Adenosine 2A Receptor Antagonism and AIH in ALS

NCT05377424 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: IRB202101568OCR41682
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

ALS

Keywords

ALS; hypoxia; breathing; istradefylline

Outcome Measures

Primary Outcomes (2)

• Treatment differences in the rate of adverse events.

  Any reported adverse events will be tracked and recorded.

  Through study completion (an average of 4-6 weeks)

• Change in resting tidal volume

  Averaged volume of breaths at rest

  120 minutes after AIH

Secondary Outcomes (4)

• Serum Istradefylline

  4 hours post- istradefylline or placebo

• Serum Istradefylline

  6 hours post- istradefylline or placebo

• Subject-reported involuntary movements

  4 hours post- istradefylline or placebo

• Change in minute ventilation

  120 minutes post-intervention.

Other Outcomes (1)

• Change in maximal voluntary pinch force

  120 minutes post-intervention.

Study Arms (4)

AIH + istradefylline (AIH+IST)

EXPERIMENTAL

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; Other: Low Oxygen therapy

Sham-AIH + istradefylline (sham+IST)

ACTIVE COMPARATOR

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; Other: SHAM counterpart to low oxygen therapy.

AIH + placebo (AIH+CON)

ACTIVE COMPARATOR

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; Drug: Placebo counterpart to the istradefylline drug

Sham-AIH + placebo (sham+CON)

ACTIVE COMPARATOR

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.

Drug: Placebo counterpart to the istradefylline drug; Other: SHAM counterpart to low oxygen therapy.

Interventions

Consume 20mg of istradefylline DRUG

Consume a single 20 mg istradefylline tablet

Also known as: Nourianz

AIH + istradefylline (AIH+IST); Sham-AIH + istradefylline (sham+IST)

Low Oxygen therapy OTHER

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.

Also known as: Acute Intermittent Hypoxia, AIH

AIH + istradefylline (AIH+IST); AIH + placebo (AIH+CON)

Placebo counterpart to the istradefylline drug DRUG

Consume a single microcrystalline cellulose

Also known as: Placebo

AIH + placebo (AIH+CON); Sham-AIH + placebo (sham+CON)

SHAM counterpart to low oxygen therapy. OTHER

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.

Also known as: SHAM acute intermittent hypoxia, SHAM-AIH

Sham-AIH + istradefylline (sham+IST); Sham-AIH + placebo (sham+CON)

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Non-smoking adults aged 21-80 years will be eligible to participate.
• \- Upon screening, eligible patients will have an
• ALS diagnosis (El Escorial diagnostic classifications of probable/definite ALS),
• vital capacity (VC) \> 60% of predicted value, and
• ALS Functional Rating Scale (ALSFRS-R) scores of 2 or greater for bulbar and respiratory items: swallowing, speech, salivation, dyspnea, orthopnea, and respiratory insufficiency.
• Additionally, patients taking riluzole and/or edaravone must be on a stable dose for \>30 days.
• Unaffected control subjects will be eligible if they have a vital capacity (VC) \> 60% of predicted value.

You may not qualify if:

• Patient and control are ineligible if they
• are pregnant
• have an active respiratory infection,
• took antibiotics within 4 weeks,
• are diagnosed with another neurodegenerative disease,
• have symptomatic cardiovascular disease or dysrhythmias (resting tachycardia and hypertension),
• exhibit history or presence of hypoxemia or hypercapnia,
• presence of rest tachypnea (RR ˃30),
• have a BMI \>35 kg/m2,
• have a seizure disorder,
• take respiratory inhalers daily for airway disease, or
• require external respiratory support while awake and upright, or
• supplemental oxygen at rest or at night.
• medications that may suppress ventilation, history of moderate renal impairment or severe hepatic impairment, and history of hallucinations or psychosis.
• Patients who cannot safety swallow thin liquids (required for administration of istradefylline and placebo) will also be ineligible.

Sponsors & Collaborators

• ALS Association: collaborator
• University of Florida: lead

Study Sites (2)

Clinical and Translational Research Building

Gainesville, Florida, 32610, United States

Location

UF Health Jacksonville

Jacksonville, Florida, 32209, United States

Location

Related Publications (5)

• Trumbower RD, Jayaraman A, Mitchell GS, Rymer WZ. Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. Neurorehabil Neural Repair. 2012 Feb;26(2):163-72. doi: 10.1177/1545968311412055. Epub 2011 Aug 5.

  PMID: 21821826 BACKGROUND

• Vivodtzev I, Tan AQ, Hermann M, Jayaraman A, Stahl V, Rymer WZ, Mitchell GS, Hayes HB, Trumbower RD. Mild to Moderate Sleep Apnea Is Linked to Hypoxia-induced Motor Recovery after Spinal Cord Injury. Am J Respir Crit Care Med. 2020 Sep 15;202(6):887-890. doi: 10.1164/rccm.202002-0245LE. No abstract available.

  PMID: 32369393 BACKGROUND

• Seven YB, Simon AK, Sajjadi E, Zwick A, Satriotomo I, Mitchell GS. Adenosine 2A receptor inhibition protects phrenic motor neurons from cell death induced by protein synthesis inhibition. Exp Neurol. 2020 Jan;323:113067. doi: 10.1016/j.expneurol.2019.113067. Epub 2019 Oct 17.

  PMID: 31629857 BACKGROUND

• Sajjadi E, Seven YB, Ehrbar JG, Wymer JP, Mitchell GS, Smith BK. Acute intermittent hypoxia and respiratory muscle recruitment in people with amyotrophic lateral sclerosis: A preliminary study. Exp Neurol. 2022 Jan;347:113890. doi: 10.1016/j.expneurol.2021.113890. Epub 2021 Oct 6.

  PMID: 34624328 BACKGROUND

• Sales de Campos P, Smith-Hublou M, Olsen WL, Souza Leite W, Wymer JP, Napoli NJ, Vose AK, Pulley MT, Mitchell GS, Smith BK. Acute Adenosine Receptor Antagonism in Combination With Acute Intermittent Hypoxia to Promote Breathing Plasticity in Amyotrophic Lateral Sclerosis: Protocol for a Randomized, Double-Blinded, Placebo-Controlled Trial. JMIR Res Protoc. 2025 Nov 7;14:e76105. doi: 10.2196/76105.

  PMID: 41202295 DERIVED

MeSH Terms

Conditions

Hypoxia; Respiratory Aspiration

Interventions

istradefylline; Insemination, Artificial, Homologous

Condition Hierarchy (Ancestors)

Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Respiratory Tract Diseases; Pathologic Processes

Intervention Hierarchy (Ancestors)

Insemination, Artificial; Reproductive Techniques, Assisted; Reproductive Techniques; Therapeutics; Investigative Techniques; Insemination; Reproduction; Reproductive Physiological Phenomena; Reproductive and Urinary Physiological Phenomena

Study Officials

• Barbara Smith

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 26, 2022
• First Posted: May 17, 2022
• Study Start: June 21, 2022
• Primary Completion: January 26, 2026
• Study Completion (Estimated): August 31, 2026
• Last Updated: March 27, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)