Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000104358
Ethics application status
Approved
Date submitted
20/08/2016
Date registered
18/01/2017
Date last updated
18/01/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Probiotics for rupture of the membranes to delay preterm birth (the Pro-PPROM trial)
Scientific title
Probiotics for women with preterm prelabour rupture of membranes (PPROM) to delay preterm birth: a randomised controlled trial
Secondary ID [1] 289983 0
None
Universal Trial Number (UTN)
N/A
Trial acronym
Pro-PPROM
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Preterm premature rupture of membranes (PPROM) 299988 0
Condition category
Condition code
Reproductive Health and Childbirth 299881 299881 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1 sachet (13mg) of probiotic 'Qiara' (Lactobacillus fermentum CECT5716) dissolved in water/juice/milk twice daily for the duration of the pregnancy.
Intervention code [1] 295678 0
Treatment: Other
Comparator / control treatment
Placebo in the form of maltodextrin (13mg) twice daily
Control group
Placebo

Outcomes
Primary outcome [1] 299359 0
The proportion of women undelivered at 7 days post PPROM onset which will be assessed by the review of medical records.
Timepoint [1] 299359 0
7 days post PPROM onset
Secondary outcome [1] 326921 0
Composite neonatal morbidity & mortality indicator including:
a) Respiratory distress syndrome (RDS)
b) Necrotising enterocolitis (NEC)
c) Neonatal sepsis
d) NICU/SCU admission
e) Hospital stay duration
f) Apgar score at 5 minutes
g) Intraventricular haemorrhage (IVH)
h) Perinatal death

All of these will be assessed by using the health record of the child.
Timepoint [1] 326921 0
At birth and during the peripartum period.
Secondary outcome [2] 326922 0
Maternal morbidity & mortality including the incidence of:
a) Antepartum/intrapartum haemorrhage
b) Intrapartum fever
c) Chorioamnionitis
d) Postpartum infection treatment with antibiotics
e) Mode of delivery
f) Maternal death

All of these will be assessed by using the health record of the mother.
Timepoint [2] 326922 0
At birth and in the peripartum period
Secondary outcome [3] 326955 0
Vaginal swab(s) PCR
- Assess for presence & quantity of Lactobacillus fermentum CECT5716 present in sample
- Assess the microbiome
Timepoint [3] 326955 0
Vaginal swabs at PPROM onset, 3 days post onset & at birth.
Secondary outcome [4] 326956 0
Meconium sample PCR
- Assess for presence & quantity of Lactobacillus fermentum CECT5716 (Qiara) present in sample
- Assess the microbiome
Timepoint [4] 326956 0
Meconium sample at birth
Secondary outcome [5] 326957 0
Placental basal plate PCR
- Assess for presence & quantity of Lactobacillus fermentum CECT5716 (Qiara) present in sample
- Assess the microbiome
Timepoint [5] 326957 0
Placental basal plate at birth

Eligibility
Key inclusion criteria
1. Pregnant women
2. Maternal age >18
3. Singleton pregnancy
4. PPROM defined as a history suggestive of spontaneous rupture of membranes followed by a sterile speculum examination demonstrating fluid pooling in the posterior fornix.
5. Gestational age less than 34 weeks
6. Ability to provide consent
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Maternal
1. Active chorioamnionitis
2. Patients in active labour
3. Multiple pregnancy
4. Hypertensive diseases of pregnancy

Neonatal
1. Evidence of foetal compromise
2. Known significant structural/chromosomal fetal anomaly
3. Known lethal congenital/structural malformation
4. Intrauterine death

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)
The study will be a randomized control trial with double blinding. Medications will be labelled using a unique trial identifier.

A computerised central randomisation service will be used.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Centralised randomisation service
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
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A sample size of 78 women (i.e. 39 women in each group) is required to demonstrate a 30% increase in the proportion of women with PPROM still pregnant after seven days (from 19.7% of women still pregnant after seven days to 25.6% of women still pregnant after seven days; mean latency 5.2 days, SD 11.9 days), with 80% power and two sided significance level of 0.05%. The sample size was calculated using latency data for women with PPROM at RNSH prior to 34 weeks’ gestation, collected as pilot data for the PPROMT trial.
Study groups will be compared with regard to their baseline characteristics. If significant differences are found, potential confounders will be adjusted for in the analysis of outcomes. Relative risks and 95% confidence intervals will be calculated for the outcome measure. If confounding factor adjustment is required, then logistic regression will be used. No subgroups analysis is planned.
Intention to treat analysis will be used on all data.

The analysis will be descriptive with the aim of estimating the parameters for sample size calculation in a large study. Data of patient drop out will not be included in the analysis.

With a categorical independent variable and a continuous dependent variable, the most appropriate test is a chi squared test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2017
Actual
Date of last participant enrolment
Anticipated
30/12/2018
Actual
Date of last data collection
Anticipated
30/12/2018
Actual
Sample size
Target
78
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 6509 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 6510 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [3] 6511 0
Royal Hospital for Women - Randwick
Recruitment hospital [4] 6513 0
Mater Sydney - North Sydney
Recruitment postcode(s) [1] 14073 0
2065 - St Leonards
Recruitment postcode(s) [2] 14074 0
2050 - Camperdown
Recruitment postcode(s) [3] 14075 0
2031 - Randwick
Recruitment postcode(s) [4] 14077 0
2060 - North Sydney

Funding & Sponsors
Funding source category [1] 294354 0
Charities/Societies/Foundations
Name [1] 294354 0
The Friends of the Mater Foundation
Country [1] 294354 0
Australia
Funding source category [2] 295225 0
Other Collaborative groups
Name [2] 295225 0
RANZCOG
Country [2] 295225 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney
Camperdown
2050 NSW
Country
Australia
Secondary sponsor category [1] 293193 0
Hospital
Name [1] 293193 0
Northern Sydney Local Health District
Address [1] 293193 0
Royal North Shore Hospital
Reserve Rd,
St Leonards
NSW 2065
Country [1] 293193 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295772 0
Northern Sydney Local Health District HREC
Ethics committee address [1] 295772 0
Kolling Institute of Medical Research
St Leonards
NSW
2065
Ethics committee country [1] 295772 0
Australia
Date submitted for ethics approval [1] 295772 0
29/08/2016
Approval date [1] 295772 0
05/12/2016
Ethics approval number [1] 295772 0
RESP/16/214

Summary
Brief summary
Preterm birth is a leading cause of death and long-term neurological disability for infants, with PPROM accounting for over one-third of preterm births. Apart from perinatal morbidity, there is also maternal morbidity from PPROM related to infection, such as chorioamnionitis. This trial aims to provide evidence demonstrating that probiotic therapy in women with PPROM prolongs pregnancy duration, thereby delaying preterm birth and improving neonatal outcomes. Delaying preterm birth will have a major impact on clinical practice and benefit the health of infants locally, nationally and internationally.

New molecular techniques using DNA sequencing methods are increasing knowledge and understanding of the organisms and microbiome of women with PPROM and preterm birth. Biospecimens collected in the pilot trial aim to demonstrate the change in the intrauterine and neonatal microbiome to provide more information on the beneficial effects of probiotics for women at risk of preterm birth. This will build on the emerging medical literature on the changes in the intrauterine and vaginal biomes of the pregnant woman and the gastrointestinal biome of the baby associated with preterm birth, antibiotics and probiotics. The changes in the maternal and neonatal biome for women with PPROM may assist in understanding the causation of PPROM and preterm birth.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes
N/A

Contacts
Principal investigator
Name 68430 0
Dr Sean Seeho
Address 68430 0
Royal North Shore Hospital
Reserve Road
St Leonards
2065 NSW
Country 68430 0
Australia
Phone 68430 0
+61412280591
Fax 68430 0
Email 68430 0
[email protected]
Contact person for public queries
Name 68431 0
Dr Jonathan Sandeford
Address 68431 0
Royal North Shore Hospital
Reserve Road
St Leonards
2065 NSW
Country 68431 0
Australia
Phone 68431 0
+61402568898
Fax 68431 0
Email 68431 0
[email protected]
Contact person for scientific queries
Name 68432 0
Dr Jonathan Sandeford
Address 68432 0
Royal North Shore Hospital
Reserve Road
St Leonards
2065 NSW
Country 68432 0
Australia
Phone 68432 0
+61402568898
Fax 68432 0
Email 68432 0
[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

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