A Short Term Open, Randomized Cross-over Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension and Vascular Dysfunction

August 15, 2016 updated by: Jan Hedner, Göteborg University

A Short Term Open, Randomized Cross Over Trial Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension

This is a short term open, randomized cross over trial to explore and compare the efficacy of pharmacological carbonic anhydrase (CA) inhibition on obstructive sleep apnea (OSA) related hypertension. Patients will be randomized to receive Acetazolamide(Diamox®)(ACZ), Continuous Positive Airway Pressure (CPAP)or CPAP plus ACZ for 2 weeks. Following a 2 week wash-out period all study participants will receive the alternative treatment regimen. The total length of the study will be 10 weeks. The effects of carbonic anhydrase inhibition on blood pressure,hemodynamics and sleep apnea will be investigated.

Study hypothesis:

Carbonic anhydrase inhibition alone or in combination with nCPAP will prominently reduce blood pressure in patients with OSA. Further it is hypothesized that CA inhibition will induce a direct pharmacological effects on vascular stiffness as evidenced in overnight non-invasive assessments of vascular stiffness and that this effect will be particularly strong in patients also responding with a reduction of blood pressure.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Sweden
    • Vastra Gotaland
      • Gothenburg, Vastra Gotaland, Sweden, 40530
        • Center for Sleep and Vigilance disorders

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Provision of informed consent prior to any study specific procedures
  • Males 18 to 75 years
  • An Apnea-Hypopnea Index (AHI)>15 and an Epworth Sleepiness Scale score (ESS)>6 as verified by a PSG recording.
  • Patients with established hypertension (systolic/diastolic blood pressure >= 160/95, either systolic or diastolic accounted for).
  • Clinically normal physical findings and laboratory values, as judged by the investigator
  • Body mass index >= 35 kg/m2

Exclusion Criteria:

  • Hypersensitivity to sulfonamides or acetazolamide-
  • Patients with ongoing medication with other sulphonamides or patients any specific antihypertensive treatment.
  • History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity.
  • Subjects with a seizure disorder
  • Patients with clinically verified central sleep apnea
  • Clinically significant renal (serum creatinine >2.0 mg/dL or >130 micromol/L), neurological, metabolic (e.g. Type 1 or 2 diabetes), haematological or hepatic disease (ASAT or ALAT >2 times the upper limit of normal).
  • Subjects with an occupational risk potentially exaggerated by daytime sleepiness such as handling complex machinery or professional driving
  • Unstable angina pectoris, unstable hypertension (or poorly controlled diabetes (HbA1C < 52 mmoles/mol, or fasting plasma glucose >7 mmoles/l).
  • Clinically significant congestive heart failure.
  • Myocardial infarction or coronary vessel intervention within the previous 6 months period.
  • Subjects with uncontrolled hypertension (defined as a diastolic blood pressure ≥110 mmHg and/or a systolic blood pressure ≥180 mmHg with or without medication).
  • Previously diagnosed or treated clinically significant cardiac arrhythmia
  • Clinically significant chronic pulmonary or gastrointestinal disease.
  • Clinical history of depression as judged by the investigator or other previous or present clinically significant psychiatric disease
  • Suspected or confirmed poor compliance
  • Alcohol or drug abuse during the last year.
  • Subjects with any other significant condition that, in the opinion of the investigator, could interfere with participation in the study.
  • Severe nocturnal hypoxia defined as more than 10 episodes with an oxygen desaturation exceeding 50% or signs of lacking resaturation between desaturations on previous recordings according to investigators judgment
  • Participation in another clinical study during the last 6 months.
  • Inability to understand and complete the questionnaires.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Acetazolamide and CPAP

Acetazolamide: Diamox®. Hard white capsule, 250 mg. The total treatment is 4 weeks (2+2 weeks). Dosing of acetazolamide will be up-titrated during 3 days according to manufacturer instruction and titration scheme of the study. Maximum dosage (750mg) following titration will be administered as morning (250 mg) and evening(500mg) dosages.Evening medication should be taken 2 hours before bedtime.

CPAP: Continuous positive nasal airway pressure (nCPAP) delivers slightly pressurized air throughout the breathing cycle and will be given through a mask that is placed and secured over the person's nose. nCPAP titration will follow clinical routines. The standard setting is a pressure delivery in the pressure range 5-15 mbar. The adequate performance of the device is controlled by user time readers and built-in memory cards and control readings are routinely performed at the end of each treatment regimen. Total duration of CPAP treatment is 4(2+2) weeks.
Drug: Acetazolamide
Acetazolamide, 250mg tablets, will be administrated as multiple doses. Dosing of acetazolamide will be up-titrated during 3 days according to manufacturer instruction and titration scheme of the study. Maximum daily dosage is 750 mg (equivalent of 3 tablets/daily). Evening medication should be taken 2 hours before bedtime. The total length of Acetazolamide treatment will be 4 weeks (2x2) including 3 days of titration phase of the drug.
Other Names:
  • Diamox®
  • ATC-code: S01E C01
Device: nasal Continuous Positive Airway Pressure (nCPAP)
Other Names:
  • nCPAP - Nasal Continuous Positive Airway Pressure.
  • ResMed - S9 AutoSet™
Active Comparator: CPAP
Continuous positive nasal airway pressure (nCPAP) delivers slightly pressurized air throughout the breathing cycle and will be given through a mask that is placed and secured over the person's nose. nCPAP titration will follow clinical routines whereby the patient is equipped with an autotitrating device (Sullivan S9). The standard setting is a pressure delivery in the pressure range 5-15 mbar and the full treatment is maintained in the patient´s home. The adequate performance of the device is controlled by user time readers and built-in memory cards and control readings are routinely performed at the end of each treatment regimen. Patients will be encouraged via telephone calls for maximum use. Total duration of CPAP treatment is 4(2+2) weeks.
Device: nasal Continuous Positive Airway Pressure (nCPAP)
Other Names:
  • nCPAP - Nasal Continuous Positive Airway Pressure.
  • ResMed - S9 AutoSet™
Experimental: Acetazolamide
Acetazolamide (Diamox®) 250 mg. Hard white capsule. The total length of acetazolamide treatment will be 4 weeks (2x2) including 3 days of titration phase of the drug. Dosing of acetazolamide will be up-titrated during 3 days according to manufacturer instruction and titration scheme of the study. Maximum dosage (750mg) following titration will be administered as morning (250 mg) and evening(500mg)dosages.Evening medication should be taken 2 hours before bedtime. The tablets will be swallowed with 300 ml of water (room temperature) in an upright body position and preferably in connection to a meal.
Drug: Acetazolamide
Acetazolamide, 250mg tablets, will be administrated as multiple doses. Dosing of acetazolamide will be up-titrated during 3 days according to manufacturer instruction and titration scheme of the study. Maximum daily dosage is 750 mg (equivalent of 3 tablets/daily). Evening medication should be taken 2 hours before bedtime. The total length of Acetazolamide treatment will be 4 weeks (2x2) including 3 days of titration phase of the drug.
Other Names:
  • Diamox®
  • ATC-code: S01E C01

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The primary efficacy variable is the reduction in systolic/diastolic office blood pressure (mmHg) between the treatment regimens
Time Frame: Baseline to 10 weeks
The effect will be expressed in terms systolic and diastolic blood pressure (resting office, provoked office and 24 hour).
Baseline to 10 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The secondary objective is to investigate the direct effect of CA inhibition on sleep disordered breathing (Apnea-hypopnea Index, AHI score (events/hour) in the subgroup of patients with OSA after treatment
Time Frame: Baseline to 10 weeks
Secondary objectives include Apnea-hypopnea Index, AHI score in patients with OSA after treatment.
Baseline to 10 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Other outcome measures include the assessment of vascular function.
Time Frame: Baseline to 10 weeks

Vascular function will be assessed by:

Cold pressor test: assessing vascular response and pulse excitability. Arteriograph: Standard radial pulse assessment to determine pulse wave and augmentation.

Aritmethic stress test: Evaluate cardiovascular responses such as heart rate, blood pressure and heart rate variability induced by mental work.

CardioPAT: Finger plethysmograph measuring peripheral arterial tone as well as endothelial function following brachial artery compression (ischemia).

Full overnight two channel MC Cardio recorder (Sleep apnea indices and recording of continuous oximetry signal for vascular stiffness, microcirculation and chemosensory vascular responsiveness)

Markers of OSA include:
Baseline to 10 weeks
Markers of OSA such as oxygen desaturation, mean overnight oxygenation, and sleep quality (by polygraphic (PG) assessment, daytime sleepiness, patient-reported outcomes as well as effects on metabolic markers.
Time Frame: Baseline to 10 weeks

Markers of OSA include: Oxygen desaturation (ODI, events/hour), Mean overnight oxygenation (Spo2, %), Daytime sleepiness: Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ).

Patient reported outcomes include: Clinical Global rating Impression and Severity (CGI/S), Columbia suicidal severity rating scale (CSSR-S) Metabolic markers include:Total Cholesterol, HDL, LDL, Triglycerides, Insulin, HbA1C, Fasting plasma glucose and cathecholamines.
Baseline to 10 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Göteborg University

Investigators

  • Principal Investigator: Jan Hedner, MD. Prof., Dept of internal medicine. Center for Sleep and Vigilance disorders.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2014

Primary Completion (Actual)

August 1, 2016

Study Completion (Actual)

August 1, 2016

Study Registration Dates

First Submitted

August 18, 2014

First Submitted That Met QC Criteria

August 19, 2014

First Posted (Estimate)

August 20, 2014

Study Record Updates

Last Update Posted (Estimate)

August 16, 2016

Last Update Submitted That Met QC Criteria

August 15, 2016

Last Verified

August 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CA-BP13
  • 2013-004866-33 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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