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Trial registered on ANZCTR


Registration number
ACTRN12616001297415
Ethics application status
Approved
Date submitted
12/09/2016
Date registered
15/09/2016
Date last updated
14/07/2024
Date data sharing statement initially provided
20/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized controlled trial assessing the combined effect of acetazolamide and oxygen therapy as a novel treatment for sleep apnoea.
Scientific title
A randomized controlled trial assessing the combined effect of acetazolamide and oxygen therapy as a novel treatment for obstructive sleep apnoea.
Secondary ID [1] 289942 0
Nil known
Universal Trial Number (UTN)
U1111-1186-5016
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnoea 299926 0
Condition category
Condition code
Respiratory 299823 299823 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study uses a double cross over design with two treatment-placebo components.

Component 1 - Acetazolamide VS. Placebo/control
Component 2 - Supplemental oxygen administered during sleep VS. room air/control administered during sleep

Arm 1: ACETAZOLAMIDE
Acetazolamide administered for 7 days (250mg oral capsule, twice daily). On days 4 or 5 and 6 or 7 participants will complete a clinical polysomnographic (PSG) sleep study from which the primary and secondary outcomes are measured. During the first clinical PSG, participants will be randomised to sleep while receiving either oxygen (sub arm 1 - see below) or a room air/control (sub arm 2 - see below). For the second PSG, participants will cross over to the other sub arm.

Sub arm 1: Supplemental oxygen
During one of the clinical PSGs, participants will sleep with supplemental 100% oxygen delivered via a nasal cannula at a flow rate of 3 litres per minute.
Sub arm 2: Room air
During one of the clinical PSGs, participants will sleep with room air delivered via a nasal cannula at a flow rate of 3 litres per minute.

WASHOUT PERIOD:
A washout period of 7 days (42x the plasma half-life of acetazolamide) will be required before participants crossover into arm 2.

Arm 2: PLACEBO
Placebo administered for 7 days (oral capsule, twice daily). On days 4 or 5 and 6 or 7 participants will complete a clinical polysomnographic (PSG) sleep study from which the primary and secondary outcomes are measured. During the first clinical PSG (either day 4 or 5), participants will be randomised to sleep while receiving either oxygen (sub arm 1 - see below) or a room air/control (sub arm 2 - see below). For the second PSG (either day 6 or 7), participants will cross over to the other sub arm.

Sub arm 1: Supplemental oxygen
During one of the clinical PSGs participants will sleep with supplemental 100% oxygen delivered via a nasal cannula at a flow rate of 3 litres per minute.
Sub arm 2: Room air
During one of the clinical PSGs participants will sleep with room air delivered via a nasal cannula at a flow rate of 3 litres per minute.

Primary and secondary outcomes are drawn from the 4 clinical PSGs (2 per arm, 1 for each sub arm) such that each of the outcomes is assessed for a total of 4 treatment conditions:
1. Combination of Acetazolamide and Oxygen (combined treatment effect)
2. Combination of Acetazolamide and room air (acetazolamide effect)
3. Combination of placebo and Oxygen (oxygen effect)
4. Combination of placebo and room air (placebo/control).

ADHERENCE MONITORING:
A pill count will be conducted at each of the 4 clinical PSGs. Furthermore, a blood test will be performed during Arms 1 and 2, in order to confirm the appropriate metabolic acidosis associated with Acetazolamide.
Intervention code [1] 295629 0
Treatment: Drugs
Intervention code [2] 295895 0
Treatment: Other
Comparator / control treatment
The design has 2 active treatment comparators as well as 1 true placebo-control.

Primary study intervention = combination of Acetazolamide and oxygen

Acetazolamide active treatment comparator = Combination of acetazolamide and room air
Oxygen active treatment comparator = Combination of placebo and oxygen
True placebo/control comparator = Combination of placebo and room air

The placebo pill is a visually identical capsule (to the Acetazolamide capsule) containing sugar.
Control group
Placebo

Outcomes
Primary outcome [1] 299299 0
Loop gain as measured from clinical polysomnography (PSG)
Timepoint [1] 299299 0
Days 4, 5, 6 or 7 after daily administration of acetazolamide/placebo
Secondary outcome [1] 326782 0
OSA severity as assessed by Total sleep 'Alternative' Apnoea-Hypopnoea Index (AHI), measured from clinical polysomnography (PSG).

This 'alternative AHI' will utilize standard AASM scoring of apnoeas, however will use an alternative hypopnoea rule that requires only a 30% reduction in flow from baseline (i,e hypopnoea scoring will not require a SpO2 desaturation or arousal).
Timepoint [1] 326782 0
Days 4, 5, 6 or 7 after daily administration of acetazolamide/placebo
Secondary outcome [2] 326784 0
Loop gain as measured by wake chemoreflex tests.
Timepoint [2] 326784 0
Days 4, 5, 6 or 7 after daily administration of acetazolamide/placebo
Secondary outcome [3] 326785 0
OSA severity as assessed by Total sleep Apnoea-Hypopnoea Index (AHI), measured from clinical polysomnography. AHI will be scored scored according to standard AASM criteria.
Timepoint [3] 326785 0
Days 4, 5, 6 or 7 after daily administration of acetazolamide/placebo
Secondary outcome [4] 326786 0
OSA severity in NREM sleep as assessed by Non-rapid eye movement (NREM) sleep 'Alternative' Apnoea-Hypopnoea Index (AHI), measured from clinical polysomnography.

This 'alternative AHI' will utilize standard AASM scoring of apnoeas, however will use an alternative hypopnoea rule that requires only a 30% reduction in flow from baseline (i,e hypopnoea scoring will not require a SpO2 desaturation or arousal).
Timepoint [4] 326786 0
Days 4, 5, 6 or 7 after daily administration of acetazolamide/placebo
Secondary outcome [5] 326961 0
OSA severity in NREM sleep as assessed by Non-rapid eye movement (NREM) sleep Apnoea-Hypopnoea Index (AHI), measured from clinical polysomnography.
Timepoint [5] 326961 0
Days 4, 5, 6 or 7 after daily administration of acetazolamide/placebo
Secondary outcome [6] 327651 0
Subjective sleepiness as assessed by Karolinksa sleepiness scale (KSS) score
Timepoint [6] 327651 0
Days 4, 5, 6 or 7 after daily administration of acetazolamide/placebo

Eligibility
Key inclusion criteria
Patients must have a confirmed diagnosis of obstructive sleep apnoea (OSA), with an apnoea hypopnoea index (AHI) greater than 15 event per hour. OSA must be diagnosed with a Level 1 or level 2 sleep study, which must have been conducted within 6 months of recruitment into the study. Participants may have trialled CPAP or another treatment for OSA, but will have to have been off treatment for at least 1 week prior to the first PSG assessment.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they have other significant diagnosed health concerns, (other than treated hypertension), such as heart, pulmonary, renal or liver disorders.

Patients will also be excluded if they have other sleep disorders that could affect ventilation during sleep such as central sleep apnoea (CSA, defined by a central apnoea index of greater than 10 events per hour AND/OR greater than 50% of all respiratory events classified as central), and Chronic obstructive pulmonary disease (COPD).

Participants will be excluded if there is evidence of renal impairment (with an estimated eGFR < 60ml/min), or evidence of an electrolyte imbalance particularly Hyponatraemia (sodium level of less than 135 mEq/L) or Hypokalaemia (serum potassium level of less than 3.5 mEq/L).

Participants will also be excluded if they are taking medication that could affect ventilation (eg. morphine derivatives, benzodiazepines, theophylline etc.) or muscle control (eg. certain sedatives).

Because participants will be untreated for OSA for a period of time (albeit only briefly), we will exclude participants with profound sleepiness (Epworth greater than or equal to 16/24) or with a history of a motor vehicle accident or near miss accident related to sleepiness in the prior 2 years.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central stratified randomization by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Minimisation: Dynamic random allocation using equally weighted baseline factors (sex [M/F], age [<=50 or >50], BMI [<30 or >=30], and OSA severity [severe or non-severe]) to ensure treatment order allocation is appropriately balanced.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Power calculations were performed in order to determine a sample size sufficient to detect a significant reduction in loop gain (primary outcome) via either oxygen or acetazolamide treatments alone (given that the combination of these two treatments is expected to produce a greater magnitude of reduction in loop gain). Unpublished preliminary data on the effect of oxygen administration on loop gain, collected by the PIs at Monash University BASE facility, from participants recruited from Monash Health, was used to provide an effect size estimate (d=0.61). This data was specifically chosen as a conservative measurement, as it represents a smaller effect size than previous published data on the effect of oxygen (Edwards et al, 2014, J Physiol, d=1.62) or acetazolamide (Edwards et al 2012, J Physiol, d=1.30) on loop gain. Using a repeated measures ANOVA with 4 treatment conditions, a two sided alpha level of 0.05 and a power of 0.80, a sample size of 20 participants will be necessary based on effect size of d=0.61. Factoring the potential for a 30% attrition rate, a total of 26 participants will be recruited for this study. Note that the intended analysis (linear mixed effect modelling, see below) will allow for the control of participant, period and order effects (modelled as random effects) and thus is expected to be a more powerful analysis than the repeated measures ANOVA used in this sample size calculation.

Linear mixed-effect modelling will be used to assess the effect of the therapeutic combination on the primary and secondary outcomes. This analysis will use treatment condition [placebo + room air, placebo + oxygen, Acetazolamide + room air, Acetazolamide + oxygen] as a fixed effect. (1) Participant, (2) ‘period’ [clinical PSG: 1, 2, 3, 4] and (3) treatment order will be each be included/modelled as random effects. Data will be analysed on a per protocol basis, but a supplementary intention to treat analysis will be conducted and the results of the two analyses will be compared for agreement.

Data from the research polysomnogram (PSG) will provide baseline pathophysiological information for each patient. Multiple linear regression will be conducted to determine which baseline clinical and physiological variables are independently related to the greatest therapeutic reduction OSA severity (measured by apnoea-hypopnoea index, AHI). Furthermore we will conduct a 'responder' versus 'non-responder' analysis. Briefly, patients will be classified as a responder to the combination of therapies (Acetazolamide & Oxygen) if they demonstrate a 50% reduction in their AHI & an AHI on therapy of less than 10 events per hour. Independent samples t-tests (or non-parametric equivalent) will then assess which clinical and physiological variables separate 'responders' from 'non-responders'. Receiver operating characteristic (ROC) curves will be created to assess the predictive accuracy of any significant predictor variables or models for determining responder vs non-responder status.

Update (14/4/2023):

A non-prespecified interim analysis of the primary outcome data was performed at n=9 (/20, information fraction = 0.45).

This analysis was designed to assess the effect size of the comparison between the combination therapy condition (Acetazolamide + Oxygen) compared to the singular therapies (Acetazolamide or Oxygen alone), and determine whether the specified final sample size estimate (n=20) was also appropriate for this comparison.
Note that the sample size estimates for this study were originally based on the effect of the singular therapies versus a placebo control condition. It was assumed the combination therapy would be at least as efficacious compared to control (and therefore this analysis should be appropriately powered). However, there was no preliminary data available to assess the sample size required to compare the combination versus the singular therapies.

These interim analyses show moderate (d=0.61, combination vs oxygen) and large effect size (d=0.90, combination vs acetazolamide) differences for the primary outcome. Therefore, these comparisons should therefore be adequately powered with the originally specified target sample size (n=20).
To adjust for ‘alpha spent’ in this interim analysis, we plan to adjust the critical alpha of the second (i.e. final analysis) to a= 0.0492 (O’ Brien-Fleming method for k=2 analyses).
We have not calculated an adjusted critical alpha level for the interim analysis, as there was no intention to end the trial early (or to make any changes that would reduce the required sample size).

Furthermore, during the interim analysis no responder analyses were performed (as described in the analysis plan) as there was no intention at this time to understand the characteristics of which patients were likely to respond to the therapy. Nor was there any desire to change to recruitment strategy.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/03/2018
Actual
10/09/2018
Date of last participant enrolment
Anticipated
20/11/2024
Actual
Date of last data collection
Anticipated
20/12/2024
Actual
Sample size
Target
26
Accrual to date
20
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6490 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 14054 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 294318 0
University
Name [1] 294318 0
Monash University
Country [1] 294318 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Sleep and Circadian Medicine Laboratory
Ground Floor, BASE Facility
264 Ferntree Gully Road
Notting Hill, Victoria, 3168
Country
Australia
Secondary sponsor category [1] 293157 0
Hospital
Name [1] 293157 0
Monash Health
Address [1] 293157 0
Monash Medical Centre
246 Clayton Road
Clayton, Victoria, 3168
Country [1] 293157 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295747 0
Monash Health Human Research Ethics Committee A - EC00382
Ethics committee address [1] 295747 0
Research Support Services
Monash Health
Monash Medical Centre
246 Clayton Road
Clayton Victoria 3168
Australia
Ethics committee country [1] 295747 0
Australia
Date submitted for ethics approval [1] 295747 0
18/05/2016
Approval date [1] 295747 0
08/12/2016
Ethics approval number [1] 295747 0

Summary
Brief summary
Recent evidence suggests that obstructive sleep apnoea (OSA) is a multifactorial disorder and is not only the result of a small, collapsible upper airway anatomy. Several non-anatomical physiological traits have been identified that can also play an important role in causing OSA. These include: (1) an oversensitive ventilatory control system (i.e. ventilatory control instability or high loop gain), (2) poor pharyngeal muscle responsiveness, and (3) a low respiratory arousal threshold. Importantly, the relative contribution of each of these traits varies between patients. Thus patients often have OSA for different reasons.
An oversensitive ventilatory control system also referred to as having “high loop gain” has been shown to contribute to OSA severity in at least one third of patients. Loop gain characterises the sensitivity of the control of breathing during sleep. Patients with high loop gain have an overly large compensatory respiratory response to any given disturbance in breathing. In such patients, even a mild disturbance to breathing (i.e. hypopnoea) during sleep can produce a self-sustaining unstable breathing pattern, leading to repetitive airway collapse.
While singular therapies targeted towards lowering loop gain have shown promise—including oxygen therapy and respiratory stimulants such as the drug acetazolamide (ACZ),— their effect size on reducing loop gain has not been large enough to resolve OSA in the majority of patients studied. Importantly, physiological studies have shown that oxygen and ACZ manipulate different sub-components of the respiratory control system; oxygen reduces ‘controller gain’ whereas ACZ reduces ‘plant gain’. That is, according to respiratory control theory, both of these treatments should have an independent and additive effect on lowering loop gain. As yet no study has assessed the therapeutic effect of manipulating loop gain with a combination of both agents. Importantly, in a sub-group of OSA patients where loop gain is abnormally high (36%), a large reduction in loop gain, is likely to be sufficient to resolve their OSA.
The primary purpose of this clinical trial is to assess, for the first time, the ability of the combination of oxygen therapy and ACZ to reduce loop gain and thereby reduce OSA severity. We expect that this combination of therapeutic agents to have a greater effect on lowering loop gain than either alone. As a secondary objective of this trial, we intend to measure, at baseline, each of the four known traits known to cause OSA (upper airway collapsibility, loop gain, pharyngeal muscle responsiveness and respiratory arousal threshold) so that we can determine the characteristics of individuals that demonstrate that greatest therapeutic benefit from this combination therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 66062 0
Dr Bradley Edwards
Address 66062 0
Sleep and Circadian Medicine Laboratory
Ground Floor BASE Facility
Monash University
264 Ferntree Gully Road
Notting Hill, Victoria, 3168
Country 66062 0
Australia
Phone 66062 0
+61 3 9905 0187
Fax 66062 0
+61 3 9905 3948
Email 66062 0
[email protected]
Contact person for public queries
Name 66063 0
Bradley Edwards
Address 66063 0
Sleep and Circadian Medicine Laboratory
Ground Floor BASE Facility
Monash University
264 Ferntree Gully Road
Notting Hill, Victoria, 3168
Country 66063 0
Australia
Phone 66063 0
+61 3 9905 0187
Fax 66063 0
+61 3 9905 3948
Email 66063 0
[email protected]
Contact person for scientific queries
Name 66064 0
Bradley Edwards
Address 66064 0
Sleep and Circadian Medicine Laboratory
Ground Floor BASE Facility
Monash University
264 Ferntree Gully Road
Notting Hill, Victoria, 3168
Country 66064 0
Australia
Phone 66064 0
+61 3 9905 0187
Fax 66064 0
+61 3 9905 3948
Email 66064 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
16143Informed consent form  [email protected]
16144Study protocol  [email protected]



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