Adenosine 2A Receptor Antagonism and AIH in ALS

ALS Clinical Trial

Official title:

Acute Adenosine Receptor Antagonism to Promote Breathing Plasticity in ALS

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05377424
• Other study ID #: IRB202101568
• Secondary ID: OCR41682
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 21, 2022
• Est. completion date: December 31, 2024

Study information

• Verified date: November 2023
• Source: University of Florida
• Contact: Julia Prascak, BS
• Phone: 3522736855
• Email: juliaprascak[@]ufl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 31, 2024
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• ALS

Intervention

Drug:
• Consume 20mg of istradefylline
Consume a single 20 mg istradefylline tablet

Other:
• 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.

Drug:
• Placebo counterpart to the istradefylline drug
Consume a single microcrystalline cellulose

Other:
• 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.

Locations

Country	Name	City	State
United States	Clinical and Translational Research Building	Gainesville	Florida
United States	UF Health Jacksonville	Jacksonville	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	ALS Association

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in maximal voluntary pinch force	Pinch force of the thumb will be evaluated in a seated position.	120 minutes post-intervention.
Primary	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)
Primary	Change in resting tidal volume	Averaged volume of breaths at rest	120 minutes after AIH
Secondary	Serum Istradefylline	Blood test to measure change in level of istradefylline	4 hours post- istradefylline or placebo
Secondary	Serum Istradefylline	Blood test to measure change in level of istradefylline	6 hours post- istradefylline or placebo
Secondary	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
Secondary	Change in minute ventilation	Change in the average volume of air during a minute of resting breathing.	120 minutes post-intervention.