<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02220803</url>
  </required_header>
  <id_info>
    <org_study_id>CA-BP13</org_study_id>
    <secondary_id>2013-004866-33</secondary_id>
    <nct_id>NCT02220803</nct_id>
  </id_info>
  <brief_title>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</brief_title>
  <official_title>A Short Term Open, Randomized Cross Over Trial Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Göteborg University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Göteborg University</source>
  <brief_summary>
    <textblock>
      This is a short term open, randomized cross over trial to explore and compare the efficacy of&#xD;
      pharmacological carbonic anhydrase (CA) inhibition on obstructive sleep apnea (OSA) related&#xD;
      hypertension. Patients will be randomized to receive Acetazolamide(Diamox®)(ACZ), Continuous&#xD;
      Positive Airway Pressure (CPAP)or CPAP plus ACZ for 2 weeks. Following a 2 week wash-out&#xD;
      period all study participants will receive the alternative treatment regimen. The total&#xD;
      length of the study will be 10 weeks. The effects of carbonic anhydrase inhibition on blood&#xD;
      pressure,hemodynamics and sleep apnea will be investigated.&#xD;
&#xD;
      Study hypothesis:&#xD;
&#xD;
      Carbonic anhydrase inhibition alone or in combination with nCPAP will prominently reduce&#xD;
      blood pressure in patients with OSA. Further it is hypothesized that CA inhibition will&#xD;
      induce a direct pharmacological effects on vascular stiffness as evidenced in overnight&#xD;
      non-invasive assessments of vascular stiffness and that this effect will be particularly&#xD;
      strong in patients also responding with a reduction of blood pressure.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>March 2014</start_date>
  <completion_date type="Actual">August 2016</completion_date>
  <primary_completion_date type="Actual">August 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The primary efficacy variable is the reduction in systolic/diastolic office blood pressure (mmHg) between the treatment regimens</measure>
    <time_frame>Baseline to 10 weeks</time_frame>
    <description>The effect will be expressed in terms systolic and diastolic blood pressure (resting office, provoked office and 24 hour).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>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</measure>
    <time_frame>Baseline to 10 weeks</time_frame>
    <description>Secondary objectives include Apnea-hypopnea Index, AHI score in patients with OSA after treatment.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Other outcome measures include the assessment of vascular function.</measure>
    <time_frame>Baseline to 10 weeks</time_frame>
    <description>Vascular function will be assessed by:&#xD;
Cold pressor test: assessing vascular response and pulse excitability. Arteriograph: Standard radial pulse assessment to determine pulse wave and augmentation.&#xD;
Aritmethic stress test: Evaluate cardiovascular responses such as heart rate, blood pressure and heart rate variability induced by mental work.&#xD;
CardioPAT: Finger plethysmograph measuring peripheral arterial tone as well as endothelial function following brachial artery compression (ischemia).&#xD;
Full overnight two channel MC Cardio recorder (Sleep apnea indices and recording of continuous oximetry signal for vascular stiffness, microcirculation and chemosensory vascular responsiveness)&#xD;
Markers of OSA include:</description>
  </other_outcome>
  <other_outcome>
    <measure>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.</measure>
    <time_frame>Baseline to 10 weeks</time_frame>
    <description>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).&#xD;
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.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Obstructive Sleep Apnea</condition>
  <condition>Sleep-Disordered Breathing</condition>
  <condition>Blood Pressure</condition>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>Acetazolamide and CPAP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.&#xD;
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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CPAP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Acetazolamide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetazolamide</intervention_name>
    <description>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.</description>
    <arm_group_label>Acetazolamide</arm_group_label>
    <arm_group_label>Acetazolamide and CPAP</arm_group_label>
    <other_name>Diamox®</other_name>
    <other_name>ATC-code: S01E C01</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>nasal Continuous Positive Airway Pressure (nCPAP)</intervention_name>
    <arm_group_label>Acetazolamide and CPAP</arm_group_label>
    <arm_group_label>CPAP</arm_group_label>
    <other_name>nCPAP - Nasal Continuous Positive Airway Pressure.</other_name>
    <other_name>ResMed - S9 AutoSet™</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
          -  Males 18 to 75 years&#xD;
&#xD;
          -  An Apnea-Hypopnea Index (AHI)&gt;15 and an Epworth Sleepiness Scale score (ESS)&gt;6 as&#xD;
             verified by a PSG recording.&#xD;
&#xD;
          -  Patients with established hypertension (systolic/diastolic blood pressure &gt;= 160/95,&#xD;
             either systolic or diastolic accounted for).&#xD;
&#xD;
          -  Clinically normal physical findings and laboratory values, as judged by the&#xD;
             investigator&#xD;
&#xD;
          -  Body mass index &gt;= 35 kg/m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Hypersensitivity to sulfonamides or acetazolamide-&#xD;
&#xD;
          -  Patients with ongoing medication with other sulphonamides or patients any specific&#xD;
             antihypertensive treatment.&#xD;
&#xD;
          -  History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity.&#xD;
&#xD;
          -  Subjects with a seizure disorder&#xD;
&#xD;
          -  Patients with clinically verified central sleep apnea&#xD;
&#xD;
          -  Clinically significant renal (serum creatinine &gt;2.0 mg/dL or &gt;130 micromol/L),&#xD;
             neurological, metabolic (e.g. Type 1 or 2 diabetes), haematological or hepatic disease&#xD;
             (ASAT or ALAT &gt;2 times the upper limit of normal).&#xD;
&#xD;
          -  Subjects with an occupational risk potentially exaggerated by daytime sleepiness such&#xD;
             as handling complex machinery or professional driving&#xD;
&#xD;
          -  Unstable angina pectoris, unstable hypertension (or poorly controlled diabetes (HbA1C&#xD;
             &lt; 52 mmoles/mol, or fasting plasma glucose &gt;7 mmoles/l).&#xD;
&#xD;
          -  Clinically significant congestive heart failure.&#xD;
&#xD;
          -  Myocardial infarction or coronary vessel intervention within the previous 6 months&#xD;
             period.&#xD;
&#xD;
          -  Subjects with uncontrolled hypertension (defined as a diastolic blood pressure ≥110&#xD;
             mmHg and/or a systolic blood pressure ≥180 mmHg with or without medication).&#xD;
&#xD;
          -  Previously diagnosed or treated clinically significant cardiac arrhythmia&#xD;
&#xD;
          -  Clinically significant chronic pulmonary or gastrointestinal disease.&#xD;
&#xD;
          -  Clinical history of depression as judged by the investigator or other previous or&#xD;
             present clinically significant psychiatric disease&#xD;
&#xD;
          -  Suspected or confirmed poor compliance&#xD;
&#xD;
          -  Alcohol or drug abuse during the last year.&#xD;
&#xD;
          -  Subjects with any other significant condition that, in the opinion of the&#xD;
             investigator, could interfere with participation in the study.&#xD;
&#xD;
          -  Severe nocturnal hypoxia defined as more than 10 episodes with an oxygen desaturation&#xD;
             exceeding 50% or signs of lacking resaturation between desaturations on previous&#xD;
             recordings according to investigators judgment&#xD;
&#xD;
          -  Participation in another clinical study during the last 6 months.&#xD;
&#xD;
          -  Inability to understand and complete the questionnaires.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jan Hedner, MD. Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dept of internal medicine. Center for Sleep and Vigilance disorders.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Sleep and Vigilance disorders</name>
      <address>
        <city>Gothenburg</city>
        <state>Vastra Gotaland</state>
        <zip>40530</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>August 18, 2014</study_first_submitted>
  <study_first_submitted_qc>August 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 20, 2014</study_first_posted>
  <last_update_submitted>August 15, 2016</last_update_submitted>
  <last_update_submitted_qc>August 15, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 16, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Göteborg University</investigator_affiliation>
    <investigator_full_name>Jan Hedner</investigator_full_name>
    <investigator_title>Professor. MD</investigator_title>
  </responsible_party>
  <keyword>Acetazolamide</keyword>
  <keyword>Zonegran</keyword>
  <keyword>Obstructive Sleep apnea</keyword>
  <keyword>Apnea</keyword>
  <keyword>Respiration Disorders</keyword>
  <keyword>Sleep Disorders</keyword>
  <keyword>Cardiovascular</keyword>
  <keyword>Hypertension</keyword>
  <keyword>Carbonic Anhydrase</keyword>
  <keyword>Carbonic Anhydrase Inhibitors</keyword>
  <keyword>Enzyme Inhibitors</keyword>
  <keyword>Sulfonamides</keyword>
  <keyword>Therapeutic Uses</keyword>
  <keyword>Pharmacologic Actions</keyword>
  <keyword>Vascular stifness</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Apnea</mesh_term>
    <mesh_term>Sleep Apnea Syndromes</mesh_term>
    <mesh_term>Sleep Apnea, Obstructive</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetazolamide</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02220803
org study id: CA-BP13
secondary id: 2013-004866-33
nct id: NCT02220803
lead sponsor: 
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The primary efficacy variable is the reduction in systolic/diastolic office blood pressure (mmHg) between the treatment regimens
time frame: Baseline to 10 weeks
description: The effect will be expressed in terms systolic and diastolic blood pressure (resting office, provoked office and 24 hour).
measure: 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
description: Secondary objectives include Apnea-hypopnea Index, AHI score in patients with OSA after treatment.
measure: Other outcome measures include the assessment of vascular function.
time frame: Baseline to 10 weeks
description: 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:
measure: 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
description: 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.
arm group label: Acetazolamide and CPAP
arm group type: Active Comparator
description: 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.
arm group label: CPAP
arm group type: Active Comparator
description: 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.
arm group label: Acetazolamide
arm group type: Experimental
description: 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 type: Drug
intervention name: Acetazolamide
description: 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.
arm group label: Acetazolamide
arm group label: Acetazolamide and CPAP
other name: Diamox®
other name: ATC-code: S01E C01
intervention type: Device
intervention name: nasal Continuous Positive Airway Pressure (nCPAP)
arm group label: Acetazolamide and CPAP
arm group label: CPAP
other name: nCPAP - Nasal Continuous Positive Airway Pressure.
other name: ResMed - S9 AutoSet™
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Jan Hedner, MD. Prof.
role: Principal Investigator
affiliation: Dept of internal medicine. Center for Sleep and Vigilance disorders.
facility: 
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Göteborg University
investigator full name: Jan Hedner
investigator title: Professor. MD
mesh term: Apnea
mesh term: Sleep Apnea Syndromes
mesh term: Sleep Apnea, Obstructive
mesh term: Hypertension
mesh term: Acetazolamide