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

Trial Summary

What is the purpose of this trial?

Contusive cervical spinal cord injury (cSCI) impairs upper limb function (reach-and-grasp) which limits daily-life activities and thus decreases the quality of life. Promoting neuroplasticity may support upper limb recovery after SCI. Repetitive exposure to acute intermittent hypoxia (rAIH) combined with motor training promotes recovery of motor function after SCI; however, the overall effects of rAIH/training are limited. The investigators will use an adult rat model of long-term contusive cSCI to study novel approaches to enhance the effect of rAIH/training on forelimb function and study the neuronal substrate underlying the effects. The findings will be used to direct the development of more effective rAIH/training approaches for people with contusive, functionally incomplete, cSCI. Because deficits in upper limb function are a major problem after stroke, amyotrophic lateral sclerosis, multiple sclerosis, and other motor disorders, this work may also be relevant for patients with other types of central nervous system (CNS) lesions.

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.

What data supports the effectiveness of the treatment AIH for Spinal Cord Injury?

Research shows that acute intermittent hypoxia (AIH), when combined with specific motor training, can improve motor function in animal models of spinal cord injury by enhancing neural plasticity (the brain's ability to adapt and reorganize). This combination has been shown to reduce errors in tasks like ladder walking in rats, suggesting potential benefits for motor recovery in humans with spinal cord injuries. ^{1 2 3 4 5}

Is AIH for Spinal Cord Injury safe for humans?

The provided research articles do not contain specific safety data for AIH (Acute Intermittent Hypoxia) or related treatments like D-cycloserine, Seromycin, or Intermittent Hypoxia Therapy in humans. Therefore, no relevant safety information is available from these sources. ^{6 7 8 9 10}

How does the treatment for spinal cord injury using AIH and D-cycloserine differ from other treatments?

This treatment is unique because it combines acute intermittent hypoxia (AIH), which involves brief periods of low oxygen to promote nerve plasticity, with D-cycloserine, a drug that may enhance the effects of AIH. This approach aims to improve motor function by leveraging the body's natural ability to adapt and reorganize after injury, which is different from traditional therapies that may not target these specific mechanisms. ^{3 11 12 13 14}

Research Team

Martin Oudega, PhD

Principal Investigator

Edward Hines Jr. VA Hospital, Hines, IL

Eligibility Criteria

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 am between 18 and 80 years old.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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) 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]

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]

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]

References

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

Delayed Intervention with Intermittent Hypoxia and Task Training Improves Forelimb Function in a Rat Model of Cervical Spinal Injury. [2015]

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

Intermittent Hypoxia and Locomotor Training Enhances Dynamic but Not Standing Balance in Patients With Incomplete Spinal Cord Injury. [2018]

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

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression. [2018]

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

Synergy between Acute Intermittent Hypoxia and Task-Specific Training. [2022]

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

Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study. [2022]

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

Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury. [2013]

7. Germany pubmed.ncbi.nlm.nih.gov

Eriodictyol corrects functional recovery and myelin loss in SCI rats. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Current status of clinical trials for acute spinal cord injury. [2007]

9. England 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. [2020]

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

Interactive Effects Between Exercise and Serotonergic Pharmacotherapy on Cortical Reorganization After Spinal Cord Injury. [2018]

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

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

12. England 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. [2018]

13. United States 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. [2021]

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

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease. [2023]