Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000015640
Ethics application status
Approved
Date submitted
3/07/2022
Date registered
9/01/2023
Date last updated
7/04/2024
Date data sharing statement initially provided
9/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
PRECeDe Trial: Prevention of neonatal Respiratory distress with antenatal corticosteroids prior to Elective Caesarean section in women with Diabetes: a Randomised Controlled Trial
Scientific title
PRECeDe Trial: Prevention of neonatal Respiratory distress with antenatal corticosteroids prior to Elective Caesarean section in women with Diabetes: a Randomised Controlled Trial
Secondary ID [1] 307131 0
PRECeDe RCT
Universal Trial Number (UTN)
Trial acronym
PRECeDe
Linked study record

Health condition
Health condition(s) or problem(s) studied:
diabetes 326300 0
gestational diabetes 326301 0
neonatal respiratory distress 326302 0
transient tachypnoea of newborn 326303 0
caesarean section 326304 0
pregnancy 326305 0
neonatal hypoglycaemia 326306 0
Condition category
Condition code
Reproductive Health and Childbirth 323611 323611 0 0
Childbirth and postnatal care
Reproductive Health and Childbirth 323612 323612 0 0
Antenatal care
Reproductive Health and Childbirth 323613 323613 0 0
Complications of newborn
Reproductive Health and Childbirth 323614 323614 0 0
Breast feeding
Reproductive Health and Childbirth 323615 323615 0 0
Fetal medicine and complications of pregnancy
Respiratory 323616 323616 0 0
Other respiratory disorders / diseases
Metabolic and Endocrine 323617 323617 0 0
Diabetes
Surgery 323618 323618 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
11.4mg of Celestone Chronodose in 2ml (betamethasone 11.4mg as betamethasone sodium phosphate and betamethasone acetate)
2 injections will be administered intramuscularly, 24 hours apart, within 7 days prior to elective caesarean section, to participants randomised to receive investigational product.
Intervention code [1] 323587 0
Prevention
Intervention code [2] 323588 0
Treatment: Drugs
Comparator / control treatment
Normal saline in 2mls in an identical appearing syringe
2 injections will be administered intramuscularly, 24 hours apart, within 7 days prior to elective caesarean section, to participants randomised to receive the placebo
Control group
Placebo

Outcomes
Primary outcome [1] 331378 0
Neonatal respiratory distress, defined as requiring admission to the neonatal nursery and any form of respiratory support (e.g. intermittent positive pressure via an endotracheal tube, nasal continuous positive airway pressure (CPAP), Hi- or Lo-flow oxygen/air mixture, or increased ambient oxygen delivered into an incubator) for 60 minutes or more. Data will be collected from the medical record.
Timepoint [1] 331378 0
60 minutes after birth
Secondary outcome [1] 409660 0
Admission to neonatal nursery and length of stay. Data will be collected from the medical record and hospital administrative datasets.
Timepoint [1] 409660 0
Discharge from the neonatal nursery
Secondary outcome [2] 410441 0
Severity of respiratory distress (defined as maximum appropriate mean airway pressure [MAP] and maximum appropriate fractional inspired oxygen [FiO2] required to maintain oxygen saturations within the appropriate gestational range as measured by pulse oximetry.
Defined as a composite according to:
Mild: MAP <7.0 and / or FiO2 <0.40
Moderate: MAP 7.0-9.9 and / or FiO2 0.40 to 0.79
Severe: MAP >/=10.0 and / or FiO2 >0.80
Timepoint [2] 410441 0
Discharge from the neonatal nursery
Secondary outcome [3] 410442 0
Need for and duration of any form of respiratory support (defined as intermittent positive pressure via an endotracheal tube, CPAP, Hi- or Lo- flow oxygen / air mixture, or increased ambient oxygen delivered into an incubator (including therapy required for less than 60 minutes). Data will be collected from the medical record at the time of discharge from the nursery
Timepoint [3] 410442 0
Discharge from the neonatal nursery
Secondary outcome [4] 410443 0
Use of exogenous surfactant (prescribed and administered according to the hospital medication chart)
Timepoint [4] 410443 0
Discharge from the neonatal nursery
Secondary outcome [5] 410444 0
Pneumothorax or air leak detected on chest radiograph requiring drainage
Timepoint [5] 410444 0
Discharge from the neonatal nursery
Secondary outcome [6] 410445 0
Presence of x-ray features suggestive of hyaline membrane disease (independently adjudicated by a neonatal radiologist blinded to treatment allocation).
Timepoint [6] 410445 0
Discharge from the neonatal nursery
Secondary outcome [7] 410446 0
Neonatal hypoglycaemia defined as any blood glucose <2.6mmol/L
Timepoint [7] 410446 0
Discharge from hospital
Secondary outcome [8] 410447 0
Neonatal hypoglycaemia defined as a blood glucose concentration <2.6mmol/l requiring treatment other than feeding (including dextrose gel, intravenous dextrose, glucagon)
Timepoint [8] 410447 0
Discharge from hospital
Secondary outcome [9] 410448 0
Requirement for additional insulin therapy for the mother to maintain fasting capillary blood sugars below site specific targets following administration of investigational product prior to caesarean section (each participating site will establish their own criteria for management of maternal hyperglycaemia according to their standard practices for managing women with diabetes in pregnancy with the aim being to maintain euglycaemia). Participants will be provided with a paper or electronic diary to record all blood sugar levels following administration of investigational product. Participants will be instructed to contact relevant staff at their individual site for advice regarding the management of hyperglycaemia. Additional insulin doses will be recorded in the participant diary (paper or electronic). Paper diaries will be collected at the time of the caesarean section.
Timepoint [9] 410448 0
At the time of the caesarean section or prior to discharge from hospital.
Secondary outcome [10] 410461 0
Highest maternal blood glucose concentration recorded between randomisation and birth. Maternal blood sugars will be tested (by participants themselves) at least prior to every meal and 2 hours after every meal during this time.
Timepoint [10] 410461 0
At the time of caesarean section
Secondary outcome [11] 410462 0
Maternal infection from the time of randomisation up until 6 weeks postpartum including chorioamnionitis (defined as clinical signs of chorioamnionitis requiring intrapartum antibiotics); maternal pyrexia (38 degrees Celsius or higher); wound infection requiring antibiotic treatment; surgical or radiological intervention of wound collection. Data will be collected using an electronic study specific questionnaire
Timepoint [11] 410462 0
6 weeks post birth
Secondary outcome [12] 410463 0
Maternally reported side effects of antenatal corticosteroid or placebo injections (eg pain at injection site, nausea, headaches, changes in fetal movements), Side effects will be reported through the use of a study specific questionnaire sent to participants via email or text message. The questionnaire will include several side effects but participants will also be invited to document any additional side effects noticed.
Timepoint [12] 410463 0
At the time of the caesarean section or within the first 48 hours after the caesarean section.
Secondary outcome [13] 410464 0
Maternal mental health assessment using the Edinburgh Postnatal Depression Scale (EPDS)
Timepoint [13] 410464 0
Baseline at randomisation and then 6 weeks post birth
Secondary outcome [14] 410465 0
Maternal general health prior to randomisation and at 6 weeks post partum using the SF12 and AQoL 8D
Timepoint [14] 410465 0
Baseline at randomisation and then 6 weeks post partum
Secondary outcome [15] 410466 0
Breastfeeding rates at hospital discharge and 6 weeks post-partum based on maternal self report through a study specific survey. Data will be collected at hospital discharge from the discharge summary and via an electronic survey sent via email or text message to participants
Timepoint [15] 410466 0
At the time of neonatal discharge and at 6 weeks post birth.
Secondary outcome [16] 410467 0
Assessment of participant, treating clinical staff and research midwives prediction of treatment allocation. (This outcome data will only be collected if recruitment is considered to be slow according to milestones established by the Trial Steering committee at the commencement of recruitment)
Timepoint [16] 410467 0
Time of discharge of mother and / or infant from the hospital

Eligibility
Key inclusion criteria
Women with a singleton or twin pregnancy between 35+0 and 39+6 weeks gestation who have pre-gestational diabetes OR gestational diabetes (diagnosed on a pregnancy 75g Oral glucose tolerance test according to the WHO criteria for gestational diabetes OR the ADIPS revised criteria during the COVID pandemic)
AND
plan to give birth by planned caesarean section within the next 7 days.
Minimum age
16 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Known major fetal anomaly or chromosomal anomaly.
Administration of intramuscular antenatal corticosteroids for the purposes of fetal lung maturation at any stage during the current pregnancy.
Thrombocytopaenia with a platelet count below 80x109 /litre
Hypersensitivity to betamethasone sodium phosphate, betamethasone acetate, or other corticosteroids
received any corticosteroids at any time during the pregnancy
Systemic fungal infection
Contraindication to corticosteroids
Previous participation in the PRECeDe trial (in a previous pregnancy). Note that participation in the PRECeDe pilot Trial is not regarded as an exclusion from participation in the current trial).

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)
Central randomisation by internet / phone. A unique code will be generated. Pharmacy will dispense the appropriate medication according to the code and the randomisation sequence
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation generated by a computer with stratification according to:
Site
Type of Diabetes - Type 1 Diabetes, Type 2 Diabetes, Gestational Diabetes
Gestation at time of Caesarean - 35+0 to 36+6 weeks, 37+0 to 38+6 weeks, 30+0 to 39+6 weeks
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
Endocrinologists / obstetric medicine physicians or diabetes educators may be required to adjust insulin doses for both the Active and Placebo group of participants. Hyperglycaemia is a common side effect of betamethasone. These staff will remain blinded to the treatment allocation but may be able to identify treatment allocation based on the presence or absence of maternal hyperglycaemia. The staff involved in managing maternal hyperglycaemia will not be involved in the collection or interpretation of outcome data.

As described in the protocol, we will monitor the assessment of blinding by asking participants, clinical staff and research staff to record their prediction of the treatment allocation if recruitment to the trial is slower than anticipated. In the event that the double blind nature of the trial affects recruitment progress (through logistic / financial challenges in ensuring sufficient trial medication available at sufficient participating sites), an interim analysis will be conducted to assess the level of blinding that can be maintained. Where the Fleiss's Kappa denoting the correlation between either the participant, clinician or researcher's prediction of treatment allocation is above 0.41, the trial steering committee may recommend pivoting to an open label trial (ie without the use of a placebo). This modification has been pre-specified in the protocol.
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Outcomes will be compared between the intervention and control groups using an intention-to-treat analysis. For all binary outcomes the magnitude of the between-group differences will be quantified by fitting a logistic regression model to estimate the odds ratio (OR) and 95% confidence interval (CI) for the corresponding population OR, stratified by type of diabetes (Type 1 diabetes, Type 2 Diabetes, Gestational Diabetes), and gestation at planned elective CS. Linear regression will be used for non-categorical outcomes. For infant outcomes models will be fitted using Generalised Estimating Equations to allow for non-independence of outcomes among twins from the same pregnancy.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/02/2023
Actual
25/03/2024
Date of last participant enrolment
Anticipated
30/06/2027
Actual
Date of last data collection
Anticipated
31/08/2027
Actual
Sample size
Target
2200
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 22498 0
Joan Kirner Women’s and Children’s Hospital - St Albans
Recruitment hospital [2] 22675 0
The Royal Women's Hospital - Parkville
Recruitment hospital [3] 22677 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [4] 22678 0
Royal Hospital for Women - Randwick
Recruitment hospital [5] 22679 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [6] 22680 0
St George Hospital - Kogarah
Recruitment hospital [7] 22681 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [8] 22682 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [9] 22683 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [10] 22684 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 37733 0
3021 - St Albans
Recruitment postcode(s) [2] 37954 0
3052 - Parkville
Recruitment postcode(s) [3] 37956 0
3084 - Heidelberg
Recruitment postcode(s) [4] 37957 0
2031 - Randwick
Recruitment postcode(s) [5] 37958 0
4029 - Herston
Recruitment postcode(s) [6] 37959 0
2217 - Kogarah
Recruitment postcode(s) [7] 37960 0
4101 - South Brisbane
Recruitment postcode(s) [8] 37961 0
3168 - Clayton
Recruitment postcode(s) [9] 37962 0
5006 - North Adelaide
Recruitment postcode(s) [10] 37963 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 24764 0
New Zealand
State/province [1] 24764 0

Funding & Sponsors
Funding source category [1] 311435 0
Government body
Name [1] 311435 0
National Health & Medical Research Council
Country [1] 311435 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Grattan St
Parkville, VIC, 3052
Country
Australia
Secondary sponsor category [1] 312830 0
None
Name [1] 312830 0
Address [1] 312830 0
Country [1] 312830 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310913 0
Melbourne Health Research Ethics Committee
Ethics committee address [1] 310913 0
Ethics committee country [1] 310913 0
Australia
Date submitted for ethics approval [1] 310913 0
29/06/2022
Approval date [1] 310913 0
28/10/2022
Ethics approval number [1] 310913 0
HREC / 85882 / MH-2022.123

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

Contacts
Principal investigator
Name 119322 0
Prof Joanne Said
Address 119322 0
Maternal Fetal Medicine Unit
Joan Kirner Women's & Children's, Sunshine Hospital
176 Furlong Rd
St Albans, Victoria, 3021
Country 119322 0
Australia
Phone 119322 0
+61 3 90552400
Fax 119322 0
+61 3 9055 2165
Email 119322 0
[email protected]
Contact person for public queries
Name 119323 0
Joanne Said
Address 119323 0
Maternal Fetal Medicine Unit
Joan Kirner Women's & Children's, Sunshine Hospital
176 Furlong Rd
St Albans, Victoria, 3021
Country 119323 0
Australia
Phone 119323 0
+61 3 90552400
Fax 119323 0
+61 3 9055 2165
Email 119323 0
[email protected]
Contact person for scientific queries
Name 119324 0
Joanne Said
Address 119324 0
Maternal Fetal Medicine Unit
Joan Kirner Women's & Children's, Sunshine Hospital
176 Furlong Rd
St Albans, Victoria, 3021
Country 119324 0
Australia
Phone 119324 0
+61 3 90552400
Fax 119324 0
+61 3 9055 2165
Email 119324 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, deidentified participant data underlying published results will be available
When will data be available (start and end dates)?
Beginning 12 months after publication up until 5 years after publication
Available to whom?
Researchers who provide a methodologically sound proposal at the discretion of the Principal Investigator and Sponsor
Available for what types of analyses?
IPD Meta-analyses
How or where can data be obtained?
By request to the Principal Investigator (email [email protected])


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.