Adenosine 2A Receptor Antagonism and AIH in ALS

Brief Title

Adenosine 2A Receptor Antagonism and AIH in ALS

Official Title

Acute Adenosine Receptor Antagonism to Promote Breathing Plasticity in ALS

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 Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Treatment differences in the rate of adverse events.

Secondary Outcome

 Serum Istradefylline

Condition

ALS

Intervention

Consume 20mg of istradefylline

Study Arms / Comparison Groups

 AIH + istradefylline (AIH+IST)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

40

Start Date

June 1, 2022

Completion Date

December 31, 2024

Primary Completion Date

June 1, 2024

Eligibility Criteria

        Inclusion Criteria:

          1. Non-smoking adults aged 21-75 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) score >30.

          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.
      

Gender

All

Ages

21 Years - 75 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Barbara Smith, (352) 273-6855, [email protected]



Administrative Informations


NCT ID

NCT05377424

Organization ID

IRB202101568

Secondary IDs

OCR41682

Responsible Party

Sponsor

Study Sponsor

University of Florida

Collaborators

 ALS Association

Study Sponsor

Barbara Smith, Principal Investigator, University of Florida


Verification Date

May 2022