Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001593325
Ethics application status
Approved
Date submitted
16/11/2017
Date registered
1/12/2017
Date last updated
29/02/2024
Date data sharing statement initially provided
4/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Preterm Birth Prevention Study - Treating vaginal infections to prevent prematurity
Scientific title
A prospective, open-label, single-centre/multi-site, randomized clinical trial of a novel maternal microbiological “screen & treat” program compared with normal care for the prevention of preterm birth.
Secondary ID [1] 293382 0
None.
Universal Trial Number (UTN)
U1111-1205-2546
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Preterm birth 305505 0
Condition category
Condition code
Reproductive Health and Childbirth 304754 304754 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Asymptomatic pregnant women will have a self-collected vaginal swab screened using our GLU microbial DNA assay (patent pending). Women who screen GLU+ve will receive oral azithromycin (250 mg for 7 days) and vaginal clindamycin cream (2%) for 7 days. Immediately following antimicrobial treatment, women will commence vaginal probiotic therapy with Canesflor (Bayer). Treatment consists of one vaginal capsule each night for six consecutive days, followed by one capsule per week for four weeks.

GLU +ve participants in the intervention group will be contacted by phone by study research midwives a few days after the medications are mailed out to ensure participants have obtained their prescription and check comprehension and compliance. Women in the intervention group will be asked to take another three vaginal swabs (two COPAN E-swabs and one COPAN UTM swab) at 22-28 weeks (after completion of the 5-week probiotic course) and mail them on the day of collection using a pre-addressed express post envelope to the lab for re-testing. One of the E-swabs will be analysed to evaluate treatment efficacy and the additional swabs will be frozen at -80 degrees C and evaluated by culture should GLU test analysis indicate treatment failure. The purpose of culture analysis will be to isolate the target organisms and ascertain antibiotic MIC values. Follow-up testing will not be conducted until the recruitment and delivery phase of the trial is complete, hence the results will not be provided to the women and will be of no relevance to their obstetric care as they will have already given birth to their child. A questionnaire on medication compliance and feedback will also be returned at the time of follow-up swab collection.

GLU -ve women will not receive any antimicrobial treatment and will continue to receive standard of care for the remainder of their pregnancy, same as in the control group.
Intervention code [1] 299633 0
Prevention
Intervention code [2] 299634 0
Treatment: Drugs
Intervention code [3] 299720 0
Early detection / Screening
Comparator / control treatment
Participants in the control group will not have the result of the screening test revealed to them or their physician during the study. They will continue to receive normal maternity care (including standard treatment options if symptoms of vaginal infection appear). They will not be notified of their allocation until after the recruitment and delivery stage of the study has been completed. A placebo will not be used as a) the placebo might itself impact upon vaginal microbiota and dysbiosis; b) knowledge of colonisation status might alter behaviour of participants; and c) this would depart from normal obstetric care, which is the primary comparator in this trial.
Control group
Active

Outcomes
Primary outcome [1] 303979 0
Spontaneous preterm birth rate <37 weeks in the intervention vs control group, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Timepoint [1] 303979 0
<37 weeks gestation.
Secondary outcome [1] 340606 0
Spontaneous preterm birth rate <34 weeks in the intervention vs control group, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Timepoint [1] 340606 0
<34 weeks gestation.
Secondary outcome [2] 340607 0
Spontaneous preterm birth rate <28 weeks in the intervention vs control group, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Timepoint [2] 340607 0
<28 weeks gestation.
Secondary outcome [3] 340608 0
Proportion of participants in each group with infant birthweight <2500gm, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Timepoint [3] 340608 0
Birthweight <2500gm at delivery.
Secondary outcome [4] 340609 0
Proportion of participants in each group with infant birthweight <1500gm, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Timepoint [4] 340609 0
Birthweight <1500gm at delivery.
Secondary outcome [5] 340610 0
Late miscarriage in the intervention vs control group, as assessed by review of participant medical records, based upon ultrasound confirmation.
Timepoint [5] 340610 0
Late miscarriage between 14-24 weeks gestation.
Secondary outcome [6] 340611 0
Preeclampsia in the intervention vs control group, as assessed by review of participant medical records, based upon blood pressure measurement, and urine/blood analyses for proteinuria and/or protein/creatinine ratio, respectively.
Timepoint [6] 340611 0
Preeclampsia between 14-37 weeks gestation.
Secondary outcome [7] 340612 0
Spontaneous preterm birth rate <37 weeks in GLU-positive women in the intervention vs. control group, as assessed by review of delivery outcome data obtained with consent from local hospital databases and in-house microbiological data (GLU test results) generated via real-time PCR.
Timepoint [7] 340612 0
<37 weeks gestation.
Secondary outcome [8] 340613 0
Preterm premature rupture of membranes in the intervention vs control group, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Timepoint [8] 340613 0
Preterm premature rupture of membranes between 14-37 weeks gestation.
Secondary outcome [9] 340614 0
Maternal mortality in the intervention vs. control group, as assessed by review of participant medical records.
Timepoint [9] 340614 0
Maternal mortality between 14-37 weeks gestation.
Secondary outcome [10] 340615 0
Maternal sepsis in the intervention vs. control group, as assessed by review of participant medical records.
Timepoint [10] 340615 0
Maternal sepsis between 14-37 weeks gestation.
Secondary outcome [11] 340616 0
Neonatal mortality in the intervention vs. control group, as assessed by review of delivery outcome data and infant medical records obtained with consent from local hospital databases.
Timepoint [11] 340616 0
Neonatal mortality within the first 90 days of life.
Secondary outcome [12] 340617 0
Early-onset neonatal sepsis in the intervention vs. control group, as assessed by review of delivery outcome data and infant medical records obtained with consent from local hospital databases.
Timepoint [12] 340617 0
Neonatal sepsis occuring within the first 72 hours of life.
Secondary outcome [13] 340618 0
Late-onset sepsis in the intervention vs. control group, as assessed by review of delivery outcome data and infant medical records obtained with consent from local hospital databases.
Timepoint [13] 340618 0
Neonatal sepsis occuring between 4-90 days of life.
Secondary outcome [14] 340619 0
NICU admission rates in the intervention vs. control group, as assessed by review of delivery outcome data and infant medical records obtained with consent from local hospital databases.
Timepoint [14] 340619 0
Overall NICU admission rates for neonates born to mothers enrolled in the study.
Secondary outcome [15] 340620 0
NICU admission duration in the intervention vs. control group, as assessed by review of delivery outcome data and infant medical records obtained with consent from local hospital databases.
Timepoint [15] 340620 0
Overall NICU admission duration (days) for neonates born to mothers enrolled in the study.
Secondary outcome [16] 340621 0
Composite neonatal morbidity (intraventricular hemorrhage, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, persistent pulmonary hypertension, hypotension requiring treatment, respiratory distress syndrome, and/or hyperbilirubinemia requiring treatment) in the intervention vs. control group, as assessed by review of delivery outcome data and infant medical records obtained with consent from local hospital databases.
Timepoint [16] 340621 0
Overall composite neonatal morbidity amongst neonates born to mothers enrolled in the study, assessed at two timepoints; Occuring within the first 72 hours of life, and occuring between 4-90 days of life.
Secondary outcome [17] 340622 0
Intrauterine growth restriction in the intervention vs. control group, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Timepoint [17] 340622 0
Intrauterine growth restriction between 14-37 weeks gestation.
Secondary outcome [18] 342041 0
Respiratory distress syndrome in the intervention vs. control group, as assessed by review of delivery outcome data and infant medical records obtained with consent from local hospital databases.
Timepoint [18] 342041 0
Respiratory distress syndrome between 18-37 weeks gestation.
Secondary outcome [19] 353193 0
Birthweight <1000gm at delivery.
Timepoint [19] 353193 0
Proportion of participants in each group with infant birthweight <1000gm, as assessed by review of delivery outcome data obtained with consent from local hospital databases.
Secondary outcome [20] 353194 0
Stillbirth in the intervention vs. control group, as assessed by review of participant medical records.
Timepoint [20] 353194 0
Stillbirth occuring after 20 weeks gestation.
Secondary outcome [21] 353195 0
Iatrogenic preterm birth in the intervention vs. control group, as assessed by review of participant medical records.
Timepoint [21] 353195 0
Iatrogenic preterm birth between 18-37 weeks gestation.
Secondary outcome [22] 353196 0
Histological chorioamnionitis in the intervention vs. control group, as assessed by review of participant medical records.
Timepoint [22] 353196 0
Histological chorioamnionitis at delivery.

Eligibility
Key inclusion criteria
Singleton pregnancy and ultrasound-confirmed gestation.
Minimum age
16 Years
Maximum age
60 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Multiple pregnancies, symptomatic vaginal infections, vaginal bleeding, rupture of membranes, active contractions, antimicrobial therapy within 14 days prior to recruitment.

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)
Allocation concealed by central randomisation via computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization to either the intervention or control arm will be performed by a customized software program that will randomly allocate treatment group while stratifying by nulliparity, history of PTB and study site (1:1 allocation ratio). The group allocations will be performed at the point of recruitment using a custom randomisation program on a Surface Pro tablet. Allocation bias will be avoided by randomizing participants before the outcome of the GLU testing procedure is known. In the event of any technical problems with the Surface Pro, randomisation will occur after sample collection using the same program on a PC in the research midwives office at the Women and Infants Research Foundation. In this case, research midwives will call participants to inform them which group they are in.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
One group of participants receives an intervention if they screen positive to a test. The second group of participants (control) receives standard of care regardless of the test result and are not aware of this result until the study has been completed.
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Based on the Western Australian 2015 singleton pregnancy PTB rate of 6.9%, assuming 70% of these are sPTBs (4.83% of all births), recruitment of 3087 women per group (6174 overall) will attain 80% power to detect a 30% reduction in the rate of sPTB in the intervention group - from 4.83% to 3.38% - when using a two-sided z-test of proportion at alpha=0.05; ~494 women per group are expected to screen positive. This sample size also allows for a single interim analysis with the O’Brien-Fleming spending function used to determine test boundaries (PASS Power Analysis and Sample Size Software, 2015). As the GA at delivery will be electronically extracted from medical records on all women, no adjustment has been made to account for loss to follow-up (NB: in our Predict1000 study the loss to follow-up was 2.5%).

Statistical analysis will be performed on an intention-to-treat principle, with a secondary assessment of treatment received based on swabs collected at 26-28 weeks GA. PTB outcomes between groups will be analysed using a z-test of proportions. Supplementary logistic regression analyses will be performed to examine group differences in sPTB rates and categorical secondary outcomes, while adjusting for the stratification factors and confounding due to maternal and/or pregnancy characteristics. Binary and nominal logistic regressions will be performed to evaluate the impact of the microbial risk factors used as screening criteria in the trial (PASS 2014). These regressions will also consider additional microbiological and immunological data, alone and together with maternal and pregnancy characteristics, to refine the risk factors for sPTB and derive risk equations for future implementation. All hypothesis tests will be two-sided with alpha=0.05.

Recruitment
Recruitment status
Suspended
Date of first participant enrolment
Anticipated
1/06/2018
Actual
22/10/2018
Date of last participant enrolment
Anticipated
31/12/2023
Actual
30/08/2023
Date of last data collection
Anticipated
30/09/2024
Actual
Sample size
Target
6174
Accrual to date
3000
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 9409 0
King Edward Memorial Hospital - Subiaco
Recruitment hospital [2] 14685 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [3] 23186 0
Armadale Kelmscott Memorial Hospital - Armadale
Recruitment hospital [4] 23187 0
Osborne Park Hospital - Stirling
Recruitment postcode(s) [1] 18111 0
6008 - Subiaco
Recruitment postcode(s) [2] 27719 0
6008 - Subiaco
Recruitment postcode(s) [3] 38552 0
6112 - Armadale
Recruitment postcode(s) [4] 38553 0
6021 - Stirling

Funding & Sponsors
Funding source category [1] 298008 0
Government body
Name [1] 298008 0
National Health and Medical Research Council
Country [1] 298008 0
Australia
Funding source category [2] 312286 0
Charities/Societies/Foundations
Name [2] 312286 0
Channel 7 Telethon Trust
Country [2] 312286 0
Australia
Funding source category [3] 312287 0
Charities/Societies/Foundations
Name [3] 312287 0
The Eastcourt Foundation
Country [3] 312287 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
35 Stirling Highway, Crawley, WA 6009.
Country
Australia
Secondary sponsor category [1] 298618 0
None
Name [1] 298618 0
Address [1] 298618 0
Country [1] 298618 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299044 0
Women and Newborn Health Service Human Research Ethics Committee
Ethics committee address [1] 299044 0
O Block, King Edward Memorial Hospital, Hensman Road, Subiaco, WA 6008.
Ethics committee country [1] 299044 0
Australia
Date submitted for ethics approval [1] 299044 0
05/12/2017
Approval date [1] 299044 0
07/02/2018
Ethics approval number [1] 299044 0
RGS0000000725
Ethics committee name [2] 304225 0
St John of God Health Care Human Research Ethics Committee
Ethics committee address [2] 304225 0
C/O St John of God Subiaco Hospital
12 Salvado Road
Subiaco Western Australia 6008
Ethics committee country [2] 304225 0
Australia
Date submitted for ethics approval [2] 304225 0
04/04/2019
Approval date [2] 304225 0
12/04/2019
Ethics approval number [2] 304225 0
1533

Summary
Brief summary
Preterm birth (PTB) is a major problem of global importance. Although it has been known for some time that PTBs at the very early gestational ages are often associated with intrauterine inflammation and infection, clinical strategies to treat the infection have largely been unsuccessful. This study aims to undertake a prospective, open-label, randomised clinical trial of a ‘screen and treat’ program aimed at preventing infection-driven spontaneous PTB (sPTB). The design is built upon an earlier European trial which achieved a 40% overall reduction in sPTB rate, and we have added improved efficacy in risk-identification and treatment strategies.

The single centre, multi-site study will recruit women with singleton pregnancies, asymptomatic for vaginal infection, attending antenatal clinics at 14-20 weeks’ gestation in two public hospitals within the Perth metropolitan area. A total of 6174 women will be recruited over a 2 year period, randomised after recruitment to either a control or intervention group (n=3087/group). Participants will self-collect a vaginal swab to be screened for microbial risk factors using a unique DNA-based assay. Participants in the control group will receive normal care and results of the tests will not available until after the pregnancy is completed. Intervention group participants will be informed of their result and mailed their antimicrobial therapy plus a vaginal probiotic to reduce relapse rates; re-screening will occur at 22-28 weeks’ to assess treatment efficacy.

The primary endpoint is reduction in sPTB <37 weeks’ gestation; secondary endpoints included additional delivery outcomes, maternal morbidities and neonatal mortality and morbidities. The trial is conservatively powered to detect a 30% reduction in overall sPTB rate from 4.83 to 3.38% (80% power, alpha=0.05). If this success were to be translated nationally, the reduction in number of PTBs each year would be approximately 4500 cases.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79098 0
Prof John Newnham
Address 79098 0
2nd Floor, Block A, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, WA 6008.
Country 79098 0
Australia
Phone 79098 0
+61 8 6458 1331
Fax 79098 0
+61 8 9381 3031
Email 79098 0
john.newnham@uwa.edu.au
Contact person for public queries
Name 79099 0
Dr Matthew Payne
Address 79099 0
University of Western Australia, 35 Stirling Highway, Crawley, WA 6009.
Country 79099 0
Australia
Phone 79099 0
+61 8 6488 7970
Fax 79099 0
Email 79099 0
matthew.payne@uwa.edu.au
Contact person for scientific queries
Name 79100 0
Dr Matthew Payne
Address 79100 0
University of Western Australia, 35 Stirling Highway, Crawley, WA 6009.
Country 79100 0
Australia
Phone 79100 0
+61 8 6488 7970
Fax 79100 0
Email 79100 0
matthew.payne@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results