Optimal Dosage of Acetazolamide for OSA Treatment

Optimal Dosage of Acetazolamide for Obstructive Sleep Apnea Treatment: a Parallel-group, Double-blind, Placebo-controlled, Randomized Trial

Acetazolamide, a carbonic anhydrase inhibitor, has received some attention as potential treatment for obstructive sleep apnea (OSA). It produces a metabolic acidosis by excreting bicarbonate, thereby stimulating baseline ventilation. Evidence suggests that acetazolamide primarily improves ventilatory control instability (expressed as loop gain), which is an important contributor to the pathophysiology of OSA.

Few studies have assessed the efficacy of acetazolamide in patients with OSA. Since most of them had a small sample size and used different therapeutic dosages, clinical applications are currently limited. Therefore, this study aims to compare the effect of two acetazolamide dosages on the severity and pathophysiology of OSA.

Study Overview

• Status: Recruiting
• Conditions: Obstructive Sleep Apnea
• Intervention / Treatment: Drug: Acetazolamide; Drug: Acetazolamide; Other: Placebo

Detailed Description

In this double-blind, parallel-group, controlled trial, eligible patients will be randomized into one of the following treatment arms: (1) placebo, (2) 250 mg of acetazolamide, or (3) 500 mg of acetazolamide. After 4 weeks, treatment outcome will be assessed by in-laboratory polysomnography. Additionally, arterial blood gas analysis and lung function tests will be performed before and during treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Eli Van de Perck, MD; Phone Number: +32 38214244; Email: eli.vandeperck@uza.be

Study Locations

• Belgium
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • Recruiting
      • Antwerp University Hospital
      • Contact: Eli Van de Perck, MD
      • Principal Investigator: Olivier Vanderveken, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• AHI between 15 and 65 events/hour
• BMI < 35 kg/m²

Exclusion Criteria:

• Craniofacial anomalies
• Central sleep apnea (defined as central AHI > 25% of total AHI)

• Contra-indications related to acetazolamide treatment

  • Hypersensitivity to sulphonamides or acetazolamide
  • Renal impairment, electrolyte imbalances, and/or adrenocortical insufficiency
  • Clinically significant metabolic, hepatic, and/or hematological disease
  • Chronic obstructive pulmonary disease
  • Closed-angle glaucoma
• Conditions likely to affect OSA physiology: neuromuscular disease or other major neurological disorders, heart failure, or any other unstable major medical condition.
• Intake of drugs that substantially stimulate or depress respiration, including benzodiazepines, opioids, theophylline, and pseudoephedrine
• Inadequately treated sleep disorders other than OSA that would confound functional sleep assessment
• Inability of the patient to understand and/or comply to the study procedures
• Active psychiatric disease (psychotic illness, major depression, anxiety attacks, alcohol or drug abuse)
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose acetazolamide; Unembellished white tablets. The drug should be taken one hour before bedtime. Total treatment duration will be 6 weeks.	Drug: Acetazolamide; 250 mg once daily; Other Names: Diamox; ATC code: S01EC01; Drug: Acetazolamide; 500 mg once daily; Other Names: Diamox; ATC code: S01EC01
Experimental: High dose acetazolamide; Unembellished white tablets. The drug should be taken one hour before bedtime. Total treatment duration will be 6 weeks.	Drug: Acetazolamide; 250 mg once daily; Other Names: Diamox; ATC code: S01EC01; Drug: Acetazolamide; 500 mg once daily; Other Names: Diamox; ATC code: S01EC01
Placebo Comparator: Placebo; Matching placebo tablets. The drug should be taken one hour before bedtime. Total treatment duration will be 6 weeks.	Other: Placebo; Once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea-hypopnea index (AHI)	Change in AHI (events/hour) from baseline to follow-up. The AHI is a measure of sleep apnea severity that encompasses the frequency of apneas (cessations in breathing) and hypopneas (reductions in airflow).	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathophysiological traits	Changes in pathophysiological traits (Vpassive, Vactive, Arousal Threshold, Loop Gain) will be quantified as %Veupnea from polysomnography data using a validated algorithm.	4 weeks
Percent responders	Treatment response will be defined as a reduction in AHI of ≥ 50%.	4 weeks
Nocturnal oxygen saturation	Change in mean and minimal SaO2 (%).	4 weeks
Oxygen desaturation index (ODI)	Change in ODI (events/hour) from baseline to follow-up. The ODI represents the average number of desaturation episodes (≥ 3%) per hour sleep.	4 weeks
Arterial blood gas measurements	Change in pO2 (mmhg) and pCO2 (mmhg) from baseline to follow-up.	4 weeks
Lung function parameters	Change in flow-volume curve from baseline to follow-up.	4 weeks
Daytime sleepiness: Epworth Sleepiness Scale (ESS)	The ESS asks respondents to rate on a 4-point scale (0-3) their usual chances of dozing off or falling asleep while engaged in eight different activities. The ESS score (the sum of 8 item scores) can range from 0 to 24. The higher the ESS score, the higher that person's sleep propensity in daily life. A score higher than 10 indicates the presence of excessive daytime sleepiness.	6 weeks
Sleep-related quality of life: Functional Outcome of Sleep Questionnaire (FOSQ-10)	This questionnaire is an abbreviated version of the original 30-item version. The FOSQ-10 consists of 10 items that are distributed among 5 subscales: general productivity (2 items), activity level (3 items), vigilance (3 items), social outcomes (1 item), and intimacy and sexual relationships (1 item). The questionnaire has a 4-point scale. The total score is calculated as the sum of the subscale means and can range from 5 to 20. The minimal important difference ranges from 1.7 to 2.0 points.	6 weeks
Snoring intensity: Visual Analogue Scale (VAS)	A standard 10-point VAS ranging from 0 (no snoring) to 10 (extreme snoring) will be used to evaluate the subjective status of snoring during sleep. Heavy snoring corresponds to a snoring index of at least 7. A decrease of 3 points after treatment is considered significant. To be considered as an important reduction, snoring needs to reduce to an index that is no longer experienced as bothersome (i.e. < 3).	6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Safety and tolerability of study treatment.	6 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Investigators: Principal Investigator: Olivier Vanderveken, MD, PhD, University Hospital, Antwerp

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2021
• Primary Completion (Anticipated): August 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: January 26, 2021
• First Submitted That Met QC Criteria: January 26, 2021
• First Posted (Actual): January 27, 2021

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: May 17, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Treatment; Pharmacotherapy; Respiration; Sleep apnea; Carbonic anhydrase inhibitor; Loop gain; Ventilatory control instability; Acidosis
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Apnea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Acetazolamide
• Other Study ID Numbers: B3002021000015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No