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

Hypertension Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02220803
• Other study ID #: CA-BP13
• Secondary ID: 2013-004866-33
• Status: Completed
• Phase: Phase 2
• First received: August 18, 2014
• Last updated: August 15, 2016
• Start date: March 2014
• Est. completion date: August 2016

Study information

• Verified date: August 2016
• Source: Göteborg University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Sweden: Regional Ethical Review BoardSweden: Medical Products Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Apnea
• Blood Pressure
• Hypertension
• Obstructive Sleep Apnea
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive
• Sleep-Disordered Breathing

Intervention

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.

Device:
• nasal Continuous Positive Airway Pressure (nCPAP)

Locations

Country	Name	City	State
Sweden	Center for Sleep and Vigilance disorders	Gothenburg	Vastra Gotaland

Sponsors (1)

Lead Sponsor	Collaborator
Göteborg University

Country where clinical trial is conducted

Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Other outcome measures include the assessment of vascular function.	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	Yes
Other	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.	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	No
Primary	The primary efficacy variable is the reduction in systolic/diastolic office blood pressure (mmHg) between the treatment regimens	The effect will be expressed in terms systolic and diastolic blood pressure (resting office, provoked office and 24 hour).	Baseline to 10 weeks	Yes
Secondary	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	Secondary objectives include Apnea-hypopnea Index, AHI score in patients with OSA after treatment.	Baseline to 10 weeks	No