Intermittent Hypoxia for Multiple Sclerosis

Overseen By Alexander Barry, MS, CCRC

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Shirley Ryan AbilityLab

Disqualifiers: Epilepsy, COPD, Uncontrolled hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 10

Duration: 4 weeks

21 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to understand the mechanisms of a novel intervention involving breathing short durations of low levels of oxygen for persons with multiple sclerosis (MS). This intervention with low levels of oxygen is called Acute Intermittent Hypoxia (AIH), the levels of oxygen experienced are similar to breathing the air on a tall mountain, for less than 1 minute at a time. Previous studies have shown that AIH is a safe and effective way to increase strength in persons with MS. Here the investigators aim to look at brain activation and ankle strength before and after AIH to gain a better understanding of how the AIH may improve strength in those persons with MS.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are using dalfampridine, you must have been on the same daily dose for at least 2 months before joining the study.

What data supports the effectiveness of the treatment Intermittent Hypoxia for Multiple Sclerosis?

Research shows that acute intermittent hypoxia (AIH) can improve nerve repair and reduce inflammation in a mouse model of Multiple Sclerosis (MS), suggesting it may help repair the nervous system and alter the disease course in MS. ^{1 2 3 4 5}

How is the treatment Acute Intermittent Hypoxia (AIH) unique for Multiple Sclerosis (MS)?

Acute Intermittent Hypoxia (AIH) is a novel, non-invasive treatment that involves brief periods of breathing low-oxygen air, which can enhance the body's ability to repair nerve damage and reduce inflammation in Multiple Sclerosis (MS). Unlike other treatments, AIH promotes remyelination (repair of nerve coverings) and alters the disease course by improving functional recovery and reducing inflammation. ^{1 2 5 6 7}

Research Team

Milap Sandhu, Pt, PhD

Principal Investigator

Shirley Ryan AbilityLab

Eligibility Criteria

This trial is for people with multiple sclerosis (MS) who are interested in a novel intervention that involves breathing low levels of oxygen intermittently, similar to the air on a tall mountain. The study will explore how this affects brain activation and ankle strength.

Inclusion Criteria

I have been free from cancer relapse for at least 1 year.

My motor function is moderately impaired.

My disability level is moderate to severe but I can still walk.

Exclusion Criteria

Uncontrolled hypertension (Systolic between 85 and 140, diastolic between 90 and 55)

Active contrast-enhancing MS lesions, or diffusion positive lesions suggestive of acute cerebrovascular disease on baseline MRI scan

History of epilepsy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 5 days of Acute Intermittent Hypoxia (AIH) or Sham-AIH interventions, followed by a 2-week washout period, and then another 5 days of the alternate intervention

4 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of neural activations and motor performance

4 weeks

Treatment Details

Interventions

• Acute Intermittent Hypoxia
• Sham-Acute Intermittent Hypoxia

Trial Overview The study is testing Acute Intermittent Hypoxia (AIH), where participants breathe short bursts of low-oxygen air. It compares AIH's effects on brain function and muscle strength against a sham procedure (a fake treatment that mimics AIH without using actual low oxygen).

Participant Groups

Group I: Sham First Experimental Treatment 2 Interventions

Participants in the Sham First arm will undergo 5 days of Sham-Acute Intermittent Hypoxia Interventions. Following the 5 Days of Sham-AIH, after a 2-week washout period, this group will then undergo 5 days of AIH Interventions. The procedures are identical to Sham-AIH but with 9-10% oxygen for the first breath cycle

Group II: AIH First Experimental Treatment 2 Interventions

Participants in the AIH First arm will undergo 5 days of Acute Intermittent Hypoxia Interventions. Following the 5 Days of AIH, after a 2-week washout period, this group will then undergo 5 days of Sham AIH Interventions. The procedures are identical to AIH but with 21% oxygen for both breath cycles

Who Is Running the Clinical Trial?

Shirley Ryan AbilityLab

Lead Sponsor

Trials

212

Recruited

17,900+

Northwestern University

Collaborator

Trials

1,674

Recruited

989,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Findings from Research

The study found that individuals with the APOE 4 genotype showed lower diaphragm motor-evoked potential (MEP) enhancements in response to acute intermittent hypercapnic-hypoxia (AIHH), indicating that genetic factors can influence the effectiveness of this rehabilitation strategy.

Additionally, the research revealed that males had a greater enhancement in diaphragm MEP compared to females, and that age negatively affected respiratory motor plasticity, highlighting the importance of biological factors in individual responses to AIHH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia. Nair, J., Welch, JF., Marciante, AB., et al.[2023]

Acute intermittent hypoxia (AIH) significantly improved functional recovery and reduced inflammation in a mouse model of Multiple Sclerosis (EAE), indicating its potential as a non-invasive therapy for CNS repair.

AIH enhanced myelination and recruited oligodendrocyte precursor cells to demyelinated areas, suggesting it could alter the disease course and promote neuroregeneration in MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS. Tokarska, N., Naniong, JMA., Johnston, JM., et al.[2023]

Intermittent hypoxia (IH) in a rat model led to increased inflammation in the liver and a significant decrease in the expression of cytochrome P450 enzymes, which are crucial for drug metabolism.

The study highlights the potential risk for patients with obstructive sleep apnea (OSA) who are on medications metabolized by the liver, as IH may impair liver function and drug processing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic Cyp1a2 Expression Reduction during Inflammation Elicited in a Rat Model of Intermittent Hypoxia. Shi, LX., Wang, X., Wu, Q., et al.[2021]

Intermittent hypobaric hypoxia (IHH) effectively protects the brain from injury caused by acute severe hypoxia (ASH) in rats, as shown by reduced oxidative stress and apoptosis-related damage.

The neuroprotective effects of IHH are linked to the downregulation of NF-κB and an increase in erythropoietin (EPO) levels, suggesting a mechanism that prevents oxidative injury and promotes cell survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia. Coimbra-Costa, D., Garzón, F., Alva, N., et al.[2021]

Acute intermittent hypoxia (AIH) is a safe treatment that involves alternating between low and normal oxygen levels, but in this study, it did not significantly change the excitability of the primary motor cortex in healthy participants.

Despite a notable drop in arterial oxygen saturation during AIH, there were no measurable effects on corticospinal excitability or intracortical circuits, suggesting that AIH may need to be adjusted in severity or tailored to individuals for potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acute intermittent hypoxia on corticospinal excitability within the primary motor cortex. Radia, S., Vallence, AM., Fujiyama, H., et al.[2022]

A 7-day intermittent hypoxia (IH) protocol with 60-minute daily exposures significantly increased the hypoxic ventilatory response (HVR) by 67%, while a protocol with shorter, multiple bouts increased HVR by 49%, indicating both methods can enhance breathing responses to low oxygen levels.

The longer duration intermittent hypoxia (LDIH) also significantly improved the hypercapnic ventilatory response (HCVR) by 44.1%, which remained elevated for a week after the protocol, while the shorter duration intermittent hypoxia (SDIH) showed smaller, non-significant improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of two different intermittent hypoxia protocols on ventilatory responses to hypoxia and carbon dioxide at rest. Koehle, M., Sheel, W., Milsom, W., et al.[2016]

In a study of 17 healthy adults, it was found that individuals with the APOE4 genotype showed lower respiratory motor plasticity in response to acute intermittent hypercapnic-hypoxia (AIHH), suggesting genetic factors can influence the effectiveness of this rehabilitation strategy.

Additionally, males demonstrated greater improvements in diaphragm motor function compared to females, and older age was associated with reduced respiratory response, highlighting the importance of sex and age as biological determinants in AIHH outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia. Nair, J., Welch, JF., Marciante, AB., et al.[2023]

References

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

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia. [2023]

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

Acute intermittent hypoxia alters disease course and promotes CNS repair including resolution of inflammation and remyelination in the experimental autoimmune encephalomyelitis model of MS. [2023]

3. China pubmed.ncbi.nlm.nih.gov

Hepatic Cyp1a2 Expression Reduction during Inflammation Elicited in a Rat Model of Intermittent Hypoxia. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Intermittent Hypobaric Hypoxic Preconditioning Provides Neuroprotection by Increasing Antioxidant Activity, Erythropoietin Expression and Preventing Apoptosis and Astrogliosis in the Brain of Adult Rats Exposed to Acute Severe Hypoxia. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Effects of acute intermittent hypoxia on corticospinal excitability within the primary motor cortex. [2022]

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

The effect of two different intermittent hypoxia protocols on ventilatory responses to hypoxia and carbon dioxide at rest. [2016]

7. England pubmed.ncbi.nlm.nih.gov

APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia. [2023]