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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

16/01/2023

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]

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

Condition category

Condition code

Respiratory

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]

Treatment: Drugs

Comparator / control treatment

Normal saline

Control group

Placebo

Outcomes

Primary outcome [1]

Oxygen desaturation index
Using the pulse oximetry recorded as part of the polysomnogram

Timepoint [1]

Overnight, during sleep

Secondary outcome [1]

Apnoea-hypopnoea index (AHI)
Calculated from the polysomnogram readings

Timepoint [1]

Overnight, during sleep

Secondary outcome [2]

Central apnoea rate
Calculated from the polysomnogram readings

Timepoint [2]

Overnight, during sleep

Secondary outcome [3]

Time spent below 90% oxygen saturation
Using the pulse oximetry recorded as part of the polysomnogram

Timepoint [3]

Overnight, during sleep

Secondary outcome [4]

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]

Overnight, during sleep

Secondary outcome [5]

Mean slow wave sleep TcpCO2
Using a Sentac(R) TcpCO2 monitor, time synced with the polysomnography device

Timepoint [5]

Overnight, during sleep

Secondary outcome [6]

Percentage change in the mean chin EMG activity during REM sleep
Calculated using the chin EMG recoding during the polysomnogram

Timepoint [6]

Overnight, during sleep

Secondary outcome [7]

Arousal index
Calculated from the polysomnogram readings

Timepoint [7]

overnight

Secondary outcome [8]

Plasma ketamine level

Timepoint [8]

one hour after stopping the infusion

Secondary outcome [9]

Plasma nor-ketamine levels

Timepoint [9]

One hour after stopping the infusion

Secondary outcome [10]

Percentage change in the mean chin EMG activity during N3 sleep
Calculated using the chin EMG recoding during the polysomnogram

Timepoint [10]

Overnight

Secondary outcome [11]

The amount of REM Sleep achieved as a percentage of total sleep time
Calculated from the polysomnogram readings

Timepoint [11]

Overnight

Secondary outcome [12]

Amount of Slow Wave Sleep achieved as a percentage of total sleep time
Calculated from the polysomnogram readings

Timepoint [12]

Overnight

Secondary outcome [13]

Oxygen saturation nadir
Using the pulse oximetry recorded as part of the polysomnogram

Timepoint [13]

Overnight

Secondary outcome [14]

Mean saturation
Using the pulse oximetry recorded as part of the polysomnogram

Timepoint [14]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

1/11/2017

Actual

22/01/2018

Date of last participant enrolment

Anticipated

15/03/2020

Actual

31/05/2022

Date of last data collection

Anticipated

15/04/2020

Actual

8/06/2022

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Westmead Hospital - Westmead

Recruitment postcode(s) [1]

2145 - Westmead

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Research Fund of The Department of Anaesthesia and Perioperative Medicine, Westmead Hospital

Address [1]

Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145

Country [1]

Australia

Funding source category [2]

Hospital

Name [2]

The Department of Respiratory and Sleep Medicine, Westmead Hospital

Address [2]

Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145

Country [2]

Australia

Funding source category [3]

Charities/Societies/Foundations

Name [3]

ANZCA research Foundation

Address [3]

The ANZCA Research Foundation
Australian and New Zealand College of Anaesthetists
ANZCA House
630 St Kilda Road
Melbourne VIC 3004
Australia

Country [3]

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]

Individual

Name [1]

Dr. KDVP Siriwardana

Address [1]

Department of Anaesthesia and Perioperative Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Western Sydney Local Health District Human Research Ethics Committee

Ethics committee address [1]

Research Office, Level 2, REN Building
Westmead Hospital, Hawkesbury & Darcy Roads, Westmead  NSW 2145

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

15/02/2017

Approval date [1]

05/05/2017

Ethics approval number [1]

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

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

Phone

+61 2 8890 6797

Fax

+61 2 8890 7286

john.wheatley@sydney.edu.au

Contact person for public queries

Name

KDVP Siriwardana

Address

Department of Anaesthesia and Perioperative Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145

Country

Australia

Phone

+61 455605555

Fax

pobox.vs@gmail.com

Contact person for scientific queries

Name

KDVP Siriwardana

Address

Department of Anaesthesia and Perioperative Medicine
Westmead Hospital
Cnr of Hawkesbury Road and Darcy Road
Westmead, NSW, 2145

Country

Australia

Phone

+61 455605555

Fax

pobox.vs@gmail.com

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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No additional documents have been identified.

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