Study Results
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Basic Information
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RECRUITING
PHASE1/PHASE2
40 participants
INTERVENTIONAL
2022-06-21
2026-05-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
TRIPLE
Study Groups
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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.
Consume 20mg of istradefylline
Consume a single 20 mg istradefylline tablet
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.
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.
Consume 20mg of istradefylline
Consume a single 20 mg istradefylline tablet
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.
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.
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.
Placebo counterpart to the istradefylline drug
Consume a single microcrystalline cellulose
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.
Placebo counterpart to the istradefylline drug
Consume a single microcrystalline cellulose
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.
Interventions
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Consume 20mg of istradefylline
Consume a single 20 mg istradefylline tablet
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.
Placebo counterpart to the istradefylline drug
Consume a single microcrystalline cellulose
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
\- 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
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.
21 Years
80 Years
ALL
Yes
Sponsors
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ALS Association
OTHER
University of Florida
OTHER
Responsible Party
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Principal Investigators
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Barbara Smith
Role: PRINCIPAL_INVESTIGATOR
University of Florida
Locations
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Clinical and Translational Research Building
Gainesville, Florida, United States
UF Health Jacksonville
Jacksonville, Florida, United States
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
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.
Other Identifiers
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OCR41682
Identifier Type: OTHER
Identifier Source: secondary_id
IRB202101568
Identifier Type: -
Identifier Source: org_study_id
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