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.

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.

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.