Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000505707
Ethics application status
Approved
Date submitted
5/05/2013
Date registered
7/05/2013
Date last updated
12/08/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Feasibility and safety of conservative versus liberal oxygen targets in the mechanically ventilated patients.
Scientific title
A multicenter pilot study to determine whether the conservative oxygenation strategy is as feasible and safe as liberal oxygenation strategy for the ICU patients requiring invasive mechanical ventilation.
Secondary ID [1] 282447 0
Nil
Universal Trial Number (UTN)
U1111-1132-8178
Trial acronym
CLOSE I study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critically ill patients requiring invasive mechanical ventilation 289063 0
Condition category
Condition code
Respiratory 289399 289399 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1. When patients are randomly allocated to the conservative oxygenation arm, then the target arterial oxygen saturation (SpO2) during the period of mechanical ventilation (MV) would be 88-92%. When FiO2 is <0.50, we suggest 90-92% SpO2 target; and when FiO2 is 0.50 or more, we suggest 88-90% SpO2.
2. In all recruited patients, PEEP will be applied at the discretion of the treating clinician. The bedside nurse will then titrate FiO2 to achieve the assigned arterial oxygen saturation targets. In addition, the bedside nurse will set lower alarm-limit for SpO2 at 87% and the higher alarm-limit for SpO2 at 93%. The oxygen saturation goal in the protocol is for SpO2, but when required it may be used interchangeably for SaO2 as per routine practice in the participating centres. For example, if the perfusion is poor or SpO2 becomes less reliable, then the target may be based on SaO2.
3. When FiO2 requirements are >0.80, oxygen saturation targets will be determined by the treating clinicians as per their usual practice.
4. The current standard of care management will be instituted in the event of any clinical deterioration or hemodynamic instability. The treating intensive care physician may alter oxygenation targets if deemed necessary according to patient’s current clinical status.
5. The oxygenation goals are the long-term SpO2 target for the participant’s entire stay in ICU while on invasive MV. Temporary measures to improve oxygenation for planned procedures involving upper airways such as tracheostomy, bronchoscopy etc will follow standard practices in the participating centres. Such temporary adjustments in oxygenation parameters will be limited to shortest duration possible.
6. Patients who are re-intubated will continue in the same study arm and data collection will proceed as if the index MV episode is uninterrupted.

Intervention code [1] 287093 0
Prevention
Intervention code [2] 287094 0
Treatment: Devices
Comparator / control treatment
1. When patients are randomly allocated to the liberal oxygenation arm, then the target SpO2 during the period of MV would be at least 96%.
2. In all recruited patients, PEEP will be applied at the discretion of the treating clinician. The bedside nurse will then titrate FiO2 to achieve the assigned arterial oxygen saturation targets. In addition, the bedside nurse will set lower alarm-limit for SpO2 at 95%. The oxygen saturation goal in the protocol is for SpO2, but when required it may be used interchangeably for SaO2 as per routine practice in the participating centres. For example, if the perfusion is poor or SpO2 becomes less reliable, then the target may be based on SaO2.
3. When FiO2 requirements are >0.80, oxygen saturation targets will be determined by the treating clinicians as per their usual practice.
4. The current standard of care management will be instituted in the event of any clinical deterioration or hemodynamic instability. The treating intensive care physician may alter oxygenation targets if deemed necessary according to patient’s current clinical status.
5. The oxygenation goals are the long-term SpO2 target for the participant’s entire stay in ICU while on invasive MV. Temporary measures to improve oxygenation for planned procedures involving upper airways such as tracheostomy, bronchoscopy etc will follow standard practices in the participating centres. Such temporary adjustments in oxygenation parameters will be limited to shortest duration possible.
6. Patients who are re-intubated will continue in the same study arm and data collection will proceed as if the index MV episode is uninterrupted.
Control group
Dose comparison

Outcomes
Primary outcome [1] 289505 0
Proportion of time spent in the assigned SpO2 range in each arm
Timepoint [1] 289505 0
SpO2 is measured using a pulse oximeter. 4 hourly SpO2 data will be extracted from the nursing observations chart on day 0 to day 7; and 12 hourly data will be extracted from the nursing observations chart on day 8 to day 28. Data will be collected only during ICU stay, while a patient is intubated and receiving MV.
Primary outcome [2] 289506 0
Area under the curve (AUC) for PaO2, FiO2 and SaO2 on day 0 to day 7 in each arm.
Timepoint [2] 289506 0
AUC will be assessed as an integrated expression of mean oxygen (O2) levels achieved over the active treatment period. AUC is a useful summary index of longitudinal data. AUC will be determined using mixed linear modeling fitting main effects for group and time and an interaction between the two to ascertain if the groups behaved differently over time. 4 hourly (0400, 0800, 1200, 1600, 2000, 2400) data on PaO2, SaO2 and FiO2 will be extracted from nursing observations chart on day 0 to day 7. Data will be collected only during ICU stay, while a patient is intubated and receiving MV.
Secondary outcome [1] 302642 0
Incidence of circulation-related events
a. Days free of hemodynamic instability (defined as cardiac arrest or addition of at least 2 vasopressor/inotropes)
b. Days free of new arrhythmia (requiring new prescription of anti-arrhythmic agents)
c. Mean vasopressor (adrenaline + noradrenaline) requirement (microgram/kg/min) on the first 7 days
Timepoint [1] 302642 0
a. 28 days
b. 28 days
c. 7 days
Secondary outcome [2] 302643 0
Incidence of respiration-related events
a. Episodes of desaturation to <86% lasting more than 5 minutes.
b. Incidence of new onset ARDS (PaO2/ FiO2 <300 AND onset within 7 days AND bilateral opacities AND unexplained by cardiac failure)
c. Episodes of barotrauma requiring intervention (insertion of intercostal catheter or surgery)
Timepoint [2] 302643 0
a. Day 0 to Day 7
b. First 7 days
c. First 28 days
Secondary outcome [3] 302644 0
Incidence of acute kidney injury
a. AUC for delta Creatinine from baseline in patients without Renal Replacement Therapy (RRT)
b. Days free of RRT
Timepoint [3] 302644 0
a. First 7 days
b. First 28 days
Secondary outcome [4] 302645 0
Incidence of other organ-systems related outcomes
a. AUC for delta Lactate from baseline,
b. AUC for delta SOFA (non-GCS) score from baseline
Timepoint [4] 302645 0
a. First 7 days
b. First 7 days
Secondary outcome [5] 302646 0
Time to successful extubation (alive and extubated for >48 hours)
Timepoint [5] 302646 0
The period between the time of randomization and the time of initial successful extubation
Secondary outcome [6] 302647 0
MV free days
Timepoint [6] 302647 0
First 28 days
Secondary outcome [7] 302648 0
ICU mortality
Timepoint [7] 302648 0
Determined on the day of ICU discharge
Secondary outcome [8] 302649 0
Hospital mortality
Timepoint [8] 302649 0
Determined on the day of hospital discharge
Secondary outcome [9] 302650 0
All cause mortality
Timepoint [9] 302650 0
Determined on day 90

Eligibility
Key inclusion criteria
1. Within the first 24 hours of initiation of invasive MV
2. Age at least 18 years
3. In the opinion of treating clinician, patient is likely to remain on MV until the day after next.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient at an imminent risk of death within the next 48-72 hours in the opinion of the treating medical team.
2. The treating clinician disagrees that a patient should be enrolled in the trial.
3. Pregnancy

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)
Enrolled patients will be randomly allocated using opaque sealed envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Using a web-based computer program, two non-clinical staff members (third party) generated a randomization list stratified for each site. Number of patients per site, number of blocks and the number of patients within each block were all decided by the third-party at their discretion. Thus, the list generated for each site has varying size blocks in random order, with random patient allocations within each block. After generating a sequence list for each site, the third party prepared sealed envelopes for each patient per site. An A4 page with patient randomization number and the corresponding allocated arm was printed for each patient. The allocated arm is typewritten in a lighter font on a coloured page. When examined closely, nothing could be made out on holding that folded-page against a bright light. This folded-page was then inserted in a sequential opaque envelope for each patient. All envelopes were then sealed and securely stored in a locked cabinet. The randomization-key list is securely stored in a password-protected folder and the hard copy is in a locked drawer of one of the department professors who is not involved in the study. The envelope-set for each site will be posted when all sites have obtained final ethics/local site regulatory approval.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
An independent senior biostatistician will perform all analysis using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). Baseline comparisons will be performed using chi-square tests for equal proportions or fishers exact tests where numbers are small and reported as n (%). Continuously normally distributed variables will be compared using student t-tests and reported as means (standard deviation) whilst non-normally distributed data will be compared using Wilcoxon rank sum tests and will be reported as medians (interquartile range). All variables will be assessed for normality and log-transformed if appropriate. Event-free days till day 28 will be compared using Poisson regression analysis. Multivariate models adjusting for baseline imbalances and known covariates will be performed using logistic or linear regression where appropriate. Sub-group analysis will be performed for patients with baseline PaO2/FiO2 <300. All analyses will be according to intention-to-treat principle. A two-sided p-value of 0.05 will be considered statistically significant.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
8/05/2013
Actual
18/06/2013
Date of last participant enrolment
Anticipated
7/12/2013
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 965 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [2] 966 0
Austin Health - Austin Hospital - Heidelberg
Recruitment outside Australia
Country [1] 5065 0
New Zealand
State/province [1] 5065 0
Wellington
Country [2] 5066 0
France
State/province [2] 5066 0
Franche-Comte

Funding & Sponsors
Funding source category [1] 287225 0
Charities/Societies/Foundations
Name [1] 287225 0
Intensive Care Foundation
Country [1] 287225 0
Australia
Primary sponsor type
Hospital
Name
John Hunter
Address
ICU, John Hunter Hospital,
Lookout road, New Lambton, NSW 2305
Country
Australia
Secondary sponsor category [1] 285978 0
Hospital
Name [1] 285978 0
Centre Hospitalier Universitaire
Address [1] 285978 0
Service de Reanimation Medicale,
Centre Hospitalier Universitaire
Boulevard Fleming
25000 Besancon- France
Country [1] 285978 0
France
Secondary sponsor category [2] 285979 0
Charities/Societies/Foundations
Name [2] 285979 0
Clinical Trials Group of the Australia and New Zealand Intensive Care Society (ANZICS-CTG)
Address [2] 285979 0
Level 3,
10 Ievers Terrace,
Carlton, VIC 3053
Country [2] 285979 0
Australia
Other collaborator category [1] 277372 0
Hospital
Name [1] 277372 0
Austin Hospital
Address [1] 277372 0
ICU, Austin Hospital
145 Studley Road
Heidelberg VIC 3084
Country [1] 277372 0
Australia
Other collaborator category [2] 277373 0
Hospital
Name [2] 277373 0
Wellington Hospital
Address [2] 277373 0
ICU, Wellington Hospital,
Private Bag 7902,
Wellington 6021
Country [2] 277373 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289211 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 289211 0
Hunter New England Human Research Ethics Committee
Locked Bag No. 1
New Lambton, NSW 2305
Ethics committee country [1] 289211 0
Australia
Date submitted for ethics approval [1] 289211 0
Approval date [1] 289211 0
30/04/2013
Ethics approval number [1] 289211 0
12/07/18/4.03
Ethics committee name [2] 289212 0
Health and Disability Ethics Committees
Ethics committee address [2] 289212 0
1 the Terrace
PO Box 5013
Wellington
6011
Ethics committee country [2] 289212 0
New Zealand
Date submitted for ethics approval [2] 289212 0
Approval date [2] 289212 0
19/04/2013
Ethics approval number [2] 289212 0
12/STH/2/AM01

Summary
Brief summary
Clinicians consider arterial oxygen saturation (SpO2) of at least 88-90% as an acceptable target for most patients undergoing mechanical ventilation (MV). Although several experimental and clinical studies report that high levels of oxygen (O2) may be injurious, and recent RCTs show that O2 therapy titrated to lower SpO2 targets (88-94%) improves clinical outcomes in some patient groups, major observational studies show that ICU patients often receive much higher levels of oxygenation in the first 24 hours of ICU admission.

Indeed, in a recently completed observational study in ICU patients on MV, we observed that high oxygenation levels were usually achieved with the use of liberal amounts of O2 in routine practice. At a teaching hospital, the 95% confidence interval for the mean time-weighted average SpO2 for the first 7 days of ventilation was 96.8-97.4% and the mean FiO2 of 0.40 or more was used to achieve mean SpO2 of >95% on 40% of the ventilated days. There are no data in literature, for adult ICU patients receiving MV, to demonstrate whether or not higher oxygenation targets (SpO2 >95%) lead to different outcomes than the alternative lower targets (SpO2 88-94%).

We aim to systematically evaluate whether liberal O2 therapy is beneficial or harmful compared to a more conservative O2 therapy in critically ill patients. To help us determine the optimal size and design of a suitable trial, a pilot study will be first performed to assess feasibility of the two oxygenation strategies.

Our hypothesis for this pilot study is that in critically ill patients on invasive MV, an effective separation of SpO2 levels can be achieved between the two (conservative vs. liberal oxygen targets) groups, without any significant problems or safety concerns in implementing the study protocol in different critical care settings.

100 eligible patients, will be randomly allocated to either a liberal oxygenation strategy with target SpO2 of at least 96% or a conservative oxygenation strategy with target SpO2 of 88-92%. The treating team will set PEEP as per usual practice. When FiO2 requirements are >0.80, SpO2 targets will be determined by the treating clinicians. The pragmatic nature of the trial allows flexibility in management decisions and allows the treating clinicians to alter oxygenation targets if necessary according to patient’s current clinical state. Other co-interventions such as sedation, nutrition and weaning from ventilation will follow standard practices.

This pilot study will provide crucial preliminary information on the likely effects of two different target levels of oxygenation in ICU patients on invasive MV. If feasibility and safety are demonstrated, we will follow this study with a definitive RCT, the results of which will have the potential to substantially influence clinical practice in relation to O2 therapy in critically ill patients.
Trial website
Trial related presentations / publications
Public notes
Pre-specified analysis and outline of data presentation

1] CONSORT Diagram of patient flow: 1. patients screened; 1 – A) met all inclusion criteria; 1 – B) patients excluded; 1 – B.1) moribund, 1 – B.2) treating clinician disagrees, 1 – B.3) pregnant, 1 – B.4) consent not obtained, 1 – C) patients randomized; 1 – C.1) patients allocated to SpO2 88-92% arm; 1 – C.1.1) withdrew consent, 1 – C.1.2) patients lost to follow up, 1 – C.1.3) included in final analysis; 1 – C.2) patients allocated to SpO2 >=96% arm; 1 – C.2.1) withdrew consent, 1 – C.2.2) patients lost to follow up, 1 – C.2.3) included in final analysis 2] Table of baseline characteristics in the two arms: *Age, weight, BMI, gender, *Diagnosis type (trauma/ medical/ surgical) *APACHE III at randomization, *Pre-randomization hospital stay *Pre-randomization MV duration *Presence of ARDS at randomization *Co-morbidities (current smoker, COPD and IHD) *Last SpO2 prior to randomization *SaO2, PaO2, pH, PaCO2, lactate, FiO2, PEEP, *Tidal volume, Peak airway pressure, Minute ventilation and *PaO2/FiO2 at randomization *Hemoglobin at randomization (T0) *SOFA score (non-GCS) 3] Figure on scatter plot of SpO2 versus FiO2 for all study time-points in both arms to assess the degree of separation. 4] Table on study process data in both arms: *Days on MV during the first 28 days *Mean SpO2, SaO2, PaO2, PaCO2, pH, lactate on days 0-7 *Mean FiO2, PEEP, Tidal volume, Minute ventilation, *Peak airway pressure on days 0-7 *Mean SpO2 and FiO2 on days 8-28 *Number of ABGs performed during the first 7 days *Net fluid balance on days 0-7 *Number (%) of patients who required RRT *Days on RRT during the first 28 days *Vasopressor-hours during the first 28 days *SOFA (non-GCS) score 5] Table on primary and secondary outcomes in both arms: *% of time-points spent in the assigned SpO2 ranges *AUC for SaO2, PaO2 and FiO2 on days 0-7 *Days free of hemodynamic instability during the first 28 days *Vasopressor-free hours during the first 28 days *Mean vasopressor requirement (µg/kg/min) on days 0-7 *Days free of new-onset arrhythmia during the first 28 days *Number of significant hypoxic episodes (those with SpO2<86% for >5 minutes) *Barotrauma-free days at day 28 *Incidence of new onset ARDS *AUC for delta PaO2/FiO2 on days 0-7 *AUC delta creatinine from day 0-7 *RRT-free days until day 28 *AUC delta lactate from day 0 to day 1-7 *AUC delta SOFA score from day 0 to day 1-7 *MV-free days until day 28 *Time to successful extubation *ICU mortality rate *Hospital mortality rate *90-day mortality rate 6] Table on primary and secondary outcomes in the subgroup of patients with Day 0 PaO2/FiO2 <300: *% of time-points spent in the assigned SpO2 ranges *AUC for SaO2 on days 0-7 *AUC for delta PaO2/FiO2 on days 0-7 *Days free of hemodynamic instability during the first 28 days *Vasopressor-free hours during the first 28 days *Mean vasopressor requirement (µg/kg/min) on days 0-7 *Days free of new-onset arrhythmia during the first 28 days *Number of significant hypoxic episodes (those with SpO2<86% for >5 minutes) *Barotrauma-free days at day 28 *Incidence of new onset ARDS *AUC delta creatinine from day 0 to day 1-7 *RRT-free days until day 28 *AUC delta lactate from day 0 to day 1-7 *AUC delta SOFA score from day 0 to day 1-7 *MV-free days until day 28 *Time to successful extubation *ICU mortality rate *Hospital mortality rate *90-day mortality rate.

Contacts
Principal investigator
Name 39798 0
Dr Rakshit Panwar
Address 39798 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 39798 0
Australia
Phone 39798 0
+61410218808
Fax 39798 0
Email 39798 0
[email protected]
Contact person for public queries
Name 39799 0
Miss Miranda Hardie
Address 39799 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 39799 0
Australia
Phone 39799 0
+61249223095
Fax 39799 0
Email 39799 0
[email protected]
Contact person for scientific queries
Name 39800 0
Dr Rakshit Panwar
Address 39800 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 39800 0
Australia
Phone 39800 0
+61410218808
Fax 39800 0
Email 39800 0
[email protected]

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseConservative versus liberal oxygenation targets for mechanically ventilated patients: A pilot multicenter randomized controlled trial.2016https://dx.doi.org/10.1164/rccm.201505-1019OC
EmbaseLiberal oxygenation versus conservative oxygenation strategy in ICU patients: Effects on systemic inflammation markers.2022https://dx.doi.org/10.1016/j.resmer.2021.100858
N.B. These documents automatically identified may not have been verified by the study sponsor.