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

NCT02220803 | Completed Phase 2

• 2 other identifiers: CA-BP132013-004866-33
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (1)

• 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

  Baseline to 10 weeks

Other Outcomes (2)

• Other outcome measures include the assessment of vascular function.

  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.

  Baseline to 10 weeks

Study Arms (3)

Acetazolamide and CPAP

ACTIVE COMPARATOR

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; Device: nasal Continuous Positive Airway Pressure (nCPAP)

CPAP

ACTIVE COMPARATOR

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)

Acetazolamide

EXPERIMENTAL

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

Interventions

Acetazolamide DRUG

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.

Also known as: Diamox®, ATC-code: S01E C01

Acetazolamide; Acetazolamide and CPAP

nasal Continuous Positive Airway Pressure (nCPAP) DEVICE

Also known as: nCPAP - Nasal Continuous Positive Airway Pressure., ResMed - S9 AutoSet™

Acetazolamide and CPAP; CPAP

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Göteborg University: lead

Study Sites (1)

Center for Sleep and Vigilance disorders

Gothenburg, Västra Götaland County, 40530, Sweden

Location

Related Publications (1)

• 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.

  PMID: 29510792 DERIVED

MeSH Terms

Conditions

Sleep Apnea, Obstructive; Sleep Apnea Syndromes; Hypertension; Apnea; Respiration Disorders; Sleep Wake Disorders

Interventions

Acetazolamide; Continuous Positive Airway Pressure

Condition Hierarchy (Ancestors)

Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurologic Manifestations; Mental Disorders

Intervention Hierarchy (Ancestors)

Thiadiazoles; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Positive-Pressure Respiration; Respiration, Artificial; Airway Management; Therapeutics; Respiratory Therapy

Study Officials

• Jan Hedner, MD. Prof.

  Dept of internal medicine. Center for Sleep and Vigilance disorders.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor. MD

Study Record Dates

• First Submitted: August 18, 2014
• First Posted: August 20, 2014
• Study Start: March 1, 2014
• Primary Completion: August 1, 2016
• Study Completion: August 1, 2016
• Last Updated: August 16, 2016

Record last verified: 2016-08

Locations

SE (1)