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AZ, MZ, and the Pulmonary System Response to Hypoxia

Primary Purpose

Altitude Sickness, Hypertension, Pulmonary

Status
Completed
Phase
Phase 4
Locations
Canada
Study Type
Interventional
Intervention
Acetazolamide
Methazolamide
Placebo
Sponsored by
University of British Columbia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Altitude Sickness focused on measuring Acetazolamide, Methazolamide, Control of breathing, Hypoxic pulmonary vasoconstriction

Eligibility Criteria

18 Years - 40 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • 18-40 years of age
  • regularly physically active
  • male

Exclusion Criteria:

  • ex-smokers
  • pulmonary function <80% of predicted
  • contraindications to carbonic anhydrase inhibitors (eg. severe or absolute glaucoma, adrenocortical insufficiency, hepatic insufficiency, renal insufficiency, sulfa allergy or an electrolyte imbalance such as hyperchloremic acidosis)
  • Obese (BMI>30Kg/m2)
  • diuretic medication use
  • blood thinner use
  • anti-platelet drug use.

Sites / Locations

  • University of British Columbia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Acetazolamide

Methazolamide

Placebo

Arm Description

Participants will be dosed 250mg Acetazolamide (p.o.) three times per day for two days prior to and a single dose on the day of study.

Participants will be dosed 100mg Methazolamide (p.o.) twice daily separated by a placebo for two days prior to and a single dose on the day of study. The placebo dose is provided to match the dosing schedule between conditions.

Participants will take (p.o.) placebo pills three times per day for two days prior to and a single dose on the day of study.

Outcomes

Primary Outcome Measures

Change in ventilation
To quantify the isocapnic hypoxic ventilatory response, the hypercapnic ventilatory response, and the hypercapnic hypoxic ventilatory response, ventilation will be measured throughout controlled changes in end-tidal gas levels. Each protocol will consist of 90s steps in end-tidal oxygen partial pressure from baseline through 65, 57, and 47 mmHg. For hypercapnic hypoxia, the end-tidal partial pressure for carbon dioxide will be increased from baseline to +6 mmHg for 7 minutes before reducing the end-tidal partial pressure of oxygen as above. The poikilocapnic hypoxic ventilatory response will be determined by measuring the change in ventilation from baseline throughout 60 minutes of poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
Change in pulmonary artery pressure
Pulmonary artery systolic pressure (PASP) will be derived using the modified Bernoulli equation and the regurgitant velocity across the tricuspid valve. Estimates of right atrial pressure will be evaluated based upon the collapsibility index of the inferior vena cave during a sniff test. The pulmonary artery pressure response will be measured during 60 minutes of exposure to poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)

Secondary Outcome Measures

Change in cerebral blood velocity
To quantify the isocapnic hypoxic cerebral blood velocity response, the hypercapnic cerebral blood velocity response, and the hypercapnic hypoxic cerebral blood velocity response, cerebral blood velocity in the middle and posterior cerebral arteries will be measured throughout controlled changes in end-tidal gas levels. Each protocol will consist of 90s steps in end-tidal oxygen partial pressure from baseline through 65, 57, and 47 mmHg. For hypercapnic hypoxia, the end-tidal carbon dioxide partial pressure will be increased from baseline to +6 mmHg for 7 minutes before reducing the end-tidal oxygen partial pressure as above. The poikilocapnic hypoxic ventilatory response will be determined by measuring the change in ventilation from baseline throughout 60 minutes of poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)

Full Information

First Posted
April 20, 2016
Last Updated
October 18, 2016
Sponsor
University of British Columbia
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1. Study Identification

Unique Protocol Identification Number
NCT02760121
Brief Title
AZ, MZ, and the Pulmonary System Response to Hypoxia
Official Title
The Effect of Carbonic Anhydrase Inhibitors on the Pulmonary System Response to Hypoxia
Study Type
Interventional

2. Study Status

Record Verification Date
October 2016
Overall Recruitment Status
Completed
Study Start Date
May 2016 (undefined)
Primary Completion Date
August 2016 (Actual)
Study Completion Date
August 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of British Columbia

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this proposal is to compare the physiological effects of acetazolamide (AZ) and methazolamide (MZ) on the control of breathing and hypoxic pulmonary vasoconstriction. The first objective is to assess the effects of AZ and MZ on the control of breathing in normoxia and hypoxia. To achieve this the ventilatory interaction between oxygen and carbon dioxide will be measured and effects compared between placebo, AZ, and MZ conditions. In addition, the isocapnic and poikilocapnic hypoxic ventilatory response and hypercapnic ventilatory response will be measured with each drug. The second objective is to assess the effects of AZ and MZ on the control of the pulmonary vasculature during hypoxia. Pulmonary pressure and cardiac output will be measured during 60 minutes of poikilocapnic hypoxia.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Altitude Sickness, Hypertension, Pulmonary
Keywords
Acetazolamide, Methazolamide, Control of breathing, Hypoxic pulmonary vasoconstriction

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Acetazolamide
Arm Type
Experimental
Arm Description
Participants will be dosed 250mg Acetazolamide (p.o.) three times per day for two days prior to and a single dose on the day of study.
Arm Title
Methazolamide
Arm Type
Experimental
Arm Description
Participants will be dosed 100mg Methazolamide (p.o.) twice daily separated by a placebo for two days prior to and a single dose on the day of study. The placebo dose is provided to match the dosing schedule between conditions.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will take (p.o.) placebo pills three times per day for two days prior to and a single dose on the day of study.
Intervention Type
Drug
Intervention Name(s)
Acetazolamide
Intervention Type
Drug
Intervention Name(s)
Methazolamide
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Change in ventilation
Description
To quantify the isocapnic hypoxic ventilatory response, the hypercapnic ventilatory response, and the hypercapnic hypoxic ventilatory response, ventilation will be measured throughout controlled changes in end-tidal gas levels. Each protocol will consist of 90s steps in end-tidal oxygen partial pressure from baseline through 65, 57, and 47 mmHg. For hypercapnic hypoxia, the end-tidal partial pressure for carbon dioxide will be increased from baseline to +6 mmHg for 7 minutes before reducing the end-tidal partial pressure of oxygen as above. The poikilocapnic hypoxic ventilatory response will be determined by measuring the change in ventilation from baseline throughout 60 minutes of poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
Time Frame
Baseline and 60 minutes of poikilocapnic hypoxia
Title
Change in pulmonary artery pressure
Description
Pulmonary artery systolic pressure (PASP) will be derived using the modified Bernoulli equation and the regurgitant velocity across the tricuspid valve. Estimates of right atrial pressure will be evaluated based upon the collapsibility index of the inferior vena cave during a sniff test. The pulmonary artery pressure response will be measured during 60 minutes of exposure to poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
Time Frame
Baseline and 60 minutes of poikilocapnic hypoxia
Secondary Outcome Measure Information:
Title
Change in cerebral blood velocity
Description
To quantify the isocapnic hypoxic cerebral blood velocity response, the hypercapnic cerebral blood velocity response, and the hypercapnic hypoxic cerebral blood velocity response, cerebral blood velocity in the middle and posterior cerebral arteries will be measured throughout controlled changes in end-tidal gas levels. Each protocol will consist of 90s steps in end-tidal oxygen partial pressure from baseline through 65, 57, and 47 mmHg. For hypercapnic hypoxia, the end-tidal carbon dioxide partial pressure will be increased from baseline to +6 mmHg for 7 minutes before reducing the end-tidal oxygen partial pressure as above. The poikilocapnic hypoxic ventilatory response will be determined by measuring the change in ventilation from baseline throughout 60 minutes of poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
Time Frame
Baseline and 60 minutes
Other Pre-specified Outcome Measures:
Title
change in arterial oxygen partial pressure
Time Frame
Baseline and 60 minutes
Title
Change in arterial carbon dioxide partial pressure
Time Frame
Baseline and 60 minutes
Title
Change in arterial pH
Time Frame
Baseline and 60 minutes
Title
Change in heart rate
Time Frame
Baseline and 60 minutes
Title
change in blood pressure
Time Frame
Baseline and 60 minutes
Title
change in end-tidal oxygen and carbon dioxide partial pressure
Time Frame
Baseline and 60 minutes
Title
Change in arterial oxygen saturation
Time Frame
Baseline and 60 minutes
Title
Change in cardiac output
Description
Cardiac output will be determined using the aortic time integral velocity and the diameter of the aortic valve annulus. Data will be collected at baseline and throughout exposure to poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
Time Frame
Baseline and 60 minutes of poikilocapnic hypoxia
Title
Change in pulmonary venous blood velocity
Description
Doppler ultrasound will be used to measure the velocity of blood draining from the pulmonary vein at baseline and throughout exposure to poikilocapnic hypoxia (fraction of inspired oxygen = 0.12)
Time Frame
Baseline and 60 minutes of poikilocapnic hypoxia
Title
Hemoglobin
Time Frame
Baseline
Title
albumin
Time Frame
Baseline
Title
iron
Time Frame
Baseline

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 18-40 years of age regularly physically active male Exclusion Criteria: ex-smokers pulmonary function <80% of predicted contraindications to carbonic anhydrase inhibitors (eg. severe or absolute glaucoma, adrenocortical insufficiency, hepatic insufficiency, renal insufficiency, sulfa allergy or an electrolyte imbalance such as hyperchloremic acidosis) Obese (BMI>30Kg/m2) diuretic medication use blood thinner use anti-platelet drug use.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Glen E Foster, Ph.D.
Organizational Affiliation
University of British Columbia
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of British Columbia
City
Kelowna
State/Province
British Columbia
ZIP/Postal Code
V1V 1V7
Country
Canada

12. IPD Sharing Statement

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AZ, MZ, and the Pulmonary System Response to Hypoxia

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