Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000408482
Ethics application status
Approved
Date submitted
23/03/2016
Date registered
30/03/2016
Date last updated
7/06/2021
Date data sharing statement initially provided
7/06/2021
Date results information initially provided
7/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral vitamin A for prevention of bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled trial
Scientific title
Oral (enteral) vitamin A for prevention of bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled trial
Secondary ID [1] 288813 0
None
Universal Trial Number (UTN)
Trial acronym
EVARO study (Enteral vitamin A to improve Respiratory Outcomes)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchopulmonary dysplasia 298081 0
Condition category
Condition code
Respiratory 298247 298247 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 298301 298301 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Enteral water-miscible vitamin A 5000 IU (0.5 mL) once daily started within 24 hours of the introduction of oral feeds and continued until 34 week post-menstrual age. The trial medication will be prescribed on the routinely used medication charts in the neonatal nursery and the medication will be administered by a nurse caring for the baby. The nurse will document the administration of the medication in the medication chart. The charts will be reviewed every week to ensure compliance.
Intervention code [1] 294266 0
Treatment: Drugs
Intervention code [2] 294267 0
Prevention
Comparator / control treatment
The control group will receive identical volume (0.5 mL) of placebo solution (normal saline mixed with Quinoline Yellow 2.5 mg/100mL) enterally.
Control group
Placebo

Outcomes
Primary outcome [1] 297737 0
Severity of bronchopulmonary dysplasia assessment using SpO2-PiO2 curve
Timepoint [1] 297737 0
36 weeks post-menstrual age (PMA) or before discharge/transfer (if it occurs before 36 weeks PMA)
Secondary outcome [1] 322080 0
Correlation between plasma and salivary retinol levels (First 30 infants)
Timepoint [1] 322080 0
Day 28-30 of the study based on availability of the staff to process blood samples
Secondary outcome [2] 322082 0
Death
Timepoint [2] 322082 0
Home discharge or transfer to other hospital
Secondary outcome [3] 322084 0
Moderate to severe BPD (defined as need for supplemental oxygen at 36 weeks' postmenstrual age (Ehrenkranz et al, 2005)) - The outcome will be assessed prospectively using Shift test / Modified Walsh Oxygen Reduction Air Trial as per ANZNN protocol (http://anznn.net/Portals/0/DataDictionaries/ANZNN_Shift_Test_protocol_template.pdf accessed on 29/03/2016)
Timepoint [3] 322084 0
36 weeks post-menstrual age
Secondary outcome [4] 322085 0
Use of postnatal steroids for BPD before discharge to home (assessed by reviewing medical records and prospective data collection)
Timepoint [4] 322085 0
Home discharge or transfer to other hospital
Secondary outcome [5] 322086 0
Duration of supplemental oxygen for the infants who did not require supplemental oxygen at the discharge/transfer (assessed by reviewing medical records and prospective data collection)
Timepoint [5] 322086 0
Home discharge or transfer to other hospital
Secondary outcome [6] 322087 0
Number of infants discharged with home oxygen (assessed by reviewing medical records and prospective data collection)
Timepoint [6] 322087 0
Discharge to home
Secondary outcome [7] 322088 0
Days of positive pressure support [mechanical ventilation + continuous positive airway pressure (CPAP) + humidified high flow (HHF)] (assessed by reviewing medical records and prospective data collection)
Timepoint [7] 322088 0
Home discharge or transfer to other hospital
Secondary outcome [8] 322091 0
Weight gain in gram per day during the period of supplementation of the study medication (assessed by reviewing medical records and prospective data collection)
Timepoint [8] 322091 0
34 weeks PMA
Secondary outcome [9] 322093 0
Retinopathy of prematurity (ROP) requiring treatment in the form of laser ablation or bevacizumab injection (assessed by reviewing medical records and prospective data collection)
Timepoint [9] 322093 0
Discharge
Secondary outcome [10] 322094 0
Diagnosis of suspected and culture positive sepsis (Blood or cerebrospinal fluid) (assessed by reviewing medical records and prospective data collection)
Timepoint [10] 322094 0
Home discharge / transfer to other hospital
Secondary outcome [11] 322095 0
Grade 3 or 4 intraventricular haemorrhage (IVH) / periventricular leucomalacia (PVL) (Volpe 2008) (assessed by reviewing medical records and prospective data collection)
Timepoint [11] 322095 0
Day 7 and 28 of age brain ultrasound scans and MRI brain at 36-38 weeks PMA
Secondary outcome [12] 322096 0
Diagnosis of necrotizing enterocolitis (NEC) using Bell’s criteria 2a or more. (Bell 1978)
Timepoint [12] 322096 0
Home discharge / transfer to other hospital
Secondary outcome [13] 322097 0
Vitamin A adverse effects: Tense or bulging fontanelle, hepatomegaly, skin changes (by weekly physical examination)
Timepoint [13] 322097 0
Death / discharge home / transfer to other hospital
Secondary outcome [14] 322208 0
Correlation between plasma and salivary relative dose response (RDR) (First 30 infants)
Timepoint [14] 322208 0
Day 28-30 of the study based on availability of the staff to process blood samples
Secondary outcome [15] 396568 0
Faecal calprotectin after 28 days of vitamin A/placebo supplementation.
Timepoint [15] 396568 0
28 to 35 days
Secondary outcome [16] 396569 0
Plasma relative dose response at 34 weeks of post-menstrual age.
Timepoint [16] 396569 0
34 weeks post-menstrual age

Eligibility
Key inclusion criteria
Gestational age at birth less than 28 weeks and postnatal age less than 72 hours and Informed parental consent
Minimum age
No limit
Maximum age
72 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Congenital gastrointestinal and respiratory tracts abnormalities

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)
Sequentially labelled opaque sealed envelopes containing information regarding group allocation will be used to conceal allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be done by a hospital pharmacist using a computer generated random table.
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size: The normal SpO2: PiO2 curve in preterm infants without BPD is shifted to the right of the adult oxygen-haemoglobin dissociation curve by 6 kPa. In the preterm infants with BPD the mean shift (standard deviation) was 16.5 (4.7) kPa. (Quine 2006) For this pilot trial, we propose a 20 % improvement in the rightward shift in the treatment group compared with the control. Allowing for up to 20 % loss of the cohort at follow-up, the required sample size is 188 (94 in each group) (power 80 %, significance 5 %).

Statistical analysis: The data will be statistically analysed using SPSS statistical package (version 23.0, IBM Corporation and others, USA). The primary outcome of “right shift in the SpO2-PiO2 curve” is a continuous outcome and will be reported as mean +/- standard deviation for two groups. The two groups will be compared for the outcome using Student’s t test.
For other outcomes the groups will be compared using Mann-Whitney U test for continuous data if not normally distributed and Student’s t test if normally distributed and 'chi-squared' test for categorical data. Correlation between serum and salivary vitamin A levels, and blood and saliva RDR values will be tested using Pearson r correlation analysis. Bland-Altman analysis will be used to analyse agreement between two assays. A “p” value of <0.05 will be considered statistically significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/10/2016
Actual
19/12/2016
Date of last participant enrolment
Anticipated
29/03/2019
Actual
16/05/2019
Date of last data collection
Anticipated
Actual
10/02/2020
Sample size
Target
188
Accrual to date
Final
188
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 5478 0
King Edward Memorial Hospital - Subiaco
Recruitment postcode(s) [1] 12961 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 293173 0
Charities/Societies/Foundations
Name [1] 293173 0
Channel 7 Telethon Trust
Country [1] 293173 0
Australia
Primary sponsor type
Individual
Name
Abhijeet Rakshasbhuvankar
Address
Department of Neonatal Paediatrics
King Edward memorial Hospital
374 Bagot Road, Subiaco, WA 6008
Australia
Country
Australia
Secondary sponsor category [1] 291967 0
None
Name [1] 291967 0
Address [1] 291967 0
Country [1] 291967 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294664 0
Human Research Ethics Committee (King Edward Memorial Hospital)
Ethics committee address [1] 294664 0
374 Bagot Road, Subiaco, WA 6008
Ethics committee country [1] 294664 0
Australia
Date submitted for ethics approval [1] 294664 0
27/01/2016
Approval date [1] 294664 0
01/03/2016
Ethics approval number [1] 294664 0
2016028EW

Summary
Brief summary
Vitamin A is required for the development and growth of lungs in premature babies who are born with low vitamin A body stores. Supplementing premature babies with additional doses of vitamin A by intramuscular injections decreases bronchopulmonary dysplasia (BPD - a chronic lung disease related to premature birth). As intramuscular injections are painful, the supplementation has not been widely practiced. Oral vitamin A, especially fat soluble form, is poorly absorbed by premature babies and therefore may be less effective. This study aims to investigate if supplementation of water soluble form, which is better absorbed, to extremely premature babies decreases risk of BPD. As a part of the study we are also looking at if we can use saliva to assess vitamin A status instead of blood in the babies. .
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 57858 0
Dr Abhijeet Rakshasbhuvankar
Address 57858 0
Department of Neonatal Paediatrics, King Edward Memorial Hospital
374 Bagot Road, Subiaco, WA 6008
Country 57858 0
Australia
Phone 57858 0
+61864581260
Fax 57858 0
+61864581266
Email 57858 0
[email protected]
Contact person for public queries
Name 57859 0
Dr Abhijeet Rakshasbhuvankar
Address 57859 0
Department of Neonatal Paediatrics, King Edward Memorial Hospital
374 Bagot Road, Subiaco, WA 6008
Country 57859 0
Australia
Phone 57859 0
+61864581260
Fax 57859 0
+61864581266
Email 57859 0
[email protected]
Contact person for scientific queries
Name 57860 0
Dr Abhijeet Rakshasbhuvankar
Address 57860 0
Department of Neonatal Paediatrics, King Edward Memorial Hospital
374 Bagot Road, Subiaco, WA 6008
Country 57860 0
Australia
Phone 57860 0
+61864581260
Fax 57860 0
+61864581266
Email 57860 0
[email protected]

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 participant data, after de-identification, related to baseline clinical characteristics and clinical outcomes
When will data be available (start and end dates)?
From immediately after publication of the trial. No specific end date at this stage.
Available to whom?
Reviewers of IPD meta-analysis
Available for what types of analyses?
IPD (Individual Participant Data) meta-analysis
How or where can data be obtained?
After contacting the corresponding author with e-mail with a proposal.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Rakshasbhuvankar AA, Simmer K, Patole SK, Stoeckli... [More Details] 368700-(Uploaded-24-05-2021-17-31-15)-Journal results publication.docx

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEffect of Enteral Vitamin A on Fecal Calprotectin in Extremely Preterm Infants: A Nested Prospective Observational Study.2021https://dx.doi.org/10.1159/000518680
EmbaseSaliva for Assessing Vitamin A Status in Extremely Preterm Infants: A Diagnostic Study.2020https://dx.doi.org/10.1159/000506132
EmbaseEnteral vitamin A for reducing severity of bronchopulmonary dysplasia: A randomized trial.2021https://dx.doi.org/10.1542/PEDS.2020-009985
EmbaseEnteral vitamin A for reducing severity of bronchopulmonary dysplasia in extremely preterm infants: A randomised controlled trial.2017https://dx.doi.org/10.1186/s12887-017-0958-x
N.B. These documents automatically identified may not have been verified by the study sponsor.