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Trial registered on ANZCTR


Registration number
ACTRN12622000672752
Ethics application status
Approved
Date submitted
16/04/2022
Date registered
9/05/2022
Date last updated
9/05/2022
Date data sharing statement initially provided
9/05/2022
Date results provided
9/05/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Feeding Interventions Because of Respiratory Events in preterm infants (FIBRE): A randomised triple crossover trial.
Scientific title
The Effect of Feeding Interventions Because of Respiratory Events in preterm infants (FIBRE): A randomised triple crossover trial.
Secondary ID [1] 306951 0
None
Universal Trial Number (UTN)
U1111-1277-2557
Trial acronym
FIBRE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
apnoea 326061 0
bradycardia 326062 0
hypoxia 326063 0
preterm, birth 326064 0
prematurity 326065 0
Condition category
Condition code
Respiratory 323374 323374 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 323375 323375 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Position Intervention
Infants undertaking Condition A (‘supine and flat’) were placed supine with the cot in neutral (horizontal) position. The positional intervention, Condition B (‘propped and prone’), combined infant position and cot position, with infants placed prone with head turned to one side and cot inclined at 15 degrees (default cot elevation achievable within the unit). Positioning during Conditions A and B was maintained as default position throughout each 24-hour test period, but allowed for position change for routine nursing and medical care. Positions were administered by the caring registered nurse. Parent handling (holding and skin-to-skin) was encouraged, however avoided during and within one hour of feeding.

Feed-Rate Intervention
Infants in Conditions A and B received usual third-hourly gravity bolus feeds via nasogastric tube, typically over 5 to 15 minutes. The feed-rate intervention (Condition C) was defined by third-hourly feed volume given over 45 minutes by pump, with usual supine/flat infant position. Pump feeds were administered via Vygon (Écouen, France) Nutrisafe-2 pump and giving set. Feeds were standard (expressed breast milk or standard hospital formula [67-81kcal/100mL as standard practice within unit])

Each condition occurred for a 24 hour period, in randomised sequence, consecutively over three days without washout period. Adherence to conditions was supported by nursing team leader and supported nursing handover.
Intervention code [1] 323397 0
Treatment: Other
Comparator / control treatment
Condition A: Usual Care
Usual care (supine in flat cot; usual nasogastric gravity bolus feeds);
Control group
Active

Outcomes
Primary outcome [1] 331112 0
Number of respiratory events in 24h period

A respiratory ‘event’ was defined as one or a combination of clinically significant apnoea, desaturation or bradycardia. Apnoea was considered a pause in breathing of at least 15s, or when accompanied by desaturation and/or bradycardia. Desaturation was defined as peripheral capillary oxygen saturation less than 80% for at least 5s. Bradycardia represented heartrate less than 100bpm for at least 5s. Coincident apnoea, bradycardia and/or desaturation was counted as one event. Events were measured using the Philips Patient Information Center iX monitoring station (Philips, Eindhoven, Netherlands) with standard leads, recording live traces of heartrate, respirations and SpO2 with 5s averaging time.
Timepoint [1] 331112 0
During three day study period for each infant
Primary outcome [2] 331228 0
Percentage of time with SpO2 less than 80% within 24h period.

Oximetry histogram generation by the Philips Patient Information Center iX monitoring station (Philips, Eindhoven, Netherlands) occurred at the conclusion of each 24-hour study period.
Timepoint [2] 331228 0
During three day study period for each infant
Secondary outcome [1] 408778 0
A secondary outcome was percentage of time with SpO2 greater than or equal to 88% over 24h.

Oximetry histogram generation by the Philips Patient Information Center iX monitoring station (Philips, Eindhoven, Netherlands) occurred at the conclusion of each 24-hour study period.
Timepoint [1] 408778 0
During three day study period for each infant

Eligibility
Key inclusion criteria
Inclusion Criteria
Preterm Infants less than 32 weeks gestation at birth can be enrolled in the study at any gestation and become eligible to enter the study period once they have met the additional criteria below:
• Off respiratory support for at least 5 days
o Infants who are on low flow sub-nasal oxygen less than 0.5 L/min are eligible
(oxygen flow rate will not be weaned during the trial)
o Infants who are receiving Caffeine Citrate will not be excluded, but the caffeine dose will only be adjusted for body weight during the trial and will not be discontinued during the trial regardless of gestational age
• Receiving full enteral feeds (greater than or equal to 150 mL/kg/day) for at least 5 days
• Receiving 3 hourly feeding for at least 48 hours

[note maximum age listed below refers to gestational age - there was no exclusion based on chronological age]
Minimum age
No limit
Maximum age
32 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria
• Currently receiving respiratory support:
o High-flow nasal cannula therapy (HFNC)
o Continuous Positive Airway Pressure (CPAP)
o Nasal Intermittent Positive Pressure Ventilation (NIPPV)
o Conventional or Oscillatory Ventilation
• Significant comorbidity:
o History of confirmed necrotising enterocolitis (NEC)
o Past surgery or condition likely to require surgery (other than inguinal hernia)
o Significant or symptomatic congenital heart disease
o Congenital airway obstruction (Pierre-Robin Sequence etc.)
• Discharge likely to occur during the trial
• Receiving nutritive suck feeds (breast or bottle feeds if counted in total fluid intake)
• Receiving pharmacological treatment for Gastro-oesophageal Reflux Disease (GORD)
• Infants for whom a decision to provide palliative care has been made

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)
Allocation at time of recruitment was not concealed..
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Infants were randomly assigned to one of six groups, defined by the sequence permutations of the three test conditions (ABC/ACB/BCA/BAC/CAB/CBA) and predicted by their order of recruitment in the study. This permitted assessment of potential period effects and carryover effects, as each treatment follows every other treatment at least once in the six sequence design, as opposed to a simpler Latin Square approach which could have been undertaken with fewer groups. The study makes use of an equal number of Study Envelopes for each group, containing the instructions for each sequence group. Randomisation is achieved through the use of a computer generated sequential list and these envelopes were randomised in a stack with the order dictated by this list. As each infant enters the study a Study Envelope is retrieved from the top of the stack (stored in a designated FIBRE Filing Tray) and in this way infants are randomised to Groups 1-6 at their time of entry into the study.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Randomised triple crossover design was employed whereby each infant underwent three test conditions in randomised sequence, each over a 24-hour period for three consecutive days without washout

Attending nurses are not blinded to the test conditions, as their care necessarily involves implementing the conditions and caring for the infant. Data collection for the number of respiratory events is blinded however, as it relies on examining the monitoring trace retrospectively for each 24-hour condition period and objectively counting the number of events. While the trace identifies which infant is monitored, the researcher is blind to the test condition for each 24-hour period. The histogram data is not blinded, as it is printed by the bedside nurse. It is, however, an objective measure of oximetry trends and derived purely from the monitoring system.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Prestudy Pilot:
A pre-study audit of n=10 infants receiving standard care (equivalent to Condition A) permitted estimates of between-subject and within-subject variance for primary outcomes. We aimed to recruit 90 infants to detect a 40% reduction in the log(number of events), with correlation between observations within the same subject of 0.6, and a 50% reduction in the log(percentage time with SpO2 <80%), with correlation between observations within the same subject of 0.4 for a two-sided test with 80% power and 5% alpha.

Study Analyses:
Data were analysed using STATA v15.1 (Texas, USA). Subject demographics were described using frequency and percentage for categorical variables, and continuous variables by mean and standard deviation or median and interquartile range (IQR) if not normally distributed. Differences between sequence and demographics were examined using Fisher’s exact test (categorical data) and one-way ANOVA or Kruskal-Wallis test (continuous data).

Number of events was examined using a generalised linear mixed effects model (GL(M)M) assuming negative binomial family and log link. Due to truncation of oxygen saturation percentage scales and skewed distribution, SpO2 <80% values of 0 were changed to 0.1 and data logit transformed prior to analysis using the formula: logit(SpO2lt80) = ln(SpO2lt80_adj/(100-SpO2lt80_adj)). For SpO2 greater than or = 88%, values of 100 were changed to 99.9 and data logit transformed. Linear mixed effects modelling (LMM) estimated treatment effect with the logit response for each respiratory outcome.

For each outcome the interaction between day and treatment was examined using their interaction as a fixed effect. Carryover effect was examined using dummy variables to describe the preceding treatment. All final models contained sequence (Group), period (Day) and Condition as fixed effects and patient (StudyID) as a random effect. Restricted maximum likelihood estimates (REML) were reported, residuals examined and homoscedasticity verified. Marginal mean estimates for each treatment and corresponding 95% confidence intervals (CIs), holding all other variables at their means, were reported. For the LMM, back-transformed marginal means and their CIs were reported. Incidence rate ratios and 95% CIs were reported for the GL(M)M. Both the modified intention-to-treat population (mITT, all randomised patients with at least one evaluation pertaining to the outcome of interest) and per-protocol population (PP) were analysed.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
22/07/2016
Date of last participant enrolment
Anticipated
Actual
22/01/2020
Date of last data collection
Anticipated
Actual
24/01/2020
Sample size
Target
90
Accrual to date
Final
68
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 22210 0
Gold Coast University Hospital - Southport
Recruitment postcode(s) [1] 37367 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 311269 0
Hospital
Name [1] 311269 0
Gold Coast University Hospital
Country [1] 311269 0
Australia
Primary sponsor type
Individual
Name
Pita Birch
Address
Neonatal Critical Care Unit, Mater Health
Aubigny Place, Raymond Terrace, South Brisbane QLD 4101
Country
Australia
Secondary sponsor category [1] 312723 0
Hospital
Name [1] 312723 0
Gold Coast Hospital University Hospital
Address [1] 312723 0
1 Hospital Blvd
Southport QLD 4215
Country [1] 312723 0
Australia
Other collaborator category [1] 282263 0
Other Collaborative groups
Name [1] 282263 0
QIMR Berghofer Medical Research Institute
Address [1] 282263 0
Statistics Unit | Level 12 Bancroft Building
300 Herston Road, Herston QLD 4006
Locked Bag 2000 Royal Brisbane Hospital, QLD 4029
Country [1] 282263 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310778 0
Gold Coast Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 310778 0
Ethics committee country [1] 310778 0
Australia
Date submitted for ethics approval [1] 310778 0
07/11/2015
Approval date [1] 310778 0
08/01/2016
Ethics approval number [1] 310778 0
HREC/15/QGC/297

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

Contacts
Principal investigator
Name 118830 0
Dr Chris Richmond
Address 118830 0
Genetic Health QLD
Block 7 Level 6, Royal Brisbane & Women’s Hospital
Butterfield Street, Herston QLD 4029
Country 118830 0
Australia
Phone 118830 0
+61736461686
Fax 118830 0
+61 7 3646 1987
Email 118830 0
chris.richmond@health.qld.gov.au
Contact person for public queries
Name 118831 0
Chris Richmond
Address 118831 0
Genetic Health QLD
Block 7 Level 6, Royal Brisbane & Women’s Hospital
Butterfield Street, Herston QLD 4029
Country 118831 0
Australia
Phone 118831 0
+61736461686
Fax 118831 0
+61 7 3646 1987
Email 118831 0
ghq@health.qld.gov.au
Contact person for scientific queries
Name 118832 0
Chris Richmond
Address 118832 0
Genetic Health QLD
Block 7 Level 6, Royal Brisbane & Women’s Hospital
Butterfield Street, Herston QLD 4029
Country 118832 0
Australia
Phone 118832 0
+61736461686
Fax 118832 0
+61 7 3646 1987
Email 118832 0
ghq@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual (line-by-line) deidentified patient data is available by request from the corresponding author.
When will data be available (start and end dates)?
Requests for IPD will be supported for a period of 5 years from end of study (2021 to end of 2025)
Available to whom?
Data will be available to researchers based on consideration of query and at discretion of corresponding author.
Available for what types of analyses?
Data will be available to support meta-analysis or other sound research queries at discretion of corresponding author.
How or where can data be obtained?
Data can be requested by correspondence with corresponding author (chris.richmond@health.qld.gov.au)


What supporting documents are/will be available?




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.