Clinical trial NCT03407157: Oral Probiotic Supplementation in Pregnancy to Reduce Group B Streptococcus Colonization
Official title: Oral Probiotic Supplementation in Pregnancy to Reduce Group B Streptococcus Colonization
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Group B Streptococcus Carrier in Childbirth
Keywords: Probiotics
Pregnancy
GBS
Group B Streptococcus
Lead sponsor: University of British Columbia
Sponsor class: OTHER
Collaborators: name: Dublin City University
First posted: 2018-01-23
Enrollment: 168
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomisation will be centrally controlled using iSTAR, a web-based computerised randomisation platform at the BC Children's Hospital Research Institute, run by the PRE-EMPT (Pre-eclampsia Eclampsia Monitoring Prevention and Treatment) research group, UBC. PRE-EMPT will provide the randomisation platform, and web-linked drug supply management system. Randomisation will occur in random blocks of 2 and 4. Women will be randomised on a 1:1 ratio to probiotic:placebo.
Primary purpose: PREVENTION

Brief summary: This is a double-blind randomized placebo controlled trial that will investigate whether the use of three specific species of probiotics taken orally in pregnancy from 25 weeks gestation will reduce the incidence of Group B Streptococcus (GBS) colonization. Participants will take 2 capsules and 1 lozenge per day of either probiotic or placebo from 25 weeks gestation. The primary outcome will be the study-specific vaginal/rectal swab collected after 35 weeks gestation and before delivery. A reduction in women testing positive for GBS would lead to a decrease risk to infants of GBS infection and a reduction in the use of antibiotics leading to less maternal and neonatal antibiotic exposure.

Detailed description: Background:

Group B streptococcus (GBS) infection of the newborn is a leading cause of neonatal morbidity and mortality in North America. Up to 30% of pregnant women are colonized with GBS. Half of the babies born to colonized mothers will become colonized themselves, and of those, about 1-2% may develop early onset GBS infection (EOGBS), which is associated with significant mortality (between 5% and 20%) and morbidity (71% bacteremia, 11% meningitis, 19% pneumonia). The current recommendation is for routine administration of IPA to women who test positive for GBS at term. Although IPA therapy may reduce the incidence of neonatal GBS infection, it can increase the risk of other infections such as E. Coli, neonatal thrush, and ampicillin resistant Enterobacteriaceae.

There is also accumulating evidence linking antibiotics in pregnancy with childhood asthma, childhood obesity, and obesity in later life. IPA is also associated with antibiotic resistance, diarrhoea (including Clostridium difficile), and fungal infections. There is a growing worldwide interest in utilizing probiotics to enhance and manipulate the human microbiome in order to reduce a wide range of communicable and non-communicable diseases. Probiotics have been studied extensively in pregnant women and are considered safe and well tolerated when ingested or used vaginally.

Probiotics in pregnancy may reduce GBS colonization and the need for intrapartum antibiotic prophylaxis through a number of mechanisms. Some probiotics produce antibacterial substances and film-like barriers to pathogens. By adhering to vaginal epithelial cells, probiotics also displace pathogens such as GBS. S. salivarius K12 has been shown to inhibit several GBS strains, including disease-implicated isolates from newborns and colonizing isolates from the vaginal tract of pregnant women. In vivo and in vitro studies demonstrate its ability to adhere to the vaginal epithelium and directly impair the growth and adherence of GBS.

Several pilot randomized trials of L. reuteri and L. rhamnosus show promise in their their ability to reduce GBS colonization and have been shown to be safe. In vivo and in vitro studies of various lactobacillus strains, including rhamnosus and reuteri, have demonstrated an inhibitory effect on GBS.

Preliminary research to date suggests the administration of probiotic supplements to women in pregnancy may reduce the incidence of GBS colonization, thus reducing the need to administer intravenous prophylactic antibiotics (IPA) to women during labour. The specific species of probiotics chosen for this trial create a combination of inhibitory and antibacterial effects that may result in a greater reduction of GBS colonization than shown in previous trials.

The study:

The OPSiP study is a three-year, two-centre, double blind randomized placebo controlled trial. The aim of this study is to assess if a combined daily oral supplementation of Lactobacillus rhamnosus, Lactobacillus reuteri and Streptococcus salivarius beginning from 25 weeks gestation and continued until delivery will reduce vaginal/rectal group B streptococcus (GBS) colonization rates. Secondary aims include reduction of maternal and neonatal antibiotic exposure, and maternal vaginal and urinary tract infections.

450 healthy pregnant women receiving care from a regulated maternity care professional and registered at either St. Paul's or BC Women's Hospitals in Vancouver, British Columbia will be recruited. Women will be introduced to the study through posters and flyers and information from their maternity care provider. Women will be provided with verbal and written information on the study and provide written consent to participate before being entered into the study. Women will be entered into the study following initial screening to confirm their eligibility to participate in the study and then randomized to the intervention or control group.

Women randomized to the intervention group will receive a daily combination of one lozenge and two capsules of oral probiotic supplements comprised of three probiotic species; Lactobacillus rhamnosus and Lactobacillus reuteri (Urex Plus VCap-5) and Streptococcus salivarius K12 (Blis K12). The control arm will receive identical placebos administered using the same route and regimen as the active probiotic. Both groups will begin taking their daily study lozenges and capsules at 25 weeks gestation until delivery.

Five study-specific swabs will be collected, three vaginal/rectal and two oral swabs. The first vaginal/rectal swab and the first oral swab will be obtained at intake, after randomization and prior to the start of the intervention. The second vaginal/rectal swab will be obtained at mid-point, between 29-33 weeks gestational age. The third vaginal/rectal swab and second oral swab will be collected between 35 weeks and delivery.

The primary outcome will be vaginal/rectal GBS status, ascertained from the last study-specific vaginal/rectal swab. Statistical analysis will be on the basis of intention to treat. Treatment effect will be estimated using logistic regression. A two-tailed p-value \<0.05 will be considered significant.

Secondary analysis will be performed on last observation moving forward, protocol-compliant groups and with adjustment for care-provider type and use of other dietary probiotic sources.

Eligibility criteria: Inclusion Criteria:

* Pregnant with a singleton
* Gestational age between 23 and 25+0 weeks
* Over the age of 18
* Registered for delivery, at one of the participating centres
* Under the care of a regulated maternity care provider (midwife, obstetrician (OB), or family physician).

Exclusion Criteria:

* Unable to provide consent
* Fetus has known major anomalies
* Significant immunosuppression
* Type I or Type II diabetes (non-gestational)
* Previous infant with GBS (these women will automatically be advised to be treated with IV antibiotic therapy)
* GBS bacteriuria diagnosed in present pregnancy (reasoning as per above)
* Plans to use oral or vaginal probiotic supplementation/therapy (capsules/tablets/lozenges/drinks) during their pregnancy (outside of natural food sources; yogurt, kimchi, kombucha etc)
* Enrolled in another study that involves the administration of a drug/product

Primary outcomes:
measure: The primary outcome will be vaginal/rectal GBS colonization status at delivery
timeFrame: Last vaginal/rectal swab taken after 35 weeks gestation and prior to delivery
Secondary outcomes:
measure: Maternal antibiotic exposure
timeFrame: Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (6 weeks post-birth)
measure: Maternal urinary tract infections
timeFrame: Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (6 weeks post-birth)
measure: Maternal bacterial vaginosis infections
timeFrame: Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (6 weeks post-birth)
measure: Maternal vaginal candida infections
timeFrame: Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (4-6 weeks postpartum)
Other outcomes:
measure: Passage of probiotic strains to gastrointestinal tract and vaginal epithelium and adherence
timeFrame: Oral and vaginal/rectal swabs taken at 23-25 weeks, 29-33 weeks, and 35 weeks
measure: Adverse events
timeFrame: From the time of randomisation to 28 days of discontinuing the study supplements
measure: Gestational diabetes
timeFrame: Number of Participants with gestational diabetes recorded in chart review at 4-6 weeks postpartum
measure: Pre-term labour
timeFrame: Number of Participants with pre-term labour, recorded in chart review at 4-6 weeks postpartum
measure: Pre-term and pre-labour rupture of membranes
timeFrame: Number of Participants with pre-term and pre-labour rupture of membranes, recorded in chart review at 4-6 weeks postpartum
measure: Chorio-amnionitis
timeFrame: Number of Participants with chorio-amnionities, recorded in chart review at 4-6 weeks postpartum
measure: Maternal BMI
timeFrame: Chart review at 4-6 weeks postpartum
measure: Pre- and/or post-partum depression
timeFrame: Number of Participants with pre- and/or post-partum depression, recorded in chart review at 4-6 weeks postpartum
measure: Infant birth weight
timeFrame: Chart review at 4-6 weeks postpartum
measure: Infant APGAR scores at 1, 5 and 10 minutes after birth
timeFrame: Chart review at 4-6 weeks postpartum
measure: (Direct) infant exposure to antibiotics
timeFrame: Chart review at 4-6 weeks postpartum
measure: Admission of infant to Neonatal Intensive Care Unit (NICU)
timeFrame: Chart review at 4-6 weeks postpartum
measure: Early onset neonatal infections, including GBS
timeFrame: Chart review at 4-6 weeks postpartum
Locations:
city: Vancouver
country: Canada
facility: BC Women's Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
Study officials:
affiliation: Dublin City University
name: Michelle M Butler, PhD, RM
role: PRINCIPAL_INVESTIGATOR
affiliation: UBC School of Population and Public Health
name: Patricia Janssen, PhD
role: PRINCIPAL_INVESTIGATOR
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