Adenosine 2A Receptor Antagonism and AIH in ALS

Study Overview
=================
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.

Official Title
-----------------
Acute Adenosine Receptor Antagonism to Promote Breathing Plasticity in ALS

Conditions
-----------------
ALS

Intervention / Treatment
-----------------
* Drug: Consume 20mg of istradefylline
* Other: Low Oxygen therapy
* Drug: Placebo counterpart to the istradefylline drug
* Other: SHAM counterpart to low oxygen therapy.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. Exclusion Criteria: 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. 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 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.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AIH + istradefylline (AIH+IST)<br>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<br>* Consume a single 20 mg istradefylline tablet<br>* Other names: Nourianz;Other: Low Oxygen therapy<br>* 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.<br>* Other names: AIH;|
| Active Comparator: Sham-AIH + istradefylline (sham+IST)<br>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<br>* Consume a single 20 mg istradefylline tablet<br>* Other names: Nourianz;Other: SHAM counterpart to low oxygen therapy.<br>* 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.<br>* Other names: SHAM-AIH;|
| Active Comparator: AIH + placebo (AIH+CON)<br>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<br>* 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.<br>* Other names: AIH;Drug: Placebo counterpart to the istradefylline drug<br>* Consume a single microcrystalline cellulose<br>* Other names: Placebo;|
| Active Comparator: Sham-AIH + placebo (sham+CON)<br>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<br>* Consume a single microcrystalline cellulose<br>* Other names: Placebo;Other: SHAM counterpart to low oxygen therapy.<br>* 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.<br>* Other names: SHAM-AIH;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Istradefylline | Blood test to measure change in level of istradefylline | 4 hours post- istradefylline or placebo | 
| Serum Istradefylline | Blood test to measure change in level of istradefylline | 6 hours post- istradefylline or placebo | 
| Subject-reported involuntary movements | 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 | Change in the average volume of air during a minute of resting breathing. | 120 minutes post-intervention. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALS, hypoxia, breathing, istradefylline