Acetazolamide Add-On Therapy to OSA Surgery (ACTOS)

Acetazolamide as add-on Therapy to Obstructive Sleep Apnea Surgery (ACTOS): a Parallel-group, Double-blind, Placebo-controlled, Randomized Trial

Surgical procedures are routinely performed as an alternative to continuous positive airway pressure treatment in patients with obstructive sleep apnea (OSA). However, the response to surgery is often variable. Instability of the respiratory control during sleep (or high loop gain) has been associated with poor surgical results in previous research. Acetazolamide (AZM), a carbonic anhydrase inhibitor, has shown potential in reducing loop gain without affecting other physiological OSA traits. In this protocol the investigators will evaluate the clinical efficacy of AZM add-on therapy to surgical procedures in patients with OSA.

Study Overview

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

Detailed Description

Seventy-four patients with diagnosed moderate to severe OSA will be equally (1:1) randomized to AZM (250 mg twice daily) or placebo add-on therapy after surgery. Two surgical procedures will be performed throughout the study: barbed reposition pharyngoplasty (BRP) and upper airway stimulation (UAS) using electrical neurostimulation of the hypoglossal nerve.

Treatment allocation will occur after a satisfactory recovery in patients undergoing BRP and after titration of the device settings in patients treated with UAS. Treatment outcome will be assessed approximately 10 weeks thereafter by in-laboratory polysomnography. Two on-site follow-up visits will be scheduled to assess adherence and adverse events. The maximum treatment duration per participant will amount to 16 weeks.

Besides the aforementioned core clinical part, the study protocol will also include an optional exploratory part prior to surgery, assessing the physiological OSA traits and airflow features by means of polysomnography and drug-induced sleep endoscopy research measurements.

• Study Type: Interventional
• Enrollment (Anticipated): 74
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Eli Van de Perck, MD; Phone Number: +32 38213436; 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 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of moderate to severe OSA (i.e. 15≤ AHI <65 events per hour)
• Eligibility for either BRP or UAS surgery
• Fitness for general anesthesia (ASA ≤2)
• Capability of giving informed consent and willingness to undergo surgery

Exclusion Criteria:

• Craniofacial anomalies affecting the UA
• Body mass index (BMI) >35 kg/m²
• General contra-indications for surgery
• Central sleep apnea (defined as central AHI ≥5 events per hour)

• Contra-indications related to acetazolamide treatment

  • Hypersensitivity to sulfonamides or acetazolamide
  • Renal impairment (eGFR <60 ml/min/1.73m²), electrolyte imbalances (sodium levels <135 mmol/L or potassium levels <3.5 mmol/L) and/or adrenocortical insufficiency
  • Clinically significant neurological, metabolic (including diabetes mellitus type 1 or 2), hepatic (alanine transaminase or aspartate transaminase >2 times the upper limit of normal) and/or hematological disease
  • Chronic obstructive pulmonary disease
  • Closed-angle glaucoma
  • Professional driving or handling complex machinery due to the potential risk of exaggerated daytime sleepiness
• Concomitant intake of drugs that influence breathing, sleep, arousal and/or muscle physiology
• Inability of the patient to understand and/or comply to the study procedures
• Active psychiatric disease (psychotic illness, major depression, anxiety attacks, and alcohol or drug abuse) which prevents compliance with the requirements of the research setting
• Pregnancy or willing to become pregnant

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Acetazolamide; Acetazolamide will be prescribed in unembellished white capsules of 250 mg. The drug will be administered twice daily in the morning and evening (approximately one hour before bedtime). The total treatment length will amount to 16 weeks. In case of side effects hampering treatment adherence, the daily dosage will be reduced to a single evening dose of 250 mg.	Drug: Acetazolamide; Oral acetazolamide tablets of 250 mg taken twice daily.; Other Names: Diamox; ATC code: S01EC01
Placebo Comparator: Placebo; The placebo regimen will be identical.	Drug: Placebo; Matching placebo tablets taken twice daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apnea-hypopnea index (AHI)	Change in AHI (events/h) from baseline to follow-up. The AHI is an index of sleep apnea severity that encompasses the frequency of apneas (cessations in breathing) and hypopneas (reductions in airflow).	10 weeks of add-on therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygen desaturation index (ODI)	Change in ODI (events/h) from baseline to follow-up. The ODI represents the average number of desaturation episodes (≥3%) per hour sleep.	10 weeks of add-on therapy
Oxygen saturation (SaO2)	Change in mean and minimal SaO2 (%) from baseline to follow-up.	10 weeks of add-on therapy
Changes in daytime sleepiness measured with the Epworth Sleepiness Scale (ESS)	The questionnaire asks subjects to rate their probability of falling asleep on a scale from 0 to 3 for eight different situations that most people encounter in their daily lives. The scores for the eight questions are added together to obtain a single number (0-24). An ESS score higher than 10 indicates the presence of excessive daytime sleepiness.	16 weeks of add-on therapy
Changes in sleep-related quality of life measured with the 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.	16 weeks of add-on therapy
Changes in snoring intensity measured with a Visual Analogue Scale (VAS)	If patients have a bed partner, a standard 10-point VAS ranging from 0 (no snoring) to 10 (extreme snoring causing the bed partner to leave the bedroom or sleep separately) 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. A satisfactory improvements is defined as a reduction to an index that is no longer experiences as bothersome (i.e. <3).	16 weeks of add-on therapy
Incidence of adverse events	Safety and tolerability of study treatment.	16 weeks of add-on therapy

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): January 22, 2020
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: December 20, 2019
• First Submitted That Met QC Criteria: January 10, 2020
• First Posted (Actual): January 13, 2020

Study Record Updates

• Last Update Posted (Actual): January 27, 2020
• Last Update Submitted That Met QC Criteria: January 23, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Surgery; Acetazolamide; Carbonic anhydrase inhibitor; Upper airway stimulation
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Acetazolamide
• Other Study ID Numbers: B300201942507

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No