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Trial registered on ANZCTR


Trial ID
ACTRN12613000858796
Ethics application status
Approved
Date submitted
7/05/2013
Date registered
2/08/2013
Date last updated
13/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of morphine on obstructive sleep apnea
Scientific title
In men with obstructive sleep apnea, what is the effect of a common clinical dose of oral slow-release morphine, compared to placebo on overnight blood oxygen levels, respiratory control and physiological causes of obstructive sleep apnea during sleep.
Secondary ID [1] 282462 0
Nil known
Universal Trial Number (UTN)
U1111-1142-7778
Trial acronym
MorphOSA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obstructive sleep apnea 289074 0
Condition category
Condition code
Respiratory 289417 289417 0 0
Sleep apnoea

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study design: double-blind, placebo-controlled crossover study in male obstructive sleep apnea patients.

Treatment arm: Oral slow-release morphine tablets in capsules (40mg MS Contin) vs. placebo. Each intervention will be taken 4 hours before sleep. Patients will be monitored overnight.

1 week washout between sleep studies (a total of 2-4 nights will be required).

Intervention code [1] 287108 0
Treatment: Drugs
Comparator / control treatment
Placebo: Oral glucose tablets (40mg) in capsules 4 hours prior to sleep. Participants will be monitored overnight.
Control group
Placebo

Outcomes
Primary outcome [1] 289522 0
Sleep time with SpO2 (oxygen) <90% (T90). This is calculated by measuring the amount of time that the oxygen levels fall below 90% during overnight polysomnography (sleep study)
Timepoint [1] 289522 0
Total amount of time (minutes) oxygen levels fall below 90% during each overnight study
Secondary outcome [1] 302671 0
Upper airway muscle responsiveness (Electromyography)
Timepoint [1] 302671 0
Monitored throughout participant's sleep in each overnight study on drug vs. placebo
Secondary outcome [2] 302672 0
Plasma morphine, M3G and M6G will be assayed by the LC-MS method.
Timepoint [2] 302672 0
Blood draws (5ml) taken at 9:00pm in the evening (3.5 hours post dose) and at 7am the following morning.
Secondary outcome [3] 302712 0
Genotyping data (A118G OPRM1 and ABCB1) (Jonckheere-Terpstra Test)
Timepoint [3] 302712 0
Blood draws (5ml) taken at 9:00pm in the evening (3.5 hours post dose) and at 7am the following morning.
Secondary outcome [4] 302713 0
Upper airway collapsibility (Pcrit)
Timepoint [4] 302713 0
Monitored throughout participant's sleep in each overnight study on drug vs. placebo
Secondary outcome [5] 302714 0
Respiratory arousal threshold (negative pharyngeal pressure immediately prior to arousal from sleep using an epiglottic pressure sensor inserted via the nostril)

Timepoint [5] 302714 0
Monitored throughout participant's sleep in each overnight study on drug vs. placebo
Secondary outcome [6] 302715 0
Standard polysomnography measures during overnight sleep studies, including but not limited to apnea-hypopnea index (AHI), oxygen saturation nadir, average oxygen saturation, oxygen desaturation index (ODI) and arousal index (AI).
Timepoint [6] 302715 0
Monitored throughout participant's sleep in each overnight study on drug vs. placebo
Secondary outcome [7] 303980 0
(Physiology): Ventilatory control. Measured using a breathing mask as the ventilatory response (litres per minute) to carbon dioxide (mmHg).
Timepoint [7] 303980 0
Awake ventilatory control tests will be evaluated 3.5 hours post morphine/placebo dose; Sleep physiology measurements will be performed 1 hour post sleep onset at various occasions during consolidated sleep

Eligibility
Key inclusion criteria
- Men aged between 18-65 years; BMI < 40 kg/m2; awake SpO2>90%
- Screening PSG: OSA patients: AHI >= 5, SpO2 nadir >= 60%.
Minimum age
18 Years
Maximum age
65 Years
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
- Do not meet the inclusion criteria listed above or unwilling to follow the study protocol. - Shift workers and/or patients with other significant sleep disorders such as PLMS. - Severe medical and/or psychiatric diseases other than sleep aponea. - History of drug abuse and/or urine drug test positive to narcotic or other illicit drugs and/or history of allergy to morphine. - Subjects with current physical complaints (eg. respiratory infections or rhinitis) will not be included until symptoms are clear for 4 weeks. - Certain concomitant CNS active drug use such as hypno-sedatives and antipsychotics. Antidepressants will not be a specific exclusion criteria. - Creatinine clearance (Cockroft-Gault) < 60 ml/min; LFTs > 2x ULN. - Patients with a known history of CO2 retention (PCO2>45mmHg during wakefulness).

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)
Treatment assignment will be determined according to a computer generated randomisation list prepared by a research pharmacist not involved with the study procedures.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified random sampling will be used.
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
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We will recruit 55 patients assuming a dropout of 2 patients to have 53 completing patients.

The Primary outcome measure is the time spent below 90% oxygen saturation as measured by overnight pulse oximetry. The trial has been been powered to detect a 7 minute difference between morphine and placebo based on a 15.4 minute standard deviation observed in our pilot study with 90% power and a false positive rate of 5% (n=53). We will use a mixed model analysis of variance procedure classifying patients as random effects and the drug and treatment order as fixed effects to test this and the secondary variables for statistical significance.

We also plan to undertake subgroup analyses to test inside a mixed model whether sleep apnea severity changes the effect of morphine on primary and secondary outcomes by classifying patients as mild or moderate-severe (AHI above or below 20). A test of group*drug will be used to to test for effect modification using an alpha of 0.05 for significance. We will also test AHI as a linear effect modifying variable in sensitivity analyses.

Linear regression will be used to test whether the placebo-adjusted effect of morphine on the primary outcome is associated with the following: plasma morphine levels (and genetic markers for morphine metabolism), wake CO2 threshold, Wake slope of ventilatory response to CO2, Basal Ventilation (litres/minute), Body Mass Index and Upper airway physiological variables (loop gain, muscle response, Pcrit, arousal threshold).

Recruitment
Recruitment status
Completed
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] 971 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 972 0
Prince of Wales Hospital - Randwick
Recruitment postcode(s) [1] 6826 0
2050 - Camperdown
Recruitment postcode(s) [2] 6827 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 287244 0
Government body
Name [1] 287244 0
National Health and Medical Research Council (NHRMC)
Address [1] 287244 0
Level 1, 16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 287244 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Woolcock Institute of Medical Research
Address
431 Glebe Point Rd, Glebe, NSW 2039
Country
Australia
Secondary sponsor category [1] 285995 0
None
Name [1] 285995 0
Address [1] 285995 0
Country [1] 285995 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289223 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 289223 0
c/- Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 289223 0
Australia
Date submitted for ethics approval [1] 289223 0
Approval date [1] 289223 0
02/05/2013
Ethics approval number [1] 289223 0
HREC/13/RPAH/64

Summary
Brief summary
This study aims to investigate the effects of morphine on obstructive sleep apnoea (OSA). Specifically, we will
measure the effects of a common clinical dose of morphine on sleep, respiratory control, and upper airway physiology.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39858 0
Dr David Wang
Address 39858 0
Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe, NSW 2039
Country 39858 0
Australia
Phone 39858 0
+61291140446
Fax 39858 0
Email 39858 0
david.wang@sydney.edu.au
Contact person for public queries
Name 39859 0
Mr Luke Rowsell
Address 39859 0
Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe, NSW 2039
Country 39859 0
Australia
Phone 39859 0
+61291140447
Fax 39859 0
Email 39859 0
luke.rowsell@sydney.edu.au
Contact person for scientific queries
Name 39860 0
Mr Luke Rowsell
Address 39860 0
Woolcock Institute of Medical Research
431 Glebe Point Road, Glebe, NSW 2039
Country 39860 0
Australia
Phone 39860 0
+61291140447
Fax 39860 0
+612 9114 0010
Email 39860 0
luke.rowsell@sydney.edu.au