Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03008421 |
| Other study ID # |
1001-2017 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2018 |
| Est. completion date |
December 16, 2019 |
Study information
| Verified date |
February 2020 |
| Source |
Medical University of Vienna |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In the present study, the investigators aim to evaluate the potential of oral probiotics,
containing Lactobacillus strains, to eradicate and reduce the vaginal colonization with group
B Streptococcus (GBS) during pregnancy. This could help to prevent neonatal morbidity and
mortality by reducing the risk for neonatal sepsis, pneumonia, and meningitis, known as
early-onset or late-onset GBS infection.
Description:
The group B Streptococcus (GBS) or Streptococcus agalactiae is a gram-positive bacterium that
is present in 10-30% of the healthy female population (1). Throughout pregnancy and the
intrapartum period, maternal colonization with GBS can lead to the vertical transmission of
the bacterium to the infant. This can result in neonatal sepsis, pneumonia, and meningitis,
known as early-onset GBS infection, as well as in maternal urinary tract infections,
arthritis, and pneumonia (2). Various strategies were tested to prevent the GBS infection.
The antenatal GBS screening was successfully proven to identify colonized women, who should
receive the intrapartum antimicrobial prophylaxis. This strategy led to a substantial
reduction of the incidence of neonatal sepsis of almost 80% (3). As a result, the general use
of a GBS screening was then integrated in the US-American recommendations, since the
screening was superior to the risk-related procedure, when comparing the rates of early-onset
neonatal sepsis (4). Later on, the GBS screening also became part of the recommendations of a
European Consensus Conference (3).
The urogenital microflora of a healthy woman comprises approximately 50 species of organisms,
which differ in composition according to the exposure to several factors. The flora of
pregnant women is dominated by a variety of Lactobacillus species, which play an essential
role in protecting them from genital infections (5). A deficiency in lactobacilli can upset
the microbial balance in the vagina, which may result in an increased susceptibility for the
colonization with pathogens such as GBS (6). As demonstrated by Gardnerella vaginalis,
Lactobacillus strains can disrupt the biofilm of these pathogens in the in-vitro setting,
which inhibits their growth (7). This led to the use of probiotics to populate the vagina
with, in order to prevent or treat infections. The supplementation of probiotics that contain
Lactobacillus strains has later been proven to improve cure rates and prevent recurrent
infections (8).
At our Department, pregnancy care includes a prenatal consultation, where women register for
a planned delivery between 10 + 0 (10 weeks plus 0 days) and 16 + 0 (16 weeks plus 0 days)
gestational weeks. During this consultation, they undergo routine screening for asymptomatic
vaginal infections by the Gram-stained analysis of their vaginal flora (9). In case of a
vaginal infection, they undergo follow-up smears after 4-6 weeks. Routine pregnancy care is
performed at outpatient gynecologists' offices, following the Austrian government's welfare
program, documented in the official mother-child booklet. This national pregnancy care
program is used for the health precautions of women and their fetuses including obligatory
examinations at predetermined points (10). European guidelines recommend the antenatal
screening for the vaginal colonization with group B Streptococcus (GBS) between 35 + 0 and 37
+ 0 gestational weeks, which is performed on demand by the outpatient gynecologists, but not
routinely covered by social health insurance in Austria (3).
During the routine registration for delivery at our Department, women will be asked to
participate in our study. Assessment for eligibility will be performed in women with a (i)
singleton pregnancy, (ii) without imminent miscarriage, (iii) without having recently
undergone antibiotic or probiotic treatment. After informed consent, study participants will
be asked to present between 34 + 0 and 36 + 0 gestational weeks for their first study visit.
At this visit, a CDC-recommended combined vaginal-to-rectal swab will be taken from the
introitus vaginae and anorectum. The combined incubation is known to increase the detection
rate of GBS by up to 30% (11). Sterile swabs will be obtained after vaginal fluid collection
from the lateral vaginal wall and posterior fornix vaginae, followed by the insertion into
the anal sphincter. For the culture based method, they will be applied to a transport medium
and subsequently inoculated in the microbiological laboratory. After inoculation, a selective
enrichment broth will be used (TransVag Broth), followed by the incubation for 18 to 24
hours. That will be followed by a subculture using selective media for another 18 to 24
hours. If colonies are present, they will undergo extraction to determine if Group A or B
streptococcus is present (12, 13). The threshold for GBS positive results will be considered
as greater than 102 colony-forming units (CFU) per swab.
In case of a negative GBS screening result, women will be excluded from the study. In case of
a positive GBS screening result, women will be randomized to the verum or the placebo group.
The study will follow a prospective randomized placebo-controlled double-blinded mono-centric
design. Randomization will be performed using Randomizer® (Institute for Medical Informatics,
Statistics and Documentation, Medical University of Graz), which is a web-based patient
randomization service for clinical trials. Women who are assigned to the verum group will
receive a patented dietary supplement of four viable lactobacilli strains (HSO Health Care
GmbH, Vienna, Austria), containing Lactobacillus crispatus Lbv88, Lactobacillus rhamnosus
Lbv96, Lactobacillus jensenii Lbv116, and Lactobacillus gasseri Lbv150. This supplementation
was proven to transmigrate from the intestinal lumen into the vaginal area, acting in the
microbial ecosystem through a barrier effect against pathogenic microorganisms, so that
symptoms related to dysbiosis and recurrent infections can be relieved or even prevented
(14-16). Supplementation will include twice daily (morning/evening) oral intake for 14 days.
Women in the placebo group will receive an identical-looking oral potato-maltodextrin-based
placebo, which will also be given twice daily (morning/evening) for 14 days. Patients,
investigators, and microbiological staff will be blinded to the treatment assignment. The
composition of the study medication is as follows: L.crispatus Lbv88 (DSM 22566) 1 x 10^9
Guaranteed viable cell count (CFU/dose), L. rhamnosus Lbv96 (DSM 22560) 1 x 10^9 CFU/dose, L.
jensenii Lbv116 (DSM 22567) 0.2 x 10^9 CFU/dose, L. gasseri Lbv150N (DSM 22583) 0.3 x 10^9
CFU/dose, Potato maltodextrin, Insoluble dietary fibre, and Silicium dioxide.
From each participant, a consecutive vaginal swab will be taken during the second study visit
between 36 + 0 and 38 + 0 gestational weeks (i.e., 2 weeks after the first study visit).
Sterile swabs will be obtained and inoculated as previously described. In case of a positive
GBS screening result, (i) patients will be subsequently informed, and the result will be
documented in (ii) the mother-child booklet and (iii) the PIA Fetal Database, version
5.6.16.917 (General Electric Company, GE Viewpoint, Munich, Germany). This procedure is
necessary to ensure intrapartum penicillin treatment, which will follow current guidelines
and routine practice (2). During both study visits, a vaginal swab will also be taken to
perform Gram-stained analysis of the vaginal flora, in order to exclude women with acute
infections (i.e., bacterial vaginosis, trichomoniasis, candidiasis) at study visit 1, and to
gain further information on their flora.
The primary endpoint of our study will be the recovery to the GBS negative state. Secondary
endpoints will include (i) the rate of early-onset neonatal sepsis (postnatal age less than 7
days), (ii) the rate of late-onset neonatal sepsis (postnatal age at more than 7 days), (iii)
the gestational age at delivery, recorded as term delivery at or after 37 + 0 gestational
weeks, (iv) the rate of preterm delivery, defined as delivery at or before 36 + 6 gestational
weeks, (v) neonatal birthweight, defined as a the weight at the time of delivery, (vi) the
rate of live birth, defined as the term or preterm delivery of an infant that had an Apgar
score at 1 minute of > 0, and (vii) the mode of delivery (i.e., spontaneous vaginal birth,
cesarean section, or instrumental vaginal delivery).
Per day, approximately 10 patients undergo routine registration for delivery at our
department. All of them will be assessed for eligibility for the study. Approximately 60% of
these patients will present with a normal vaginal flora without infection, which would lead
to the number of 6/10 potentially eligible patients per day. A systematic review on the
prevalence of maternal GBS colonization in Europe reported rates ranging from 6.5% to 36%.
The carriage rates varied with Eastern Europe 19.7% to 29.3%, Western Europe 11% to 21%,
Scandinavia 24.3% to 36%, and Southern Europe 6.5% to 32% (17). The investigators therefore
conclude that the GBS colonization rates within our obstetric population will be
approximately 25%. This will lead to the number of 1.5/6 potentially eligible patients per
day, who could then be assigned to randomization.
The power for the present study was calculated using the dichotomized endpoint: recovery y/n.
(i.e., defined as GBS negative). For the sample size calculation, the investigators assume
that 43% of the women in the verum group will achieve the primary endpoint (i.e., recovery to
the GBS negative state). This calculation is based on previously published clinical and
preclinical data (18-20). The investigators expect a 18% recovery rate in the placebo group.
Under these assumptions, the Chi-Squared test at two-sided significance level α = 0.05 will
have 90% power to detect the group difference in a sample of N = 70 per group. With regard to
a drop-out rate of 10%, the investigators will therefore need to screen N = 1040 at study
visit 1, which would lead to 624/1040 (60%) patients without infection, of which 156/624
(25%) will be GBS-positive. Out of these, N = 78 per group will then be randomized, which
would lead to N = 70 per group after the estimated drop-out of 10%. The investigators will
need between 9-12 months to screen 1040 patients for study inclusion.
--
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