Istradefylline + Low Oxygen Therapy for Spinal Cord Injury

Overseen By William Muter

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Randy Trumbower, PT, PhD

Must not be taking: Caffeine, NSAIDs

Disqualifiers: Cardiovascular disease, Diabetes, Epilepsy, others

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

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining istradefylline with low oxygen therapy can improve walking in individuals with spinal cord injuries. Low oxygen therapy involves breathing reduced oxygen levels to strengthen nerve connections for better mobility. The study will assess whether istradefylline can enhance these benefits by counteracting certain effects of low oxygen therapy. Participants should have had a spinal cord injury for over a year, with some ability to move their legs and take a step unassisted. As a Phase 1/Phase 2 trial, this research seeks to understand how the treatment works and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in spinal cord injury treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you have allergies or intolerances to caffeine or NSAIDs, you may not be eligible to participate.

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

Research has shown that istradefylline is generally safe for people. The FDA has already approved it for treating Parkinson's disease, indicating its safety for this new use. Common side effects include dizziness and nausea, but serious problems are rare.

Studies have found that low oxygen therapy is also quite safe. This simple method helps people with spinal cord injuries improve mobility. While it can cause temporary changes in blood pressure or heart rate, these effects are usually mild and manageable.

Together, these treatments appear promising for improving walking ability after a spinal cord injury, with safety data supporting their use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine Istradefylline, a drug that targets adenosine receptors, with low oxygen therapy, offering a fresh approach to spinal cord injury. Unlike typical treatments focusing on inflammation or nerve growth, Istradefylline works by modulating neural activity, which could enhance recovery. Additionally, the use of therapeutic intermittent hypoxia is unique, as it aims to stimulate the body's natural repair mechanisms by exposing patients to controlled low oxygen levels, potentially improving outcomes more effectively than traditional approaches.

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

Research has shown that breathing sessions with less oxygen, known as low oxygen therapy, can help people with spinal cord injuries walk faster and longer. This therapy strengthens the nervous system's connections. In this trial, one group of participants will receive low oxygen therapy combined with istradefylline, a drug approved for Parkinson’s disease that blocks certain effects of the brain chemical adenosine. This combination might enhance the benefits of low oxygen therapy. Early findings suggest that using istradefylline with low oxygen therapy could improve walking recovery after a spinal cord injury. Another group will receive low oxygen therapy with a placebo, while a third group will receive istradefylline with SHAM therapy to compare the effects. ^{4 6 7 8 9}

Who Is on the Research Team?

Randy Trumbower, PT, PhD

Principal Investigator

Spaulding Rehabilitation Hospital

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with a spinal cord injury that happened over a year ago. They must be able to move their legs voluntarily and take one step without help. The injury should be between the C2 and T12 levels of the spine, not getting worse over time. People with diabetes, severe illnesses, allergies to caffeine or NSAIDs, pregnant women, or those with seizure disorders can't join.

Inclusion Criteria

Medical clearance to participate

You had a significant injury more than 12 months ago.

My spinal injury is between my neck and upper back and is not getting worse.

Exclusion Criteria

I do not have any severe illnesses like heart disease or unhealed wounds.

You are allergic to caffeine or non-steroidal anti-inflammatory drugs (NSAIDs), or these substances make you feel unwell.

I have diabetes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combinatorial intervention of istradefylline or placebo with low oxygen therapy or SHAM therapy for 4 weeks

4 weeks

4 sessions per week

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of walking speed and distance

3 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Istradefylline
• Low Oxygen Therapy

Trial Overview The study tests if low oxygen therapy (LOT) combined with an adenosine A2a receptor blocker called Istradefylline improves walking in people after spinal cord injuries. LOT may boost nerve pathway strength but could be less effective due to increased adenosine; this trial checks if blocking adenosine helps recovery.

How Is the Trial Designed?

Group I: Istradefylline+low oxygen training Experimental Treatment 2 Interventions

Drug: Nourianz Other Names: KW6002, Istradefylline Participants enrolled in this study arm will ingest a 20mg tablet/day containing istradefylline starting 14 days prior to the first low oxygen therapy and continuing for 14 additional days. Participants will consume a total of 28 istradefylline tablets. Other: low oxygen training Other Names: therapeutic intermittent hypoxia, acute intermittent hypoxia Participants will breathe 15 episodes/session of acute low oxygen via an automated air generator system (4 sessions/week x 2 weeks). During the 90-second episodes of low oxygen, air concentrations will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.10±0.02 (hypoxia) with 60-second room-air intervals (FIO2 0.21±0.02). Throughout experimentation, blood pressure, respiratory rate, and heart rate will be monitored. We also will assess for changes in sleep quality and pain level.

Group II: Placebo+low oxygen training Active Control 1 Intervention

This is a placebo counterpart to the istradefylline drug. Participants enrolled in this study arm will ingest a 20mg placebo tablet/day containing dextrose starting 14 days prior to the first low oxygen therapy (LOT) and continuing for 14 additional days. Participants will consume a total of 28 placebo tablets. Other: low oxygen training Other Names: therapeutic intermittent hypoxia, acute intermittent hypoxia Participants will breathe 15 episodes/session of acute low oxygen via an automated air generator system (4 sessions/week x 2 weeks). During the 90-second episodes of low oxygen, air concentrations will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.10±0.02 (hypoxia) with 60-second room-air intervals (FIO2 0.21±0.02). Throughout experimentation, blood pressure, respiratory rate, and heart rate will be monitored. We also will assess for changes in sleep quality and pain level.

Group III: Istradefylline+SHAM Active Control 1 Intervention

Drug: Nourianz Other Names: KW6002, Istradefylline This is a SHAM counterpart to low oxygen therapy. Participants enrolled in this study arm will ingest a 20mg tablet/day containing istradefylline starting 14 days prior to the first SHAM therapy and continuing for 14 additional days. Participants will consume a total of 28 istradefylline tablets. Participants will breathe 15 episodes/session of SHAM via an automated air generator system (4 sessions/week x 2 weeks). The system will fill reservoir bags attached to a non-rebreathing face mask. During the 90-second episodes of SHAM, air concentrations will be continuously monitored to ensure delivery of FIO2 (fraction of inspired oxygen) = 0.21±0.02 (normoxia) with 60-second room-air intervals (FIO2 0.21±0.02). Throughout experimentation, blood pressure, respiratory rate, and heart rate will be monitored. We also will assess for changes in sleep quality and pain level.

Istradefylline is already approved in United States, Japan for the following indications:

Approved in United States as Nourianz for:

• Parkinson's disease

Approved in Japan as Nouriast for:

• Parkinson's disease

Who Is Running the Clinical Trial?

Randy Trumbower, PT, PhD

Lead Sponsor

Trials

1

Recruited

40+

Published Research Related to This Trial

Daily acute intermittent hypoxia (dAIH) significantly improved walking speed and endurance in individuals with chronic incomplete spinal cord injury, as shown by measurable improvements in the 10-Meter and 6-Minute Walk Tests after just one day of treatment.

Combining dAIH with overground walking further enhanced these benefits, indicating that this combination therapy could be a more effective approach for improving mobility in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Hayes, HB., Jayaraman, A., Herrmann, M., et al.[2022]

In a study of 2040 individuals with spinal cord injury, a total of 775 unique medications were administered within the first 60 days post-injury, highlighting a significant prevalence of polypharmacy, with some patients taking up to 43 medications per day.

The findings suggest that the high number of medications, including those given for prophylactic reasons, could potentially influence neurological recovery, emphasizing the need for careful management of pharmacological treatments in acute spinal cord injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study. Jutzeler, CR., Bourguignon, L., Tong, B., et al.[2023]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05217498?term=Nourianz&rank=2

Combining Low Oxygen Therapy and an Adenosine A2a ... This randomized, placebo-controlled clinical trial will examine the efficacy of a selective adenosine 2a antagonist (istradefylline) to enhance the beneficial ...

2. withpower.com withpower.com/trial/phase-2-spinal-cord-injuries-5-2022-b9af4

Istradefylline + Low Oxygen Therapy for Spinal Cord Injury Research shows that daily intermittent low oxygen therapy can improve walking speed and endurance in people with chronic spinal cord injury, suggesting ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7367999/

The belated US FDA approval of the adenosine A2A ... Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0014488615000291

Daily acute intermittent hypoxia elicits functional recovery ... Daily acute intermittent hypoxia enhances ventilatory capacity after acute cervical spinal injury. Daily acute intermittent hypoxia increases motor function of ...

5. nourianzhcp.com nourianzhcp.com/efficacy/

Explore NOURIANZ® (istradefylline) Efficacy & Primary ... Patients treated with NOURIANZ 40 mg once daily experienced a statistically significant decrease from baseline in percentage of daily awake “off” time (-10.49%) ...

6. nourianzhcp.com nourianzhcp.com/safety/

NOURIANZ® (istradefylline) Clinical Trial Details & Side ... Explore the safety data of NOURIANZ® (istradefylline), including clinical trial details, side effects or adverse reactions, and discontinuation rates.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2019/022075s000lbl.pdf

Nourianz - accessdata.fda.gov In animal studies (see Data), oral administration of istradefylline during pregnancy resulted in teratogenicity (increased incidences of fetal structural ...

8. go.drugbank.com go.drugbank.com/drugs/DB11757

Istradefylline: Uses, Interactions, Mechanism of Action Istradefylline, or KW6002, was developed by Kyowa Hakko Kirin in Japan for the treatment of Parkinson's disease as an adjunct to standard therapy.

9. medchemexpress.com medchemexpress.com/Istradefylline.html?srsltid=AfmBOorIBdvH-Qg8MwF_oWaCu52cutm9NAaF3nHdmPVOwHzNdbABGNgQ

Istradefylline (KW-6002) | Adenosine A2A Receptor ... Istradefylline is a very potent, selective and orally active adenosine A2A receptor antagonist with K i of 2.2 nM in experimental models of Parkinson's disease.