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Trial registered on ANZCTR


Registration number
ACTRN12620000207910
Ethics application status
Approved
Date submitted
5/05/2019
Date registered
20/02/2020
Date last updated
20/02/2020
Date data sharing statement initially provided
20/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Prevention of opioid-associated constipation in ventilated intensive care patients
Scientific title
PRevention of Opioid-associated constipation in Ventilated INtensive CarE patients (PROVINCE) Study: A randomised controlled trial of enterally-administered naloxone for the prevention of opioid-associated constipation in ventilated intensive care patients.
Secondary ID [1] 298158 0
None
Universal Trial Number (UTN)
U1111-1232-8574
Trial acronym
PROVINCE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Constipation 312711 0
Condition category
Condition code
Oral and Gastrointestinal 311207 311207 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Anaesthesiology 311208 311208 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Enteral administration of a preparation of Naloxone Hydrochloride:

5mg 8-hourly to ventilated intensive care patients for 7 days.

Administration will be performed by the bedside ICU nurse, who will be blinded to the intervention.

Administration of the trial drug or control drug will be documented in an appropriate position on the ICU drug chart. A research coordinator will ensure that an appropriate field on the ICU drug chart is present each day.
Intervention code [1] 314383 0
Prevention
Intervention code [2] 314384 0
Treatment: Drugs
Comparator / control treatment
Enteral administration of a placebo sodium chloride 0.9% solution 8-hourly to ventilated intensive care patients.
Control group
Placebo

Outcomes
Primary outcome [1] 319968 0
Time to first bowel motion.

This will be assessed as time from enrolment in the trial to first bowel motion. Bowel opening is recorded on the ICU chart by nursing staff. A form will be present with the nursing staff in order to record specific times of bowel opening.
Timepoint [1] 319968 0
Time to first bowel motion will be assessed hourly for 7 days until the first bowel movement occurs. Specific time that a bowel motion is noted will be recorded on a specific form kept at the ICU Nurse's station at the patient bedside.
Secondary outcome [1] 370011 0
Time to bowel movements.

This differs from the primary outcome in that further bowel motions are recorded on on a specific data collection form, and on the ICU chart. This outcome records ongoing frequency of bowel motions following the first bowel movement. These ongoing bowel movement times will be analysed as a recurrent event, differing from the primary endpoint of time to first bowel motion.
Timepoint [1] 370011 0
Time to subsequent bowel movements, recorded for 7 days
Secondary outcome [2] 370012 0
Rates of constipation (defined as no bowel movement for >72 hours). This data is collected from the bowel motion record outlined above. If there are no bowel motions recorded for >72 hours, the patient is deemed to have met the criteria for a diagnosis of constipation. Ongoing monitoring for bowel motions will continue.
Timepoint [2] 370012 0
72 hours from enrolment in the trial.
Secondary outcome [3] 370013 0
Number of bowel actions per day, recorded by bedside ICU nursing staff on a specific data collection form, and on the ICU chart.
Timepoint [3] 370013 0
Daily for 7 days
Secondary outcome [4] 370014 0
Daily opioid requirements, recorded from the ICU chart, e.g. Total fentanyl requirement (microg/day).
Timepoint [4] 370014 0
Daily for 7 days
Secondary outcome [5] 370015 0
Rates of aperient use, recorded as frequency of aperient prescription per patient, determined from the ICU daily chart.
Timepoint [5] 370015 0
Daily for 7 days
Secondary outcome [6] 370016 0
Rates of Diarrhoea (defined as greater than or equal to 3 loose/liquid stools within any 24-hours or need for faecal management system.
Timepoint [6] 370016 0
Daily for 7 days
Secondary outcome [7] 370017 0
Mean %goal calorie delivery, determined from enteral feed rate and enteral feed type recorded on ICU chart, and compared with calculated total calorie requirement based on standard ICU nutrition formulae.
Timepoint [7] 370017 0
7 days from enrolment in study
Secondary outcome [8] 370018 0
Duration of mechanical ventilation, measured as length of time from initiation of mechanical ventilation to extubation/discontinuation of invasive mechanical ventilation, recorded from ICU medical record.
Timepoint [8] 370018 0
Total length of time requiring mechanical ventilation from initiation of mechanical ventilation to discharge from ICU. Assessed daily, and time of discontinuation of mechanical ventilation recorded from ICU medical record.
Secondary outcome [9] 370019 0
Ventilator free days to day 28, recorded from ICU medical record up to day 28 or discharge from ICU.
Timepoint [9] 370019 0
28 days from enrolment in study
Secondary outcome [10] 370020 0
ICU Length of Stay, determined from the ICU medical record.
Timepoint [10] 370020 0
Total length of ICU stay
Secondary outcome [11] 370021 0
In-hospital length of stay, determined from the hospital electronic medical record system and discharge summary.
Timepoint [11] 370021 0
Total length of stay in-hospital
Secondary outcome [12] 370022 0
Hospital outcome, determined from the hospital electronic medical record system and discharge summary.
Timepoint [12] 370022 0
Hospital discharge

Eligibility
Key inclusion criteria
- Age greater than or equal to 18 years.
- Receiving opiates.
- Mechanically ventilated.
- Suitable for or receiving enteral nutrition.
- Likely to stay in the ICU for at least 72h
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Age <18 years.
- Contraindications to the use of enteral naloxone/oxycodone combination.
- Have a colostomy
- Bowel obstruction

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random sequence
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
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
There was insufficient data in the ICU literature, both for the contemporary incident rate of constipation and the likely treatment effect of enteral naloxone, to make a meaningful power calculation. A study size of 300 patients was pragmatically selected based upon recent studies performed at our institution with similar inclusion criteria, assuming a 12 month recruitment interval. Incidence data from this vanguard study will then enable meaningful power calculations for future studies. This sample size would achieve 80% power at alpha = 0.05 if the hazard ratio for the primary outcome were 1.5 with a 25% censor rate, or the incident rate for constipation (secondary outcome) were as high as 30% with a 15% reduction with enteral naloxone, allowing for a 10% loss to follow-up.

Data will be described as number (%), mean (standard deviation) or median [interquartile range]; with univariate comparisons between groups performed by Chi-squared, t-test or rank-sum test as indicated. The primary outcome will be analysed using a gap-time, recurring events survival model, stratified by event number, with adjustment for patient covariates considered significant at p<0.1. The effect estimate will be presented as a hazard ratio (HR), 95% confidence interval (CI), and as median time to event (CI). A secondary analysis will be conducted as time to ‘first event’ using a Cox proportional hazards model.

Secondary outcomes will be analysed using linear or logistic regression models, including adjustment for patient covariates significant at p<0.1. All analyses will be performed on an intention to treat analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/03/2020
Actual
Date of last participant enrolment
Anticipated
7/02/2021
Actual
Date of last data collection
Anticipated
14/02/2021
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 13689 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 26380 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 302685 0
Hospital
Name [1] 302685 0
Royal Adelaide Hospital Research Fund Clinical Projects Grant
Country [1] 302685 0
Australia
Primary sponsor type
Individual
Name
Dr Eamon Raith
Address
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
SA 5000
Country
Australia
Secondary sponsor category [1] 302617 0
None
Name [1] 302617 0
Address [1] 302617 0
Country [1] 302617 0
Other collaborator category [1] 280671 0
Individual
Name [1] 280671 0
Dr. Emily Gannon
Address [1] 280671 0
Department of Anaesthesia
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [1] 280671 0
Australia
Other collaborator category [2] 280672 0
Individual
Name [2] 280672 0
Ms. Stephanie O'Connor
Address [2] 280672 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [2] 280672 0
Australia
Other collaborator category [3] 280673 0
Individual
Name [3] 280673 0
Ms. Mardi Wills
Address [3] 280673 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [3] 280673 0
Australia
Other collaborator category [4] 280674 0
Individual
Name [4] 280674 0
Dr Benjamin Reddi
Address [4] 280674 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [4] 280674 0
Australia
Other collaborator category [5] 280675 0
Individual
Name [5] 280675 0
Dr Mark Finnis
Address [5] 280675 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [5] 280675 0
Australia
Other collaborator category [6] 280676 0
Individual
Name [6] 280676 0
Dr Michael Anderson
Address [6] 280676 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [6] 280676 0
Australia
Other collaborator category [7] 280677 0
Individual
Name [7] 280677 0
Prof. Marianne Chapman
Address [7] 280677 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [7] 280677 0
Australia
Other collaborator category [8] 281148 0
Individual
Name [8] 281148 0
Dr Jason Chapman
Address [8] 281148 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country [8] 281148 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303303 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [1] 303303 0
Ethics committee country [1] 303303 0
Australia
Date submitted for ethics approval [1] 303303 0
06/05/2019
Approval date [1] 303303 0
12/11/2019
Ethics approval number [1] 303303 0
HREC/19/CALHN/239
Ethics committee name [2] 305209 0
Central Adelaide Local Health Network Research Ethics Committee
Ethics committee address [2] 305209 0
Ethics committee country [2] 305209 0
Australia
Date submitted for ethics approval [2] 305209 0
05/07/2019
Approval date [2] 305209 0
12/11/2019
Ethics approval number [2] 305209 0
HREC/19/CALHN/239

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93202 0
Prof Marianne Chapman
Address 93202 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country 93202 0
Australia
Phone 93202 0
+61 8 7074 0000
Fax 93202 0
Email 93202 0
eamon.raith@adelaide.edu.au
Contact person for public queries
Name 93203 0
Eamon Raith
Address 93203 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country 93203 0
Australia
Phone 93203 0
+61 8 7074 0000
Fax 93203 0
Email 93203 0
eamon.raith@adelaide.edu.au
Contact person for scientific queries
Name 93204 0
Eamon Raith
Address 93204 0
Department of Intensive Care Medicine
Royal Adelaide Hospital
Port Road
Adelaide
SA 5000
Country 93204 0
Australia
Phone 93204 0
+61 8 7074 0000
Fax 93204 0
Email 93204 0
eamon.raith@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Deidentified collated data only will be published in academic peer-reviewed publications.


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.