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AIH for Spinal Cord Repair

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ClinicalTrials.gov Identifier: NCT03780829
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : April 6, 2021
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
SCI Behavioral: hypoxia Behavioral: sham hypoxia Drug: D-cycloserine Drug: sham-NMDA agonist Behavioral: exercise training Early Phase 1

Detailed Description:

The overall goal is to develop effective, clinically applicable, approaches to restore upper limb function (reach-and-grasp) after chronic contusive cervical spinal cord injury (cSCI). Impairments in upper limb function significantly reduce the quality of life for people with cSCI. Reach-and-grasp actions in animals and humans are largely controlled by the corticospinal tract (CST). The investigators argue that promoting plasticity within the CST may support the recovery of upper limb function after cSCI. Repetitive exposure to acute intermittent hypoxia (rAIH) combined with motor training is a safe, minimally invasive, treatment that elicits neuroplasticity resulting in improved recovery after cSCI, but its overall effects remain limited. The main goals are to: 1) enhance rAIH/training-induced aftereffects on forelimb function and increase the understanding of the neuronal substrates in an adult rat model of chronic contusive cSCI, and 2) use this knowledge to guide the development of more effective rAIH/training approaches to improve upper limb function in humans with chronic contusive cSCI.

In Specific Aim 1, using an adult rat model of chronic contusive cSCI, the investigators will investigate the effects of rAIH frequency and dose on rAIH/training-mediated functional recovery of the impaired forelimb. Also, the investigators will combine rAIH/training with N-methyl-D-aspartate receptor (NMDA)-mediated synaptic plasticity through D-cycloserine treatment and study the effects on recovery of forelimb function. Immunocytochemistry with imaging techniques will be used to assess structural neuronal plasticity in the CST after rAIH/training. In Specific Aim 2, in people with chronic incomplete cSCI, guided by the findings in Specific Aim 1, the investigators will study the effects of rAIH frequency and concurrent D-cycloserine treatment on rAIH/training-mediated upper limb function recovery. The investigators will comprehensively analyze the effects of rAIH on the strength of electrophysiological and functional aftereffects in the upper limb.

The proposed research will provide new knowledge on rAIH/training-mediated functional and anatomical aftereffects (Specific Aim 1), which will be used to develop effective rAIH/training protocols for people with contusive, functionally incomplete, cSCI (Specific Aim 2). The data from the investigators' experiments may lead to clinically applicable approaches that improve arm and hand function recovery after chronic contusive cSCI, which would positively impact the quality of life of Veterans with cSCI. The relevance of this proposal is emphasized by the limited efficacy of current strategies to improve upper limb function after cSCI.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 175 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: repetitive intermittent hypoxia treatment combined with exercise and/or NMDA agonist
Masking: Double (Participant, Investigator)
Masking Description: participants and some research personnel will be blinded
Primary Purpose: Treatment
Official Title: Repetitive Acute Intermittent Hypoxia for Spinal Cord Repair
Actual Study Start Date : February 25, 2020
Estimated Primary Completion Date : January 31, 2024
Estimated Study Completion Date : January 31, 2024
Arms and Interventions
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Arm Intervention/treatment
Experimental: hypoxia plus training
combined hypoxia treatment with exercise training
 Behavioral: hypoxia
intermittent cycles of normoxia-hypoxia

Behavioral: exercise training
bimanual massed practice training
Sham Comparator: sham hypoxia plus training
combined sham hypoxia treatment with exercise training
 Behavioral: sham hypoxia
intermittent cycles of sham hypoxia

Behavioral: exercise training
bimanual massed practice training
Experimental: hypoxia plus training plus NMDA agonist
combined hypoxia treatment with exercise training and with NMDA agonist treatment
 Behavioral: hypoxia
intermittent cycles of normoxia-hypoxia

Drug: D-cycloserine
NMDA agonist treatment
Other Name: NMDA agonist

Behavioral: exercise training
bimanual massed practice training
Placebo Comparator: hypoxia plus training plus sham NMDA agonist
combined hypoxia treatment with exercise training and with sham NMDA agonist treatment
 Behavioral: hypoxia
intermittent cycles of normoxia-hypoxia

Drug: sham-NMDA agonist
sham-NMDA agonist treatment

Behavioral: exercise training
bimanual massed practice training


Outcome Measures
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Primary Outcome Measures :
  1. Change in grip strength [ Time Frame: baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week ]
    Grip strength will be measured using a hand-held dynamometer, with an average force (measured in dynes) taken over the course of three trials. A rest break is provided between trials. Strength testing will be completed bilaterally.

  2. Change in pinch strength [ Time Frame: baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week ]
    Pinch strength will be assessed using a digital pinch gauge (unit of Force= Newton). The minimum value of zero will be assigned when a participant cannot actively squeeze the pinch meter between the thumb and index finger. The mean value of total of 3 trials will be assessed, with a rest break provided between trials.

  3. Change in motor evoked potential size [ Time Frame: 30 minutes before and 30 minutes after intervention ]
    Resting and active motor thresholds (RMT and AMT) will be tested in each of the muscles using a stimulator.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male and females Veterans between 18-80 years
  • Chronic cSCI (1 yr of injury)
  • Cervical injury at C8 or above
  • Sensory function: impaired (score of 1) but not absent (score of 0) or intact (score of 2) innervations in dermatomes C6, C7 and C8 during light touch and pin prick stimulus using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) sensory scores
  • Motor function: Able to grasp small objects with one hand and able to perform a visible precision grasp between the index finger and thumb

  • Motor scores ISNCSCI: 1 to 4 but not 5 on finger flexors and finger abductors on the hand tested.

    • These criteria were selected to ensure that hand impairment will not interfere with the ability to perform training and proposed tests

Inclusion criteria for controls:

  • Male and females (18-80 years)
  • Right handed
  • Able to complete precision and power grips

Exclusion Criteria:

  • Uncontrolled medical problems including pulmonary, cardiovascular or orthopedic disease
  • Any debilitating disease prior to the SCI that caused exercise intolerance
  • Premorbid, ongoing major depression or psychosis, altered cognitive status
  • History of head injury or stroke
  • Pacemaker
  • Metal plate in skull
  • History of seizures

  • Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold such as antipsychotic drugs

    • chlorpromazine
    • clozapine
    • or tricyclic antidepressants
  • Pregnant females
  • Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal cord disease as spinal stenosis, spina bifida or herniated cervical disk
  • Presence of autonomic dysreflexia

Exclusion criteria for healthy controls:

  • Same as for SCI individuals
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03780829


Contacts
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Contact: Martin Oudega, PhD (305) 575-7000 moudega@sralab.org
Contact: Monica A Perez, PhD (708) 202-5702 Monica.Perez@va.gov

Locations
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United States, Illinois
Edward Hines Jr. VA Hospital, Hines, IL Recruiting
Hines, Illinois, United States, 60141-5000
Contact: Martin Oudega, PhD    305-575-7000    moudega@sralab.org   
Principal Investigator: Martin Oudega, PhD         
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Principal Investigator: Martin Oudega, PhD Edward Hines Jr. VA Hospital, Hines, IL
More Information
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT03780829    
Other Study ID Numbers: B2848-R
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: April 6, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by VA Office of Research and Development:
spinal cord injury
hypoxia
plasticity
Additional relevant MeSH terms:
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Cycloserine
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Antibiotics, Antitubercular
 Antitubercular Agents
Anti-Bacterial Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action