AIH for Spinal Cord Injury

Overseen By Monica A Perez, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: VA Office of Research and Development

Must not be taking: Antipsychotics, Tricyclic antidepressants

Disqualifiers: Pulmonary, Cardiovascular, Orthopedic, others

Compensation: Varies

Number of Visits: 1

Duration: 12 weeks

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new methods to help people with spinal cord injuries improve arm and hand movements. The study combines breathing treatments, exercise, and medication to enhance recovery. Researchers aim to determine if these combinations can restore more movement in the arms and hands. Candidates may qualify if they have had a spinal cord injury for over a year, can grip small objects, and have some feeling in their hands. As an Early Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects on people.

Will I have to stop taking my current medications?

The trial requires that participants do not take drugs that act primarily on the central nervous system and lower the seizure threshold, such as antipsychotic drugs and tricyclic antidepressants. If you are on these medications, you may need to stop taking them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that combining acute intermittent hypoxia (AIH) with exercise is generally safe and can improve movement in people with spinal cord injuries. Studies have found that short AIH sessions aid in walking and motor skills without causing serious side effects, making this approach a safe and noninvasive therapy.

Less information exists about the treatment that combines AIH, exercise, and an NMDA agonist (a drug affecting brain signals). However, AIH paired with exercise has improved movement in animal studies. This combination appears promising but remains in the early stages of research, where scientists primarily observe its effects on people and monitor for side effects.

In early-stage trials like this, researchers focus on ensuring the treatments are safe for humans. If major safety concerns arose, the trial would not proceed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for spinal cord injury, which often focus on stabilizing the spine or managing symptoms, these investigational approaches are unique because they combine hypoxia (a condition of reduced oxygen) with exercise training. This combination aims to potentially enhance neuroplasticity, which is the brain and spinal cord's ability to reorganize and form new connections. Additionally, some arms of the treatment explore the use of D-cycloserine, an NMDA receptor agonist, thought to further promote neural recovery. Researchers are excited about these treatments because they target the underlying mechanisms of injury recovery rather than just alleviating symptoms, offering hope for improved functional outcomes.

What evidence suggests that this trial's treatments could be effective for spinal cord injury?

Studies have shown that brief periods of low oxygen levels, known as acute intermittent hypoxia (AIH), can improve physical and motor functions in people with partial spinal cord injuries. This process involves short sessions of breathing low-oxygen air followed by normal air, which helps the body adjust and improve. In this trial, some participants will receive AIH combined with exercise training, which has enhanced recovery of skills like walking and using the arms. Other participants will receive AIH and exercise training with an NMDA agonist, a chemical that boosts brain activity, which research suggests might further aid motor recovery. Although the exact effects are still under study, these methods show promise in improving recovery after spinal cord injuries. ^{1 2 3 6 7}

Who Is on the Research Team?

Martin Oudega, PhD

Principal Investigator

Edward Hines Jr. VA Hospital, Hines, IL

Are You a Good Fit for This Trial?

This trial is for adults aged 18-85 with chronic cervical spinal cord injury (cSCI) at least a year old, who can perform certain hand grips and have some sensory function in specific areas. It's not for those with severe heart conditions, uncontrolled medical issues, major depression or psychosis, history of head injury or stroke, metal plates in the skull, seizure history, CNS-affecting drugs use, pregnancy or ongoing spinal complications.

Inclusion Criteria

I am a veteran aged between 18 and 85.

I have a lung condition like COPD.

I have had a spinal cord injury for over a year.

Exclusion Criteria

I am taking medication that affects my brain and could make seizures more likely.

I have had a head injury or stroke in the past.

I do not have unmanaged lung, heart, or bone problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo repetitive acute intermittent hypoxia (rAIH) combined with motor training, with or without NMDA agonist treatment, to promote recovery of motor function after chronic contusive cervical spinal cord injury (cSCI).

12 weeks

Baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of grip and pinch strength.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• D-cycloserine
• exercise training
• hypoxia
• sham-NMDA agonist

Trial Overview The study tests whether combining acute intermittent hypoxia (rAIH) with motor training enhances upper limb function recovery after cSCI. Using an adult rat model first to inform human trials later on. Participants will undergo rAIH and exercise training versus sham treatments to compare effects on motor skills.

How Is the Trial Designed?

Group I: hypoxia plus training plus NMDA agonist Experimental Treatment 3 Interventions

combined hypoxia treatment with exercise training and with NMDA agonist treatment

Group II: hypoxia plus training Experimental Treatment 2 Interventions

combined hypoxia treatment with exercise training

Group III: sham hypoxia plus training Placebo Group 2 Interventions

combined sham hypoxia treatment with exercise training

Group IV: hypoxia plus training plus sham NMDA agonist Placebo Group 3 Interventions

combined hypoxia treatment with exercise training and with sham NMDA agonist treatment

D-cycloserine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Seromycin for:

• Tuberculosis

Approved in European Union as Seromycin for:

• Tuberculosis

Approved in Canada as Seromycin for:

• Tuberculosis

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

This pilot study aims to assess the safety and feasibility of administering oral glyburide to 10 patients with acute cervical spinal cord injury within 8 hours of injury, building on preclinical evidence that glyburide can reduce secondary injury effects like progressive hemorrhagic necrosis.

Glyburide is considered a promising neuroprotective strategy due to its potential to mitigate secondary injury mechanisms, despite the risk of hypoglycemia, making it an interesting addition to standard care for spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SCING-Spinal Cord Injury Neuroprotection with Glyburide: a pilot, open-label, multicentre, prospective evaluation of oral glyburide in patients with acute traumatic spinal cord injury in the USA. Minnema, AJ., Mehta, A., Boling, WW., et al.[2020]

Eriodictyol (EDC) treatment in spinal cord injury (SCI) rats significantly improved locomotor activity and reduced myelin loss, indicating its potential as a therapeutic agent.

The neuroprotective effects of EDC are linked to increased levels of neurotrophic factors GCDNF and BDNF, as well as the modulation of apoptosis-related proteins Bcl-2 and Bax.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eriodictyol corrects functional recovery and myelin loss in SCI rats. Li, C., Wang, C.[2023]

Gacyclidine (GK-11) demonstrated the most effective neuroprotective efficacy among the tested NMDA receptor antagonists, significantly reducing the time needed for functional recovery in a rat spinal cord injury model.

Compared to Dizocilpine (MK-801) and Cerestat (CNS-1102), which showed only partial effects, Gacyclidine's single dose treatment was optimal, suggesting prolonged use may be harmful, and indicating its potential as a promising agent for improving recovery after spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury. Feldblum, S., Arnaud, S., Simon, M., et al.[2013]

Acute intermittent hypoxia (AIH) treatment, when combined with specific motor training, can enhance motor recovery in rats with incomplete spinal cord injuries, as evidenced by improved performance on a ladder-crossing task after 7 days of treatment starting 4 weeks post-injury.

However, AIH alone or in combination with non-specific training did not lead to improvements in other motor tasks, highlighting the importance of task-specific training for maximizing the benefits of AIH in promoting neural plasticity and recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed Intervention with Intermittent Hypoxia and Task Training Improves Forelimb Function in a Rat Model of Cervical Spinal Injury. Prosser-Loose, EJ., Hassan, A., Mitchell, GS., et al.[2015]

Acute intermittent hypoxia (AIH) is a safe and effective therapy that can enhance strength, walking speed, endurance, and dynamic balance in individuals with chronic, incomplete spinal cord injury (SCI).

AIH shows promise for promoting walking recovery through neuroplasticity mechanisms, but more research is needed to determine its effectiveness across larger groups and to identify optimal treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute intermittent hypoxia as a potential adjuvant to improve walking following spinal cord injury: evidence, challenges, and future directions. Tan, AQ., Barth, S., Trumbower, RD.[2022]

Acute intermittent hypoxia (AIH) significantly improved lower extremity muscle strength in adults with chronic incomplete spinal cord injury, with torque increasing by approximately 20% at 30 minutes and 30% at 60 minutes post-AIH.

Pretreatment with ibuprofen did not enhance the effects of AIH on muscle strength, indicating that while AIH is effective for improving leg strength, systemic inflammation management with ibuprofen may not be necessary for its benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of acute intermittent hypoxia on motor function in individuals with chronic spinal cord injury following ibuprofen pretreatment: A pilot study. Lynch, M., Duffell, L., Sandhu, M., et al.[2018]

Therapeutic acute intermittent hypoxia (tAIH) shows promise in improving both respiratory and non-respiratory motor functions in individuals with neuromuscular disorders, particularly those with chronic spinal cord injuries, as highlighted in recent workshops aimed at clinical translation.

Key recommendations for advancing tAIH include enhancing our understanding of its mechanisms, optimizing treatment protocols, identifying effective combinatorial therapies, and ensuring long-term safety, which are essential for its potential routine clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease. Vose, AK., Welch, JF., Nair, J., et al.[2023]

The study involved 35 participants with incomplete spinal cord injury, testing the effects of combined intermittent hypoxia and body weight-supported treadmill training over 4 weeks.

Results showed that while standing balance did not improve significantly, participants receiving intermittent hypoxia demonstrated significantly faster dynamic balance measures, indicating potential benefits for mobility in individuals with spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent Hypoxia and Locomotor Training Enhances Dynamic but Not Standing Balance in Patients With Incomplete Spinal Cord Injury. Navarrete-Opazo, A., Alcayaga, JJ., Sepúlveda, O., et al.[2018]

In a study involving spinally transected adult rats, it was found that active exercise (treadmill) and serotonergic pharmacotherapy (quipazine) work together to enhance cortical reorganization, while passive exercise (bike) and quipazine compete against each other, limiting the reorganization effects.

The research highlights the importance of combining different therapeutic strategies for spinal cord injury, suggesting that an integrated approach can lead to better outcomes in promoting cortical reorganization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactive Effects Between Exercise and Serotonergic Pharmacotherapy on Cortical Reorganization After Spinal Cord Injury. Foffani, G., Shumsky, J., Knudsen, EB., et al.[2018]

Acute intermittent hypoxia (AIH) combined with motor training significantly increases the expression of key proteins related to plasticity and recovery in spinal neurons after spinal cord injury (SCI), suggesting a mechanism for improved recovery.

In a study involving SCI rats, both 1 and 7 days of AIH treatment led to increased levels of hypoxia-inducible factor-1α (HIF-1α), while longer treatment (7 days) also elevated vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), indicating that AIH may enhance recovery of motor function by promoting cellular changes in the spinal cord.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression. Hassan, A., Arnold, BM., Caine, S., et al.[2018]

Repetitive acute intermittent hypoxia (AIH) for 12 weeks significantly improved forelimb reach-to-grasp performance in rats with chronic cervical spinal cord injury, showing sustained benefits even 12 weeks post-treatment.

While AIH enhanced specific motor functions related to reaching tasks, it did not impact other motor tasks like ladder walking or adhesive removal, indicating that the benefits of AIH are task-specific when combined with targeted training.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged acute intermittent hypoxia improves forelimb reach-to-grasp function in a rat model of chronic cervical spinal cord injury. Arnold, BM., Toosi, BM., Caine, S., et al.[2021]

Acute spinal cord injury (ASCI) leads to significant motor, sensory, and autonomic deficits, primarily affecting young adults and requiring extensive long-term care, highlighting the need for effective treatments.

Current research has identified several pharmacological agents, such as methylprednisolone and GM-1 ganglioside, that show modest benefits in clinical trials, but there is a pressing need for more effective neuroprotective therapies like riluzole and minocycline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of clinical trials for acute spinal cord injury. Fehlings, MG., Baptiste, DC.[2007]

Acute intermittent hypoxia (AIH) combined with task-specific training (TST) can significantly enhance motor function recovery after spinal cord injuries, suggesting a promising therapeutic approach.

The study proposes a hypothetical model to explain how AIH and TST work together at the neural and cellular levels, aiming to guide future experiments that could optimize their combined neurotherapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergy between Acute Intermittent Hypoxia and Task-Specific Training. Welch, JF., Sutor, TW., Vose, AK., et al.[2022]

Daily acute intermittent hypoxia (AIH) combined with hand opening practice significantly improved hand dexterity and function in all six participants with chronic cervical spinal cord injury, as evidenced by better scores on the Box and Block Test and reduced times on the Jebsen-Taylor Hand Function Test.

The study suggests that AIH may enhance the effectiveness of rehabilitation by promoting neural plasticity, but further research is needed to determine the optimal dosage, safety, and long-term effects of this intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study. Trumbower, RD., Hayes, HB., Mitchell, GS., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4475712/

Efficacy of Acute Intermittent Hypoxia on Physical Function ... Exposure to relatively brief sessions of intermittent hypoxia has been shown to benefit respiratory, physical, and motor function in humans with incomplete SCI.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26167303/

Efficacy of Acute Intermittent Hypoxia on Physical Function ... A promising approach to improve physical function in persons with SCI is exposure to acute intermittent hypoxia (IH) in the form of a small amount of sessions ...

3. ahajournals.org ahajournals.org/doi/10.1161/STROKEAHA.124.047261

Acute Intermittent Hypoxia With High-Intensity Gait Training ... Participants received up to 15 sessions of AIH for 30 minutes using 15 cycles of hypoxia (60–90 seconds; 8%–9% O2) and normoxia (30–60 seconds; ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03922802

SCI Acute Intermittent Hypoxia and Non-Invasive Spinal ... This is a single blind, sham controlled crossover trial that will evaluate the effectiveness of acute intermittent hypoxia therapy (AIH) combined with ...

5. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0197486

Acute intermittent hypoxia and rehabilitative training following ... AIH treatment and motor training for 7 days increased the expression of BDNF protein in spinal neurons in both C6-7 and L4-5 segments of spinal cord relative to ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0014488621000741

Daily acute intermittent hypoxia combined with walking ... Five days of AIH and walking practice (AIH+WALK) improved walking speed and endurance in persons with chronic, incomplete SCI.

7. bmcneurol.biomedcentral.com bmcneurol.biomedcentral.com/articles/10.1186/s12883-020-01851-9

Daily acute intermittent hypoxia to improve walking function in ... Acute intermittent hypoxia (AIH) is a relatively safe and noninvasive therapy that holds tremendous promise in promoting walking recovery in ...