Adenosine 2A Receptor Antagonism and AIH in ALS

March 26, 2026 updated by: University of Florida

Acute Adenosine Receptor Antagonism to Promote Breathing Plasticity in ALS

The purpose of this research study is to determine the effects of a medication, istradefylline, in conjunction with breathing air with reduced oxygen for short periods of time (called acute intermittent hypoxia, or AIH), on breathing. This project will study breathing in people with amyotrophic lateral sclerosis (ALS) and unaffected, age-matched adults. Istradefylline is prescribed to increase movement in people with other neuromuscular conditions. A recently completed study found that people with ALS took deeper breaths, 60 minutes after using AIH.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

This repeated measures, placebo-controlled, randomized study will study feasibility and efficacy of istradefylline, an adenosine 2A receptor antagonist in conjunction with acute intermittent hypoxia (AIH).

Participation in this study includes a screening for eligibility, plus 4 individual study visits separated by 1 week. The eligibility screening will include a review of medical history and medications, along with a breathing test and sleep study.

Each participant will experience a different study condition on each of their 4 study visits: an "AIH + istradefylline" (AIH+IST) visit, and a "sham-AIH + istradefylline" (sham+IST) visit, an "AIH + placebo (AIH+CON)" visit, and a "sham-AIH + placebo" (sham+CON) visit. The visits will be in random order for each subject. Participants and the testing investigators will not be told which order the visits will be. Participants need to avoid exercise and caffeine and nicotine products for >8 hours before each study visit.

AIH + istradefylline visit: participants will take 20 mg of istradefylline. After a 4-hour break, participants will receive a 45-minute session of AIH, consisting of 15, one-minute periods of low oxygen (10% O2) with two-minute periods of normal oxygen (21% O2).

Sham AIH + istradefylline visit: participants will take 20 mg of istradefylline. After a 4-hour break, participants will receive a 45-minute session of SHAM AIH, consisting of 15, one-minute intervals of normal oxygen (21% O2) with two-minute periods of normal oxygen (21% O2).

AIH + placebo visit: participants will take 20 mg of microcrystalline cellulose. After a 4-hour break, participants will receive a 45-minute session of AIH, consisting of 15, one-minute periods of low oxygen (10% O2) with two-minute periods of normal oxygen (21% O2).

Sham AIH + placebo visit: participants will take 20 mg of microcrystalline cellulose. After a 4-hour break, participants will receive a 45-minute session of SHAM AIH, consisting of 15, one-minute intervals of normal oxygen (21% O2) with two-minute periods of normal oxygen (21% O2).

Venous blood samples will be collected at the start of each visit as general safety labs (complete blood count, uric acid, blood chemistry), and to assess levels of istradefylline levels in the blood. Additional blood tests 4 and 6 hours later will measure changes in serum istradefylline.

The study will assess vital signs, patient-reported symptoms, resting breathing, strength of the breathing muscles, and maximal voluntary pinch force at the start of each visit. These measures will then be repeated 1 and 2 hours after AIH or SHAM. Throughout the AIH and SHAM interventions, respiratory rate, oxygen saturation, end-tidal carbon dioxide (CO2), heart rate, and blood pressure will be monitored.

For the primary efficacy endpoint, the study will measure breath volume at the start of each visit, and 1 and 2 hours after the AIH and SHAM interventions. A linear mixed model will be used to compare differences in tidal volume. Main effects include treatment and time, with participants as random effects.

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Gainesville, Florida, United States, 32610
        • Clinical and Translational Research Building
      • Jacksonville, Florida, United States, 32209
        • UF Health Jacksonville

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  1. Non-smoking adults aged 21-80 years will be eligible to participate.

    - Upon screening, eligible patients will have an

  2. ALS diagnosis (El Escorial diagnostic classifications of probable/definite ALS),
  3. vital capacity (VC) > 60% of predicted value, and
  4. ALS Functional Rating Scale (ALSFRS-R) scores of 2 or greater for bulbar and respiratory items: swallowing, speech, salivation, dyspnea, orthopnea, and respiratory insufficiency.
  5. Additionally, patients taking riluzole and/or edaravone must be on a stable dose for >30 days.
  6. Unaffected control subjects will be eligible if they have a vital capacity (VC) > 60% of predicted value.

Exclusion Criteria:

Patient and control are ineligible if they

  1. are pregnant
  2. have an active respiratory infection,
  3. took antibiotics within 4 weeks,
  4. are diagnosed with another neurodegenerative disease,
  5. have symptomatic cardiovascular disease or dysrhythmias (resting tachycardia and hypertension),
  6. exhibit history or presence of hypoxemia or hypercapnia,
  7. presence of rest tachypnea (RR ˃30),
  8. have a BMI >35 kg/m2,
  9. have a seizure disorder,
  10. take respiratory inhalers daily for airway disease, or
  11. require external respiratory support while awake and upright, or
  12. supplemental oxygen at rest or at night.
  13. In addition, the following conditions are exclusionary for the use of istradefylline: routine use of CYP3A4 inducers (i.e. carbamazepine, phenobarbitol, rifampin, phenytoin, St. John's Wort, glucocorticoids) or
  14. medications that may suppress ventilation, history of moderate renal impairment or severe hepatic impairment, and history of hallucinations or psychosis.
  15. Patients who cannot safety swallow thin liquids (required for administration of istradefylline and placebo) will also be ineligible.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: AIH + istradefylline (AIH+IST)
Participants enrolled in this study arm will ingest a 20mg tablet containing istradefylline. Four hours later, participants will receive acute intermittent hypoxia (AIH). Breathing and pinch strength will be tested prior to taking the medication, and then immediately before, 60 minutes and 120 minutes after AIH. Participants will breathe 15 episodes/session of acute low oxygen. Air concentrations will be monitored to ensure delivery of 1-minute episodes of low oxygen, with 2 minutes room-air intervals. Respiratory rate, oxygen saturation, heart rate/rhythm, and blood pressure will be monitored throughout the session.
Drug: Consume 20mg of istradefylline
Consume a single 20 mg istradefylline tablet
Other Names:
  • Nourianz
Other: Low Oxygen therapy
Breathing short periods of low oxygen, consisting of 15 episodes of 1 minute of breathing 10% oxygen, with 2 minutes of breathing 21% oxygen. 45 minutes total.
Other Names:
  • AIH
  • Acute Intermittent Hypoxia
Active Comparator: Sham-AIH + istradefylline (sham+IST)
This is a sham counterpart to the low oxygen. Participants enrolled in this study arm will ingest a 20mg tablet containing istradefylline. Four hours later, participants will receive SHAM acute intermittent hypoxia (SHAM). Breathing and pinch strength will be tested prior to taking the medication, and then immediately before, 60 minutes and 120 minutes after SHAM. Participants will breathe 15 episodes/session of sham low oxygen, in which normal air is used. One-minute episodes of sham low oxygen are separated by 2 minutes room-air intervals. Respiratory rate, oxygen saturation, heart rate/rhythm, and blood pressure will be monitored throughout the session.
Drug: Consume 20mg of istradefylline
Consume a single 20 mg istradefylline tablet
Other Names:
  • Nourianz
Other: SHAM counterpart to low oxygen therapy.
Breathing short periods of sham low oxygen, consisting of 15 episodes of 1 minute of breathing 21% oxygen, separated by 2 minutes of breathing 21% oxygen. 45 minutes total.
Other Names:
  • SHAM acute intermittent hypoxia
  • SHAM-AIH
Active Comparator: AIH + placebo (AIH+CON)
This is a placebo counterpart to the istradefylline drug. Participants enrolled in this study arm will ingest a 20mg tablet containing microcrystalline cellulose. Four hours later, participants will receive acute intermittent hypoxia (AIH). Breathing and pinch strength will be tested prior to taking the medication, and then immediately before, 60 minutes and 120 minutes after AIH. Participants will breathe 15 episodes/session of acute low oxygen. Air concentrations will be monitored to ensure delivery of 1-minute episodes of low oxygen, with 2 minutes room-air intervals. Respiratory rate, oxygen saturation, heart rate/rhythm, and blood pressure will be monitored throughout the session.
Other: Low Oxygen therapy
Breathing short periods of low oxygen, consisting of 15 episodes of 1 minute of breathing 10% oxygen, with 2 minutes of breathing 21% oxygen. 45 minutes total.
Other Names:
  • AIH
  • Acute Intermittent Hypoxia
Drug: Placebo counterpart to the istradefylline drug
Consume a single microcrystalline cellulose
Other Names:
  • Placebo
Active Comparator: Sham-AIH + placebo (sham+CON)
This is a sham counterpart to low oxygen, and a placebo counterpart to the istradefylline drug. Participants enrolled in this study arm will ingest a 20mg tablet containing microcrystalline cellulose. Four hours later, participants will receive SHAM acute intermittent hypoxia (SHAM). Breathing and pinch strength will be tested prior to taking the medication, and then immediately before, 60 minutes and 120 minutes after SHAM. Participants will breathe 15 episodes/session of sham low oxygen, in which normal air is used. One-minute episodes of sham low oxygen are separated by 2 minutes room-air intervals. Respiratory rate, oxygen saturation, heart rate/rhythm, and blood pressure will be monitored throughout the session.
Other: SHAM counterpart to low oxygen therapy.
Breathing short periods of sham low oxygen, consisting of 15 episodes of 1 minute of breathing 21% oxygen, separated by 2 minutes of breathing 21% oxygen. 45 minutes total.
Other Names:
  • SHAM acute intermittent hypoxia
  • SHAM-AIH
Drug: Placebo counterpart to the istradefylline drug
Consume a single microcrystalline cellulose
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment differences in the rate of adverse events.
Time Frame: Through study completion (an average of 4-6 weeks)
Any reported adverse events will be tracked and recorded.
Through study completion (an average of 4-6 weeks)
Change in resting tidal volume
Time Frame: 120 minutes after AIH
Averaged volume of breaths at rest
120 minutes after AIH

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum Istradefylline
Time Frame: 4 hours post- istradefylline or placebo
Blood test to measure change in level of istradefylline
4 hours post- istradefylline or placebo
Serum Istradefylline
Time Frame: 6 hours post- istradefylline or placebo
Blood test to measure change in level of istradefylline
6 hours post- istradefylline or placebo
Subject-reported involuntary movements
Time Frame: 4 hours post- istradefylline or placebo
Participants will use a 0-10 scale to report the intensity of any involuntary movements or tremors. (a higher number would correspond to more involuntary movements or tremors)
4 hours post- istradefylline or placebo
Change in minute ventilation
Time Frame: 120 minutes post-intervention.
Change in the average volume of air during a minute of resting breathing.
120 minutes post-intervention.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in maximal voluntary pinch force
Time Frame: 120 minutes post-intervention.
Pinch force of the thumb will be evaluated in a seated position.
120 minutes post-intervention.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Florida

Collaborators

ALS Association

Investigators

  • Principal Investigator: Barbara Smith, University of Florida

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 21, 2022

Primary Completion (Actual)

January 26, 2026

Study Completion (Estimated)

August 31, 2026

Study Registration Dates

First Submitted

April 26, 2022

First Submitted That Met QC Criteria

May 11, 2022

First Posted (Actual)

May 17, 2022

Study Record Updates

Last Update Posted (Actual)

March 27, 2026

Last Update Submitted That Met QC Criteria

March 26, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB202101568
  • OCR41682 (Other Identifier: UF OnCore)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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