Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000916943
Ethics application status
Approved
Date submitted
27/07/2020
Date registered
17/09/2020
Date last updated
11/05/2022
Date data sharing statement initially provided
17/09/2020
Date results information initially provided
11/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Proof of concept study on the combined effect of dronabinol and acetazolamide on apnoea hypopnoea index (AHI) in adults with obstructive sleep apnoea
Scientific title
Dose finding crossover trial investigating the effect of dronabinol combined with acetazolamide on Apnoea Hypopnea Index (AHI) in adults with obstructive sleep apnoea (OSA)
Secondary ID [1] 301883 0
Sponsor (Incannex) issued number- IHLOSAPOC1
Universal Trial Number (UTN)
U1111-1256-1417
Trial acronym
IHLOSAPOC1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive Sleep Apnoea 318386 0
Condition category
Condition code
Respiratory 316403 316403 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will determine the therapeutic benefit of a combination of dronabinol and acetazolamide at reducing AHI in adults with obstructive sleep apnoea. Investigational product will be administered by mouth as two separate gel capsules. The first dose will be administered at the study site on the afternoon of day one of the treatment period. For the next six nights the dose will be administered approximately 60 min before bedtime each night. There are a total of seven doses, one per day, over a seven day treatment period. The study will consist of four treatment periods.
Three doses, low (2.5 mg dronabinol 125 mg acetazolamide) medium (5 mg dronabinol 250 mg acetazolamide) and high (10 mg dronabinol 500 mg acetazolamide) and a placebo will be compared in this study to identify the dose with the best therapeutic benefit and least side effects. This is a cross-over trial where all patients will receive all of the treatments. Each treatment will be administered for one seven-day treatment period. Treatment periods will be separated by seven-day washout periods. The study will consist of four treatment periods and four washout periods for 56 days total.
Participants will be provided with a blister pack containing the investigational product at the start of each treatment period. Each blister will contain a single dose, one dronabinol and one acetazolamide gel capsule (or matched placebo), of the investigational product. Treatment adherence will be monitored through a self-reporting treatment administration log and return of blister packs to the study team at the end of each treatment period.
Intervention code [1] 318173 0
Treatment: Drugs
Comparator / control treatment
This study is placebo controlled. Placebo and treatments will be identical in appearance.
The placebo gel capsules will contain microcrystalline cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 324556 0
Change in apnoea hyponea index (AHI) compared to baseline as assessed by overnight, in-clinic polysomnography.
Timepoint [1] 324556 0
Night seven of the treatment period
Secondary outcome [1] 384964 0
Change in oxygen desaturation index (ODI) assessed by overnight, in-clinic polysomnography.
Timepoint [1] 384964 0
Night seven of the treatment period
Secondary outcome [2] 384965 0
Change in daytime somnolence measured by Epworth Sleepiness Scale
Timepoint [2] 384965 0
Night seven of the treatment period
Secondary outcome [3] 384966 0
Change in mood measured by the Profile of Mood States (POMS) questionnaire
Timepoint [3] 384966 0
Night seven of the treatment period
Secondary outcome [4] 384967 0
Change in quality of life measured by Short-form 36 questionnaire
Timepoint [4] 384967 0
Night seven of the treatment period
Secondary outcome [5] 384968 0
Plasma levels of THC the morning after dosing measured by LC-MS
Timepoint [5] 384968 0
The morning after night seven of the treatment period
Secondary outcome [6] 385910 0
Plasma levels of COOHTHC the morning after dosing measured by LC-MS.
Timepoint [6] 385910 0
The morning after night seven of the treatment period
Secondary outcome [7] 385911 0
Plasma levels of OHTHC the morning after dosing measured by LC-MS
Timepoint [7] 385911 0
The morning after night seven of the treatment period
Secondary outcome [8] 385912 0
Change in alterness measured using the Stanford Sleepiness Scale
Timepoint [8] 385912 0
Night seven of the treatment period
Secondary outcome [9] 385924 0
Seizure frequency in patients with comorbid epilepsy and sleep apnoea measured by self-report seizure diary
Timepoint [9] 385924 0
Total over each seven day treatment period

Eligibility
Key inclusion criteria
Aged between 21 and 65 years
- Evidence of OSA based on AHI greater than or equal to 15. The first PSG study will be analysed within 2 business days to confirm AHI criteria.
- No known allergic reaction to cannabis products with previous use (self-disclosure).
- No known allergic reaction to sesame oil (dronabinol is formulated in sesame oil)
- No know allergic reaction to acetazolamide or other sulphonamides.
- Have no history of past substance abuse or current abuse of illicit drugs
- Physically well, in the opinion of the investigator, with no severe psychiatric,
cardiac, renal, endocrine, gastrointestinal, or bleeding disorders
- If male, agree to be sexually abstinent or agree to use two approved methods of contraception when engaging in sexual activity from study Visit 1 through to the end of the study. Subjects must agree to use two approved methods of contraception for 10 days following the last administration of the study drug, and not donate sperm during this same period of time. In the event that the sexual partner is surgically sterile, contraception is not necessary.
- Females of non-childbearing potential with serum FSH levels greater than 40mlU/ml are either postmenopausal or have undergone one of the following sterilization procedures at least 6 months prior to Visit 1;
o Bilateral tubal ligation
o Hysterectomy
o Hysterectomy with unilateral or bilateral oophorectomy o Bilateral oophorectomy
- Females of childbearing potential that are not currently pregnant or lactating
- Not taken any vitamins, herbal remedies or supplements within 5 days of
admission
- Voluntarily consent to participate in the study and complete all study required
tasks, as instructed by the protocol, including the completion of
questionnaires and logs
- Willing to abstain from driving a vehicle during the treatment periods plus 2
days after (4 x 9 days)
- Willing and able to self-administer two capsules by mouth, at the clinic visit
or 60 minutes before bedtime, each night during the treatment periods of the
study (4 x 7 days)
Minimum age
21 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Other pre-existing sleep disorder (restless legs syndrome, narcolepsy, parasomnias etc.)
- Currently using CPAP, or other treatment for OSA including mandibular advancement splint, or positional device
- Severe blood O2 desaturation as measured in V1 PSG.
- Body Mass Index (BMI) greater than 45
- ESS less than 7 (excludes non-sleepy participants)
-History of known hypokalmia (low blood potassium), hyponatremia (low blood sodium), hypocholremic acidosis, adrenal insufficiency, impaired kidney
function, marked liver disease or impaired liver function, within the last 6 months.

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)
allocation involved contacting the holder of the allocation schedule who was "off-site" or at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Estimating sample size in three-way crossover studies is not supported by standard statistical programs. However, crossover studies yield more efficient comparisons than parallel studies, that is fewer Subjects are required in order to attain the same level of statistical power or precision in cross over studies than parallel studies. This is because each patient serves as their own matched control and the intra-patient variability is generally lower than inter-patient variability. Thus, the sample size calculation for a parallel study with a small effect size (0.3) can serve as a proxy for the cross over study. Using G*Power we have estimated the sample size requirement for a study to measure a small effect size (0.3) with a power of 80% and p-value of 0.05 is 23 participants. This number of participants in this study is consistent with published simulation studies estimating the required sample size for three-way crossover studies.


All statistical tests will be performed two tailed at the 5% significance level and performed using IBM SPSS statistical package. Z scores for the distribution will be calculated for each variable and displayed in histogram form. Out of range values will be recoded as missing values.
Results for the PSG (AHI) and from the sleep quality/ length/ well-being measures will also be compared using a mixed design analysis of covariance (MANCOVA), with treatment (placebo, low, medium, high dose) as the between-subject variable, time as the within-subjects variable, and baseline score as the covariate.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
19/10/2020
Actual
26/11/2020
Date of last participant enrolment
Anticipated
Actual
9/02/2021
Date of last data collection
Anticipated
Actual
15/12/2021
Sample size
Target
12
Accrual to date
Final
11
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment hospital [1] 17153 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 30833 0
3004 - Melbourne
Recruitment postcode(s) [2] 34333 0
6009 - Crawley

Funding & Sponsors
Funding source category [1] 306303 0
Commercial sector/Industry
Name [1] 306303 0
Incannex Healthcare Limited
Country [1] 306303 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Incannex Healthcare Limited
Address
Level 39, Rialto South Tower, 525 Collins Street, Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 306796 0
None
Name [1] 306796 0
Address [1] 306796 0
Country [1] 306796 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306518 0
The Alfred Ethics Committee
Ethics committee address [1] 306518 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 306518 0
Australia
Date submitted for ethics approval [1] 306518 0
27/07/2020
Approval date [1] 306518 0
22/09/2020
Ethics approval number [1] 306518 0
423/20 (HREC/66994/Alfred-2020)

Summary
Brief summary
This is a randomised crossover study to determine the therapeutic benefit of a combination of dronabinol and acetazolamide in subjects with suspected or diagnosed mild to moderate Obstructive Sleep Apnoea (OSA). Subjects will be required to undergo five sleep tests. Prior to each sleep test the Subjects will complete questionnaires to assess daytime somnolence, mood and quality of life. The first sleep test will confirm OSA and establish baseline levels for AHI, daytime somnolence, mood and quality of life. Once OSA is confirmed Subjects will be randomised into one of six treatment arms. All Subjects will undergo four treatment periods where they will receive treatment one of placebo or low, medium or high dose combination of dronabinol with acetazolamide. All subjects will receive all treatments over the course of the study but the order or treatment periods will be random. Each treatment will last for seven nights with a seven-night washout period between treatments. On night 7 of each treatment period the Subjects will undergo a sleep study using a polysomnography (PSG) machine at the sleep clinic. Sleepiness, mood and quality of life questionnaires with completed prior to PSG set up on night 7. AHI, daytime somnolence, mood and quality of life scores will be compared to baseline across the 4 treatments to establish the optimal dose for the therapeutic benefit for the combination of dronabinol with acetazolamide for treatment of OSA.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104138 0
Prof Terence O'Brien
Address 104138 0
Department of Neurosciences
4th Floor, Centre Block
The Alfred Hospital
55 Commerical Road
Melbourne VIC 3004
Country 104138 0
Australia
Phone 104138 0
+61 3 9903 0855
Fax 104138 0
Email 104138 0
te.obrien@alfred.org.au
Contact person for public queries
Name 104139 0
Mr Jack Germaine
Address 104139 0
Epilepsy Research Unit – 4 Centre Block, Level 4
The Alfred Hospital
55 Commercial Rd,
Melbourne VIC 3004
Country 104139 0
Australia
Phone 104139 0
+61 3 9076 2029
Fax 104139 0
Email 104139 0
J.Germaine@alfred.org.au
Contact person for scientific queries
Name 104140 0
Prof Terence O'Brien
Address 104140 0
Department of Neurosciences
4th Floor, Centre Block
The Alfred Hospital
55 Commerical Road
Melbourne VIC 3004
Country 104140 0
Australia
Phone 104140 0
+61 3 9903 0855
Fax 104140 0
Email 104140 0
te.obrien@alfred.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a proof of concept study and the data will be commercially sensitive


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.