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Trial registered on ANZCTR


Registration number
ACTRN12617001481369
Ethics application status
Approved
Date submitted
2/10/2017
Date registered
19/10/2017
Date last updated
30/01/2019
Date data sharing statement initially provided
30/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of an overnight low-dose ketamine infusion on the breathing pattern in patients diagnosed with severe sleep apnoea
Scientific title
Effect of intravenous ketamine on oxygen desaturation index in severe Obstructive Sleep Apnoea patients
Secondary ID [1] 293041 0
ANZCA research grant support N18/011
Universal Trial Number (UTN)
U1111-1202-9930
Trial acronym
KOSA trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive sleep apnoea 304942 0
Condition category
Condition code
Respiratory 304269 304269 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a single centre, double-blind, randomised, crossover study. Patients with severe OSA will be randomly assigned to receive an intravenous ketamine or a placebo infusion in the sequence given below, during an in-lab, overnight polysomnogram (PSG).

Sequence A – infusion of ketamine during PSG 1 and a placebo infusion during PSG 2.
Sequence B – placebo infusion during PSG 1 and ketamine infusion during PSG 2.

A ketamine dose of 100micrograms per kilogram per hour as an infusion with a maximum dose of 12mg per hour for patients weighing over 120kg will be administered to the study participants. Target duration for the infusion is 8hrs. The infusion will be stopped at 8 hours, excluding times the infusion was interrupted for any reason. Infusion duration will be less if the patient wakes up earlier than expected or cessation of infusion due to side effects.
The total volume of trial infusion administered and the duration of the infusion will be recorded by the investigators.

Minimum of a 7 day washout period will be included between the two infusions for every participant.
Intervention code [1] 299264 0
Treatment: Drugs
Comparator / control treatment
Normal saline
Control group
Placebo

Outcomes
Primary outcome [1] 303549 0
Oxygen desaturation index
Using the pulse oximetry recorded as part of the polysomnogram
Timepoint [1] 303549 0
Overnight, during sleep
Secondary outcome [1] 339318 0
Apnoea-hypopnoea index (AHI)
Calculated from the polysomnogram readings
Timepoint [1] 339318 0
Overnight, during sleep
Secondary outcome [2] 339319 0
Central apnoea rate
Calculated from the polysomnogram readings
Timepoint [2] 339319 0
Overnight, during sleep
Secondary outcome [3] 339320 0
Time spent below 90% oxygen saturation
Using the pulse oximetry recorded as part of the polysomnogram
Timepoint [3] 339320 0
Overnight, during sleep
Secondary outcome [4] 339321 0
Mean 'Rapid-Eye-Movement sleep' related transcutaneous partial pressure of carbon dioxide (TcpCO2)
Using a Sentac(R) TcpCO2 monitor, time synced with the polysomnography device
Timepoint [4] 339321 0
Overnight, during sleep
Secondary outcome [5] 339322 0
Mean slow wave sleep TcpCO2
Using a Sentac(R) TcpCO2 monitor, time synced with the polysomnography device
Timepoint [5] 339322 0
Overnight, during sleep
Secondary outcome [6] 339323 0
Percentage change in the mean chin EMG activity during REM sleep
Calculated using the chin EMG recoding during the polysomnogram
Timepoint [6] 339323 0
Overnight, during sleep
Secondary outcome [7] 339324 0
Arousal index
Calculated from the polysomnogram readings
Timepoint [7] 339324 0
overnight
Secondary outcome [8] 339325 0
Plasma ketamine level
Timepoint [8] 339325 0
one hour after stopping the infusion
Secondary outcome [9] 339885 0
Plasma nor-ketamine levels
Timepoint [9] 339885 0
One hour after stopping the infusion
Secondary outcome [10] 339886 0
Percentage change in the mean chin EMG activity during N3 sleep
Calculated using the chin EMG recoding during the polysomnogram
Timepoint [10] 339886 0
Overnight
Secondary outcome [11] 339887 0
The amount of REM Sleep achieved as a percentage of total sleep time
Calculated from the polysomnogram readings
Timepoint [11] 339887 0
Overnight
Secondary outcome [12] 339888 0
Amount of Slow Wave Sleep achieved as a percentage of total sleep time
Calculated from the polysomnogram readings
Timepoint [12] 339888 0
Overnight
Secondary outcome [13] 339889 0
Oxygen saturation nadir
Using the pulse oximetry recorded as part of the polysomnogram
Timepoint [13] 339889 0
Overnight
Secondary outcome [14] 339890 0
Mean saturation
Using the pulse oximetry recorded as part of the polysomnogram
Timepoint [14] 339890 0
Overnight

Eligibility
Key inclusion criteria
Patients diagnosed with severe obstructive sleep apnoea with an AHI >30/hour on a polysomnogram (PSG) done in the Westmead Sleep Disorders Laboratory
Minimum age
20 Years
Maximum age
90 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Hypersensitivity to ketamine
2. Severe COPD (FEV1/FVC < 70%; FEV1 < 50% predicted)
3. Diagnosis of moderate to severe pulmonary hypertension (mean PAP >40mmHg) as per WHO criteria.
4. Neuromuscular disorder causing muscle weakness
5. Patients with a previous diagnosis of OSA who are already receiving CPAP therapy
6. Pre-menopausal women
7. Patients with neurotic traits or psychiatric illness (e.g., schizophrenia and acute psychosis)
8. Severe cardiovascular disease (i.e. heart failure, severe or poorly controlled hypertension,
recent myocardial infarction)
9. History of stroke, cerebral trauma, intracerebral mass or haemorrhage
10. Participants who are required to operating machinery or engaging in other hazardous
activities within 24 hrs after the infusion.
11. History of chronic opioid, benzodiazepine or other sedative medication use/abuse
Regular use of more than one standard drink of alcohol before sleep

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)
Patients will be randomised to one of the two trial medication administration sequences. This would be done on the day of PSG 1 using paid a third party internet-based randomisation service.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomly assigned to sequence A or B following an internet-based stratified block randomisation. Patients will be stratified according to their age (<50 or >50), BMI (<35 or >35) and gender (male or female) with a block size of 4
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
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Patients will be randomised to one of the two trial medication administration sequences (A or B as given below). This would be done on the day of PSG 1 using an internet-based randomisation service. The randomisation procedure is explained below. A minimum washout interval of 7days will be observed between the two PSGs.

Sequence A – participants will receive the infusion of ketamine during PSG 1 (Night 1) and the placebo infusion during PSG 2 (Night 2).

Sequence B – participants will receive the placebo infusion during PSG 1(Night 1) and ketamine infusion during PSG 2 (Night 2)
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We require 22 patients with severe OSA to have a probability of =80% to detect a before and after relationship in the dependent variable at a two-sided 0.05 significance level, looking for a =10% change in the dependent variable ODI.
Our sample size is based on the data from 47 consecutive patients newly diagnosed to have severe OSA at the Westmead Hospital Sleep Laboratory. The PSG for these patients will be equal to a PSG with a placebo infusion in our study. The mean ODI during sleep in these patients was 50.84 events/hr with a standard deviation of 12.9.

There are insufficient data in the literature on ketamine infusions used in crossover trials and its effect on ODI values. Hence these data needed to be predicted. Each patient in the Control data was assumed to decrease their ODI value by 0 – 25% after the ketamine infusion. The amount of change for each patient was allocated by a random number generator. The mean of the predicted infusion data: 45.51.

The actual correlation between the control data and the predicted data was 0.9. Hence it is a reasonable approach to use a conservative correlation of 0.7.

Statistical Analysis
A per-protocol analysis will be carried out at the end of the study. Hence, data from the participants who drop out before completion of the second PSG will not be included in the analysis.

Analysis method for the primary outcome
The variation in the ‘oxygen desaturation index’ in an individual during sleep will
be compared to the placebo PSG and the ketamine PSG using a paired t-test.

Analysis methods for secondary outcomes
Comparison of the individual variation between the placebo PSG and the ketamine PSG for AHI, Central apnoea rate, Time spent below 90% oxygen saturation, Oxygen saturation nadir, Mean saturation, Mean REM TcpCO2 and Mean slow wave sleep TcpCO2, will be assessed using a paired t-test.
Percentage change in the mean chin EMG activity during REM sleep, the percentage change in the mean chin EMG activity during N3 sleep, the amount of REM Sleep achieved as a percentage of total sleep time and the amount of Slow Wave Sleep achieved as a percentage of total sleep time will be assessed using the relevant non-parametric tests (e.g. McNemar’s test, direction of change analysis)


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 9149 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 17660 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 297653 0
Hospital
Name [1] 297653 0
Research Fund of The Department of Anaesthesia and Perioperative Medicine, Westmead Hospital
Address [1] 297653 0
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145
Country [1] 297653 0
Australia
Funding source category [2] 297655 0
Hospital
Name [2] 297655 0
The Department of Respiratory and Sleep Medicine, Westmead Hospital
Address [2] 297655 0
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145
Country [2] 297655 0
Australia
Funding source category [3] 301805 0
Charities/Societies/Foundations
Name [3] 301805 0
ANZCA research Foundation
Address [3] 301805 0
The ANZCA Research Foundation
Australian and New Zealand College of Anaesthetists
ANZCA House
630 St Kilda Road
Melbourne VIC 3004
Australia
Country [3] 301805 0
Australia
Primary sponsor type
Individual
Name
Prof. John R Wheatley
Address
Department of Respiratory and Sleep Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145
Country
Australia
Secondary sponsor category [1] 296676 0
Individual
Name [1] 296676 0
Dr. KDVP Siriwardana
Address [1] 296676 0
Department of Anaesthesia and Perioperative Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145
Country [1] 296676 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298738 0
Western Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 298738 0
Research Office, Level 2, REN Building
Westmead Hospital, Hawkesbury & Darcy Roads, Westmead NSW 2145
Ethics committee country [1] 298738 0
Australia
Date submitted for ethics approval [1] 298738 0
15/02/2017
Approval date [1] 298738 0
05/05/2017
Ethics approval number [1] 298738 0
AU RED HREC/17/WMEAD/ 57

Summary
Brief summary
This project intends to investigate the respiratory effects of a low dose ketamine infusion in patients suffering from obstructive sleep apnoea (OSA).

Recent studies have shown that over 25% of patients undergoing surgery may be suffering from Obstructive sleep apnoea (OSA). An estimated 80% of patients with OSA would undergo surgery without a diagnosis. Due to the epidemic of obesity on the rise, the prevalence of OSA, which is common among overweight people, is expected to increase over time.

Ketamine is a medication different from the morphine family of medications (opioids), that is used as an adjunct to opioids in pain management following surgery. Low-dose ketamine infusion results in reduced opioid requirements, less sedation, a lower rate of postoperative nausea and vomiting with no change in breathing patterns. Previous trials, both in volunteers and postoperative patients not suffering from OSA, has shown improved oxygen saturation and a lower carbon dioxide level in the blood when ketamine was used with opioid medications.

Hypothesis:
Based on results from previous trials involving ketamine, we anticipate this medication to have a beneficial effect on breathing during sleep in patients suffering from OSA.

The results of this study will enable us to identify whether ketamine is a suitable medication for use in patients suffering from OSA. This will help create accurate guidelines on the management of patients with OSA undergoing surgery.

Design:
We will administer either low-dose ketamine or a placebo (normal saline) as an infusion to volunteers suffering from severe OSA and conduct a standard in-lab sleep study to assess the blood oxygen level,
breathing pattern and sleep pattern. Each patient will receive both a ketamine infusion and the placebo infusion in a random order with a period of one week between the two sleep studies.
This will be a single centre, double-blind, randomised, crossover study. Patients with severe OSA will be randomly assigned to receive either ketamine or a placebo in the sequence given below, during an in-lab, overnight polysomnogram (PSG).

Sequence A – infusion of ketamine during PSG 1 and a placebo infusion during PSG 2.
Sequence B – placebo infusion during PSG 1 and ketamine infusion during PSG 2.

Sample size: 22 patients

Study duration: 12 months

Aim:
To identify whether a ketamine infusion significantly affects the ventilation of OSA patients during sleep, when given in doses used for pain relief following surgery.

Primary endpoint:
‘Oxygen desaturation index’ of the patients will be compared between the PSG with a ketamine infusion and the PSG with a placebo infusion.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78066 0
Prof John R Wheatley
Address 78066 0
Department of Respiratory and Sleep Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW 2145
Country 78066 0
Australia
Phone 78066 0
+61 2 8890 6797
Fax 78066 0
+61 2 8890 7286
Email 78066 0
john.wheatley@sydney.edu.au
Contact person for public queries
Name 78067 0
Dr KDVP Siriwardana
Address 78067 0
Department of Anaesthesia and Perioperative Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145
Country 78067 0
Australia
Phone 78067 0
+61 455605555
Fax 78067 0
Email 78067 0
pobox.vs@gmail.com
Contact person for scientific queries
Name 78068 0
Dr KDVP Siriwardana
Address 78068 0
Department of Anaesthesia and Perioperative Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145
Country 78068 0
Australia
Phone 78068 0
+61 455605555
Fax 78068 0
Email 78068 0
pobox.vs@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Current ethics approval is for the use of de-identified data from patients. We are hoping to publish all the data that cannot be traced back to an individual in the future.
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable