, 2022
• Study Start: January 1, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: December 4, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)