ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12622001411730

Ethics application status

Approved

Date submitted

25/10/2022

Date registered

4/11/2022

Date last updated

29/10/2024

Date data sharing statement initially provided

4/11/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone on the incidence of intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial.

Scientific title

High-flow Oxygen and Nitric Oxide inhalation versus high-flow oxygen alone on the incidence of intubation in hypoxaemic Respiratory failure (HONOR): a pilot randomised controlled trial.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

HONOR

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Respiratory Failure

Condition category

Condition code

Respiratory

Other respiratory disorders / diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

High-flow oxygen (HFO2) combined with Nitric Oxide (NO) gas as per the following protocol:

• Initial fraction of inspired oxygen (FiO2) set at 100% with an initial flow of 60L/min
• NO set at 20 parts per million (ppm) via high-flow nasal cannula (HFNC) as per local clinical work unit guideline. NO will be initiated by ICU nursing staff following medical approval. *Ratio of oxygen to nitric oxide is not calculable due to differences in units of measurement.
• HFO2+NO support for a minimum of 24 hours, initiated as soon as possible following consent to trial. However, if emergency treatment is required rapidly, and the involvement in the research carries no more risk to participants than not participating, study procedures will be performed and consent to continue will be sought from the substitute decision maker (SDM), or the participant, should they regain capacity to consent as soon as possible (within a maximum of three days)
• HFO2+NO will be delivered with humidification (approximately 98% humidity delivered at 37°C to the nares)
• Flows down-titrated in increments of 10L/min if needed for tolerance, to a minimum of 30L/min corresponding with FiO2 listed in the table below:
Flow rate FiO2
50-60L/min 0.6 – 1.0
40L/min 0.4-0.6
30L/min 0.21-0.4
• After 24 hours, wean NO 1ppm every 20 minutes as per local clinical work unit guideline or as directed by the ICU Consultant
• Audits of electronic notes (capturing continuous measures) within ICU will occur to assess adherence to the intervention.

Intervention code [1]

Prevention

Comparator / control treatment

High-flow oxygen (HFO2) as per the following protocol:

• Initial fraction of inspired oxygen (FiO2) set at 100% with an initial flow of 60L/min
• HFO2 will be delivered with humidification (approximately 98% humidity delivered at 37°C to the nares) for a minimum of 18 hours. Down titration will occur during this period as listed below.
• Down titrate FiO2 in the first hour, targeting SpO2> 92% and PaO2> 60mm Hg
• Further down titrate FiO2 every subsequent two hours maintaining SpO2> 92% and PaO2> 60mm Hg
• Down titrate flows in increments of 10L/min if needed for tolerance, to a minimum of 30L/min corresponding with FiO2 listed in the table below:
Flow rate FiO2
50-60L/min 0.6 – 1.0
40L/min 0.4-0.6
30L/min 0.21-0.4

Control group

Active

Outcomes

Primary outcome [1]

UpdateFeasibility (eligibility, recruitment, retention, protocol fidelity, missing data) as a composite primary measure. Feasibility data will be specifically collected via paper case report forms capturing the following data: a. Eligibility (% of screened patients that meet criteria) b. Recruitment (% of all eligible patients recruited using approved consent methods) c. Retention (% of patients withdrawing consent) d. Protocol fidelity (% of patients in intervention group receiving HFO2 + NO for at least 22 hours a day) e. Missing data (% of primary and secondary outcome data unable to be collected)

Timepoint [1]

Assessed at the completion of the trial.

Primary outcome [2]

Safety measures:
-Methaemaglobin levels measured via ABGs at inclusion, and then one hour, between four to six hours, 12 hours, 24 hours, and 48 hours after randomisation.
-Daily serum creatinine and urine output levels will be collected to monitor renal function and/or renal impairment.

Timepoint [2]

Assessed daily for the duration of the patient's hospital admission (including ICU and inpatient stay on ward or rehabilitation up to 28 days) via electronic medical records.

Primary outcome [3]

Number of patients in each arm progressed to invasive mechanical ventilation as assessed bu review of medical records.

Timepoint [3]

Within 28 days of enrolment to study.

Secondary outcome [1]

Any change in partial pressure of arterial oxygen (PaO2) assessed by arterial blood gas.

Timepoint [1]

Baseline, between four to six hours, 12 hours, 24 hours and 48 hours post-commencement of intervention.

Secondary outcome [2]

Respiratory rate as assessed by review of electronic medical records.

Timepoint [2]

Baseline, between four to six hours, 12 hours, 24 hours and 48 hours post-commencement of intervention.

Secondary outcome [3]

Illness severity as estimated by sequential organ failure assessment (SOFA) score.

Timepoint [3]

Daily for the duration of ICU admission.

Secondary outcome [4]

Worst partial pressure of arterial oxygen to fraction of inspired oxygen (PF) ratio as assessed by review of electronic medical records.

Timepoint [4]

Daily for the duration of ICU admission.

Secondary outcome [5]

Respiratory rate-oxygenation (ROX) index scores as assessed by review of electronic medical records.

Timepoint [5]

Baseline, between four to six hours, 12 hours, 24 hours and 48 hours post-commencement of intervention.

Secondary outcome [6]

Reason for intubation as assessed by review of electronic medical records.

Timepoint [6]

Within 28 days post-commencement of intervention.

Secondary outcome [7]

Dyspnoea scores as assessed by a modified BORG scale.

Timepoint [7]

Baseline and one hour post intervention.

Secondary outcome [8]

Hospital length of stay as assessed by review of medical records.

Timepoint [8]

On day of discharge from hospital.

Secondary outcome [9]

Mechanical ventilation hours as assessed by review of electronic medical records.

Timepoint [9]

Within 28 days of ICU admission.

Secondary outcome [10]

Number of ventilator free days as assessed by review of electronic medical records.

Timepoint [10]

Within 28 days of ICU admission.

Secondary outcome [11]

Time to mobilisation (Classification 4 (standing) on the ICU mobility score).

Timepoint [11]

Within 28 days of ICU admission.

Secondary outcome [12]

Best mobility on the ICU mobility score, as assessed by review of electronic medical records.

Timepoint [12]

Within first 24 hours of ICU admission and during whole hospital length of stay.

Secondary outcome [13]

Delirium incidence as assessed by the Confusion Assessment method for the ICU (CAM-ICU score) and recorded in the electronic medical records.

Timepoint [13]

Daily for the duration of ICU admission.

Secondary outcome [14]

Need for anxiolytic and sedative medication as a composite measure, assessed by review of the electronic medical records.

Timepoint [14]

During hospital admission.

Secondary outcome [15]

Mortality.

Timepoint [15]

During ICU stay.

Secondary outcome [16]

Mortality.

Timepoint [16]

Within 90 days of randomisation.

Secondary outcome [17]

Methaemaglobin levels (primary outcome).

Timepoint [17]

Measured via arterial blood gas at inclusion, and then one hour, between four to six hours, 12 hours, 24 hours and 48 hours after randomisation.

Secondary outcome [18]

Serum creatinine levels (primary outcome).

Timepoint [18]

Daily, assessed by routine blood test in ICU.

Secondary outcome [19]

Urine output levels (primary outcome).

Timepoint [19]

Daily, assessed by review of electronic medical records.

Secondary outcome [20]

Oxygen saturations assessed by review of electronic medical records.

Timepoint [20]

Baseline, between four to six hours, 12 hours, 24 hours and 48 hours post-commencement of intervention.

Secondary outcome [21]

Systolic blood pressure assessed by review of electronic medical records

Timepoint [21]

Baseline, between four to six hours, 12 hours, 24 hours and 48 hours post-commencement of intervention.

Secondary outcome [22]

Heart rate assessed by review of electronic medical records.

Timepoint [22]

Baseline, between four to six hours, 12 hours, 24 hours and 48 hours post-commencement of intervention.

Secondary outcome [23]

Intensive care unit (ICU) length of stay (LOS) as assessed by review of electronic medical records.

Timepoint [23]

At completion of ICU admission.

Eligibility

Key inclusion criteria

• Age greater than or equal to 18 years, meeting the following criteria
o De novo type I respiratory failure (hypoxaemia in the absence of chronic lung condition) (41)
o PF ratio <300mmHg
o High flow nasal cannula determined by ICU medical team to be primary method for delivery of oxygen therapy
o Anticipated high-flow oxygen (HFO2) requirement >24 hours
o Arterial line in-situ for blood gas sampling

• Ability to provide informed consent, or consent via a substitute decision maker

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Underlying chronic respiratory failure or exacerbation of asthma (including COPD or another chronic respiratory disease)
• Documented cardiogenic pulmonary oedema or acute coronary syndrome
• Hypercapnic respiratory failure with PaCO2 > 45mmHg
• Deterioration of neurologic status demonstrated by Glasgow Coma Scale (GCS) less than or equal to 12
• Urgent need for intubation (evaluated by the medical officer in charge)
• Haemodynamic instability (defined by systolic arterial blood pressure <90mmHg or mean arterial blood pressure <65 mmHg)
• Use of vasopressors
• Do not intubate orders
• Enrolled in any other trial of targeted oxygen therapy

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)

Sealed envelope.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation using a randomisation table created by computer software (Sealed Envelope).

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

Consistent with published recommendations for pilot studies, we will refrain from a detailed inferential statistical analysis in this pilot study. The sample size is based on the pragmatics of recruitment and the necessities for examining feasibility. Inclusion of HFO2 as control group in this pilot is deliberate and will allow realistic examination of recruitment, randomisation and implementation of interventions. Analysis will be performed on an intention-to-treat basis.

Categorical variables will be summarised as frequencies (percentage) and continuous measures will be summarised as mean (SD) or median (IQR) as appropriate. Binary outcome measures for each group will be presented with estimated proportions with 95% confidence intervals to convey precision. Kaplan-Meier curves will be plotted to explore time from enrolment to intubation or death in each group. Associations between baseline factors and intubation will be explored using logistic regression analysis.

For outcome measures with continuous repeated measures, within-group change, between-group differences and differences in rates of change over time will be explored using mixed effects linear regression modelling with an interaction term for time by group.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

4/11/2024

Actual

Date of last participant enrolment

Anticipated

4/11/2026

Actual

Date of last data collection

Anticipated

2/12/2026

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

The Prince Charles Hospital - Chermside

Recruitment postcode(s) [1]

4032 - Chermside

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

The Prince Charles Hospital - Common Good Foundation

Address [1]

The Prince Charles Hospital,
Rode Rd, CHERMSIDE, QLD, 4032

Country [1]

Australia

Primary sponsor type

Hospital

Name

Metro North Hospital and Health Service

Address

The Prince Charles Hospital,
Rode Rd, CHERMSIDE, QLD, 4032

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Metro North Health Human Research Ethics Committee

Ethics committee address [1]

Level 14 Block 7
Royal Brisbane and Women's Hospital
Cnr Butterfield St and Bowen Bridge Rd
HERSTON QLD 4029

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

16/06/2022

Approval date [1]

06/09/2022

Ethics approval number [1]

HREC/2022/MNHA/54454

Summary

Brief summary

Induced coma and breathing machines have become synonymous with intensive care units (ICU). Breathing machines are undoubtedly life-saving in many situations where a person can’t breathe for themselves. Despite it being one of the most potent life-sustaining technology available, it causes significant increases in hospital length of stay, an increased hospital cost burden and a leading cause of distress for patients and families in ICU. 

Non-invasive alternatives such as nasal high-flow oxygen delivery systems or pressurised face masks are usually used as first line treatment to prevent a breathing machine. Low oxygen levels can also be improved with the addition of nitric oxide gas. One study has demonstrated a trend toward decreased need for breathing machines for a portion of patients receiving nasal high-flow oxygen and nitric oxide gas, however this research remains sparse. Our study will examine the feasibility and clinical outcomes of comparing nasal high-flow oxygen alone over nasal high-flow oxygen with nitric oxide gas in preventing patients to require a breathing machine. Based on previous research and physiological rationale, we hypothesise the latter to be superior.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Kiran Shekar

Address

Adult Intensive care Services, the Prince Charles Hospital, Chermside, QLD, 4032.

Country

Australia

Phone

+61 0411294763

Fax

[email protected]

Contact person for public queries

Name

Kiran Shekar

Address

Adult Intensive care Services, the Prince Charles Hospital, Chermside, QLD, 4032.

Country

Australia

Phone

+61 0411294763

Fax

[email protected]

Contact person for scientific queries

Name

Kiran Shekar

Address

Adult Intensive care Services, the Prince Charles Hospital, Chermside, QLD, 4032.

Country

Australia

Phone

+61 0411294763

Fax

[email protected]

Data sharing statement

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

No/undecided IPD sharing reason/comment

Data that is collected during the project will be reidentifiable via a coding system and not of an individual nature.
Information linking named participants to these code numbers will be kept separately from any research databases and destroyed once data collection has been completed. We will ensure that all data subject to analysis and archiving is nonidentifiable in any final publications or presentations.

What supporting documents are/will be available?

Doc. No.	Type	Attachment
17456	Informed consent form	384881-(Uploaded-31-10-2022-18-31-06)-Study-related document.docx
17457	Ethical approval	384881-(Uploaded-25-10-2022-12-45-47)-Study-related document.pdf
24208	Study protocol	384881-(Uploaded-19-09-2024-11-43-24)-54454 HONOR Protocol.docx

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.

Trial Review

Documents added manually

Documents added automatically