Clinical trial NCT02220803: 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: A Short Term Open, Randomized Cross Over Trial Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Obstructive Sleep Apnea
Sleep-Disordered Breathing
Blood Pressure
Hypertension
Keywords: Acetazolamide
Zonegran
Obstructive Sleep apnea
Apnea
Respiration Disorders
Sleep Disorders
Cardiovascular
Hypertension
Carbonic Anhydrase
Carbonic Anhydrase Inhibitors
Enzyme Inhibitors
Sulfonamides
Therapeutic Uses
Pharmacologic Actions
Vascular stifness
Lead sponsor: Göteborg University
Sponsor class: OTHER
First posted: 2014-08-20
Enrollment: 13
Sex: MALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: The primary efficacy variable is the reduction in systolic/diastolic office blood pressure (mmHg) between the treatment regimens
timeFrame: Baseline to 10 weeks
Secondary outcomes:
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
timeFrame: Baseline to 10 weeks
Other outcomes:
measure: Other outcome measures include the assessment of vascular function.
timeFrame: Baseline to 10 weeks
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.
timeFrame: Baseline to 10 weeks
Locations:
city: Gothenburg
country: Sweden
facility: Center for Sleep and Vigilance disorders
state: Vastra Gotaland
Study officials:
affiliation: Dept of internal medicine. Center for Sleep and Vigilance disorders.
name: Jan Hedner, MD. Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.