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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]

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

Condition category

Condition code

Respiratory

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]

Prevention

Intervention code [2]

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]

Proportion of time spent in the assigned SpO2 range in each arm

Timepoint [1]

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]

Area under the curve (AUC) for PaO2, FiO2 and SaO2 on day 0 to day 7 in each arm.

Timepoint [2]

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]

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]

a. 28 days
b. 28 days
c. 7 days

Secondary outcome [2]

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]

a. Day 0 to Day 7
b. First 7 days
c. First 28 days

Secondary outcome [3]

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]

a. First 7 days
b. First 28 days

Secondary outcome [4]

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]

a. First 7 days
b. First 7 days

Secondary outcome [5]

Time to successful extubation (alive and extubated for >48 hours)

Timepoint [5]

The period between the time of randomization and the time of initial successful extubation

Secondary outcome [6]

MV free days

Timepoint [6]

First 28 days

Secondary outcome [7]

ICU mortality

Timepoint [7]

Determined on the day of ICU discharge

Secondary outcome [8]

Hospital mortality

Timepoint [8]

Determined on the day of hospital discharge

Secondary outcome [9]

All cause mortality

Timepoint [9]

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?

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]

John Hunter Hospital Royal Newcastle Centre - New Lambton

Recruitment hospital [2]

Austin Health - Austin Hospital - Heidelberg

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Wellington

Country [2]

France

State/province [2]

Franche-Comte

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Intensive Care Foundation

Address [1]

Level 2, 10 Ievers Terrace,
Carlton, VIC 3053

Country [1]

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]

Hospital

Name [1]

Centre Hospitalier Universitaire

Address [1]

Service de Reanimation Medicale,
Centre Hospitalier Universitaire
Boulevard Fleming
25000 Besancon- France

Country [1]

France

Secondary sponsor category [2]

Charities/Societies/Foundations

Name [2]

Clinical Trials Group of the Australia and New Zealand Intensive Care Society (ANZICS-CTG)

Address [2]

Level 3,
10 Ievers Terrace,
Carlton, VIC 3053

Country [2]

Australia

Other collaborator category [1]

Hospital

Name [1]

Austin Hospital

Address [1]

ICU, Austin Hospital
145 Studley Road
Heidelberg VIC 3084

Country [1]

Australia

Other collaborator category [2]

Hospital

Name [2]

Wellington Hospital

Address [2]

ICU, Wellington Hospital,
Private Bag 7902,
Wellington 6021

Country [2]

New Zealand

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hunter New England Human Research Ethics Committee

Ethics committee address [1]

Hunter New England Human Research Ethics Committee
Locked Bag No. 1
New Lambton, NSW 2305

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

30/04/2013

Ethics approval number [1]

12/07/18/4.03

Ethics committee name [2]

Health and Disability Ethics Committees

Ethics committee address [2]

1 the Terrace
PO Box 5013
Wellington
6011

Ethics committee country [2]

New Zealand

Date submitted for ethics approval [2]

Approval date [2]

19/04/2013

Ethics approval number [2]

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

Dr Rakshit Panwar

Address

ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310

Country

Australia

Phone

+61410218808

Fax

[email protected]

Contact person for public queries

Name

Miranda Hardie

Address

ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310

Country

Australia

Phone

+61249223095

Fax

[email protected]

Contact person for scientific queries

Name

Rakshit Panwar

Address

ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310

Country

Australia

Phone

+61410218808

Fax

[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

Source	Title	Year of Publication	DOI
Embase	Conservative versus liberal oxygenation targets for mechanically ventilated patients: A pilot multicenter randomized controlled trial.	2016	https://dx.doi.org/10.1164/rccm.201505-1019OC
Embase	Liberal oxygenation versus conservative oxygenation strategy in ICU patients: Effects on systemic inflammation markers.	2022	https://dx.doi.org/10.1016/j.resmer.2021.100858

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically