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AT1R Blockade and Periodic Breathing During Sleep in Hypoxia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03335904
Recruitment Status : Completed
First Posted : November 8, 2017
Last Update Posted : September 4, 2020
Sponsor:
Information provided by (Responsible Party):
Glen Foster, University of British Columbia

Brief Summary:
Sleep disordered breathing (SDB) is characterized by regular periods of no breathing (apnea) or low levels of breathing (hypopnea) and leads to repeated periods of low oxygenation, termed intermittent hypoxia that causes fluctuations in blood oxygen levels. This leads to increased peripheral chemoreflex sensitivity that is thought to occur through the stimulation of angiotensin-II, type-I receptors (AT1R) that are expressed primarily on glomus cells within the peripheral chemoreflex and ultimately results in long lasting hypertension. The goal of this study is to determine if AT1R receptor blockade can prevent the increase in chemoreflex sensitivity following one night of hypoxia and improve the severity of SDB.

Condition or disease Intervention/treatment Phase
Sleep Disordered Breathing Hypoxia Respiration; Sleep Disorder Chemoreceptor Apnea Other: Hyperoxic Hypercapnic Ventilatory Response Test Other: Hypoxic Hypercapnic Ventilatory Response Test Other: Repeated Hypoxic Apneas Other: Hypoxic Sleep Study Drug: Losartan Drug: Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Effect of Angiotensin Receptor Blockers on Periodic Breathing During Sleep in Hypoxia
Actual Study Start Date : January 1, 2018
Actual Primary Completion Date : August 1, 2019
Actual Study Completion Date : August 1, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo
Participants will ingest microcrystalline cellulose by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
Other: Hyperoxic Hypercapnic Ventilatory Response Test
End-tidal PO2 will be clamped at 300 mmHg while end-tidal PCO2 will be increased in three minutes stages from baseline to +2, +4, and +6 mmHg.

Other: Hypoxic Hypercapnic Ventilatory Response Test
End-tidal PO2 will be clamped at normoxic levels while end-tidal PCO2 will be increased in three minutes stages from baseline to +2, +4, and +6 mmHg.

Other: Repeated Hypoxic Apneas
Six hypoxic apnea cycles will be performed. One apneic cycle involves breathing 2-3 breaths of 100% Nitrogen and breath-holding for 20s followed by room air breathing.

Other: Hypoxic Sleep Study
Participants will be instrumented with a sleep monitoring system and will sleep in a normobaric hypoxic chamber with a fraction of inspired oxygen of 13.5%.

Drug: Placebo
Placebo, 50mg, BID
Other Name: microcrystalline cellulose

Experimental: Losartan
Participants will ingest 50 mg of losartan, an angiotensin receptor blocker, by mouth on two consecutive days. The first tablet will be consumed on day 1 at 0700 hrs. The second tablet will be consumed at 1900 hrs and the final tablet will be consumed at 0700hrs on day 2. Participants will undergo a Hyperoxic Hypercapnic Ventilatory Response Test, a Hypoxic Hypercapnic Ventilatory Response Test, and Repeated Hypoxic Apneas before and after a Hypoxic Sleep Study.
Other: Hyperoxic Hypercapnic Ventilatory Response Test
End-tidal PO2 will be clamped at 300 mmHg while end-tidal PCO2 will be increased in three minutes stages from baseline to +2, +4, and +6 mmHg.

Other: Hypoxic Hypercapnic Ventilatory Response Test
End-tidal PO2 will be clamped at normoxic levels while end-tidal PCO2 will be increased in three minutes stages from baseline to +2, +4, and +6 mmHg.

Other: Repeated Hypoxic Apneas
Six hypoxic apnea cycles will be performed. One apneic cycle involves breathing 2-3 breaths of 100% Nitrogen and breath-holding for 20s followed by room air breathing.

Other: Hypoxic Sleep Study
Participants will be instrumented with a sleep monitoring system and will sleep in a normobaric hypoxic chamber with a fraction of inspired oxygen of 13.5%.

Drug: Losartan
Losartan, 50mg, BID
Other Name: Cozaar




Primary Outcome Measures :
  1. apnea-hypopnea index [ Time Frame: 8 hours ]
    the number of apnea and hypopneas per hour during sleep in hypoxia


Secondary Outcome Measures :
  1. Average oxygen saturation [ Time Frame: 8 hours ]
    average oxyhemoglobin saturation measured during sleep in hypoxia

  2. Hyperoxic Hypercapnic Ventilatory Response [ Time Frame: 0 and 8 hours ]
    The change in ventilation per change in end-tidal PCO2 measured in a background of hyperoxia

  3. Hypoxic Hypercapnic Ventilatory Response [ Time Frame: 0 and 8 hours ]
    The change in ventilation per change in end-tidal PCO2 measured in a background of hypoxia

  4. Change in systolic and diastolic blood pressure during breath-hold [ Time Frame: 0 and 8 hours ]
    The blood pressure response to repeated 20s hypoxic breath-holds.

  5. Hyperoxic Hypercapnic Cerebral Blood Flow Response [ Time Frame: 0 and 8 hours ]
    the change in middle cerebral and posterior cerebral blood velocity per change in end-tidal PCO2 measured in a background of hyperoxia

  6. Hypoxic Hypercapnic Cerebral Blood Flow Response [ Time Frame: 0 and 8 hours ]
    the change in middle cerebral and posterior cerebral blood velocity per change in end-tidal PCO2 measured in a background of hypoxia.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • normotensive
  • forced expiratory volume in 1s : forced vital capacity ratio > 0.75
  • no medical history of cardiovascular and respiratory disease
  • not taking medications other than oral contraceptives
  • free from sleep apnea
  • body mass index less than 30 kg/m2

Exclusion Criteria:

  • history of hypertension
  • known impaired renal function
  • liver disease
  • heart failure
  • myocardial infarction
  • coronary artery disease
  • smoked within the past year
  • apnea hypopnea index > 5 events per hour

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03335904


Locations
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Canada, British Columbia
University of British Columbia
Kelowna, British Columbia, Canada, V1V 1V7
Sponsors and Collaborators
University of British Columbia
Investigators
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Principal Investigator: Glen Foster, PhD University of British Columbia
Publications of Results:
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Responsible Party: Glen Foster, Assistant Professor, University of British Columbia
ClinicalTrials.gov Identifier: NCT03335904    
Other Study ID Numbers: H17-02920
First Posted: November 8, 2017    Key Record Dates
Last Update Posted: September 4, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Glen Foster, University of British Columbia:
Angiotensin receptor blockade
control of breathing
breath-holding
Additional relevant MeSH terms:
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Respiratory Aspiration
Sleep Apnea Syndromes
Sleep Wake Disorders
Hypoxia
Respiration Disorders
Respiratory Tract Diseases
Pathologic Processes
Signs and Symptoms, Respiratory
Nervous System Diseases
Neurologic Manifestations
Mental Disorders
Apnea
Sleep Disorders, Intrinsic
Dyssomnias
Losartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action