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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

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ClinicalTrials.gov Identifier: NCT02220803
Recruitment Status : Completed
First Posted : August 20, 2014
Last Update Posted : August 16, 2016
Sponsor:
Information provided by (Responsible Party):
Jan Hedner, Göteborg University

Tracking Information
First Submitted Date  ICMJE August 18, 2014
First Posted Date  ICMJE August 20, 2014
Last Update Posted Date August 16, 2016
Study Start Date  ICMJE March 2014
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 19, 2014)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 19, 2014)
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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: August 19, 2014)
  • 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:
  • 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE A Short Term Open, Randomized Cross Over Trial Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Obstructive Sleep Apnea
  • Sleep-Disordered Breathing
  • Blood Pressure
  • Hypertension
Intervention  ICMJE
  • 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™
Study Arms  ICMJE
  • 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.

    Interventions:
    • Drug: Acetazolamide
    • Device: nasal Continuous Positive Airway Pressure (nCPAP)
  • 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.
    Intervention: Device: nasal Continuous Positive Airway Pressure (nCPAP)
  • 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.
    Intervention: Drug: Acetazolamide
Publications * Eskandari D, Zou D, Grote L, Hoff E, Hedner J. Acetazolamide Reduces Blood Pressure and Sleep-Disordered Breathing in Patients With Hypertension and Obstructive Sleep Apnea: A Randomized Controlled Trial. J Clin Sleep Med. 2018 Mar 15;14(3):309-317. doi: 10.5664/jcsm.6968.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 15, 2016)
13
Original Estimated Enrollment  ICMJE
 (submitted: August 19, 2014)
12
Actual Study Completion Date  ICMJE August 2016
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02220803
Other Study ID Numbers  ICMJE CA-BP13
2013-004866-33 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jan Hedner, Göteborg University
Study Sponsor  ICMJE Göteborg University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jan Hedner, MD. Prof. Dept of internal medicine. Center for Sleep and Vigilance disorders.
PRS Account Göteborg University
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP