ACTOS: Acetazolamide Add-On Therapy to OSA Surgery

Sponsor

University Hospital, Antwerp (Other)

Overall Status

Recruiting

CT.gov ID

NCT04227093

Collaborator

(none)

Enrollment

Location

Arms

34.3

Anticipated Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Obstructive Sleep Apnea	Drug: Acetazolamide Drug: Placebo	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

74 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Randomized, double-blind, placebo-controlled trialRandomized, double-blind, placebo-controlled trial

Masking:

Double (Participant, Care Provider)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 22, 2020

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Apnea-hypopnea index (AHI) [10 weeks of add-on therapy]
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).

Secondary Outcome Measures

Oxygen desaturation index (ODI) [10 weeks of add-on therapy]
Change in ODI (events/h) from baseline to follow-up. The ODI represents the average number of desaturation episodes (≥3%) per hour sleep.
Oxygen saturation (SaO2) [10 weeks of add-on therapy]
Change in mean and minimal SaO2 (%) from baseline to follow-up.
Changes in daytime sleepiness measured with the Epworth Sleepiness Scale (ESS) [16 weeks of add-on therapy]
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.
Changes in sleep-related quality of life measured with the Functional Outcome of Sleep Questionnaire (FOSQ-10) [16 weeks of add-on therapy]
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.
Changes in snoring intensity measured with a Visual Analogue Scale (VAS) [16 weeks of add-on therapy]
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).
Incidence of adverse events [16 weeks of add-on therapy]
Safety and tolerability of study treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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