Adenosine 2A Receptor Antagonism and AIH in ALS

Phase 1

Recruiting

• Conditions: ALS
• Interventions: Drug: Consume 20mg of istradefylline; Drug: Placebo counterpart to the istradefylline drug; Other: Low Oxygen therapy; Other: SHAM counterpart to low oxygen therapy.

• Registration Number: NCT05377424
• Lead Sponsor: University of Florida

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.

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 Timeline

• Study First Submitted: 2022-04-26
• Study First Submitted QC: 2022-05-11
• Study First Posted: 2022-05-17
• Study Start: 2022-06-21
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-12
• Last Update Posted: 2024-11-14
• Primary Completion: 2025-12-01
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 40

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sham-AIH + istradefylline (sham+IST)	Consume 20mg of istradefylline	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.
AIH + placebo (AIH+CON)	Placebo counterpart to the istradefylline drug	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.
AIH + istradefylline (AIH+IST)	Low Oxygen therapy	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.
AIH + istradefylline (AIH+IST)	Consume 20mg of istradefylline	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.
AIH + placebo (AIH+CON)	Low Oxygen therapy	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.
Sham-AIH + placebo (sham+CON)	Placebo counterpart to the istradefylline drug	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.
Sham-AIH + placebo (sham+CON)	SHAM counterpart to low oxygen therapy.	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.
Sham-AIH + istradefylline (sham+IST)	SHAM counterpart to low oxygen therapy.	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Subject-reported involuntary movements	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)
Change in minute ventilation	120 minutes post-intervention.	Change in the average volume of air during a minute of resting breathing.
Serum Istradefylline	6 hours post- istradefylline or placebo	Blood test to measure change in level of istradefylline

Trial Locations

Locations (2)

Clinical and Translational Research Building; 🇺🇸 Gainesville, Florida, United States

UF Health Jacksonville; 🇺🇸 Jacksonville, Florida, United States