Maternal Probiotic Intervention to Improve Gut Health-Trial II-Pakistan

ConditionsEnvironmental Enteric Dysfunction (EED)Stunting

Trial statusRecruiting

Trial phasePhase 2

Trial typeInterventional

Biological sexFemale

Age18-49

SponsorAga Khan University

About this trial

Burden: Environmental Enteric Dysfunction (EED) is an enteropathic condition characterised by altered gut permeability, infiltration of immune cells, and changes in villous architecture and cell differentiation. EED is a major reason of malnourishment, poor neurological development, stunting, oral vaccine failure, and infection. It is believed that EED is responsible for 40% of all childhood stunting.

Relevance: This trial aims to investigate the concept that a probiotic or live biotherapeutic product, capable of improving gut microbiota composition, can also displace enteropathogens and reduce biomarkers of intestinal inflammation, thereby promoting gut health. This will restore healthy microbial signalling to the host epithelium, ameliorate barrier function through secretion of mucus and antimicrobial factors, and improve nutrient availability.

Objectives: The primary objective is to assess if administration of oral vancomycin followed by VE818 to pregnant women colonised with at least 2 out of 11 selected bacterial enteropathogens results in a significant change in the mean count of these organisms between the baseline and 2 weeks after completion of the intervention (Study Day 35d +2), compared to oral vancomycin followed by placebo.

Methods: Pregnant women will be recruited from the community of Matiari in Pakistan. The study population will be women aged 18 years or older in the first trimester or early second trimester of pregnancy. Study procedures will be explained in detail, and written consent will be taken before enrollment. Those women who give consent to participation will undergo a screening process, which will check if any exclusion criteria are fulfilled. After consent and screening, they will be randomised into one of the three arms: intervention arm (oral vancomycin followed by VE818), placebo-control arm (oral vancomycin followed by placebo), or observation-only arm. The allocation sequence will be generated by the trial statistician using a code with block permutation. The participant will remain free to withdraw at any time from the trial without giving reasons and without prejudicing her further treatment. Biological samples, including blood, saliva, urine, stool, vaginal swab, and intestinal luminal contents through CapScan. CapScan is a non-invasive device (capsule) that collects gastrointestinal samples along the gastrointestinal tract following ingestion and passes into the stool.

Outcome measures/variables: The primary endpoint is the change in the mean count in the number of 11 selected fecal bacterial pathogen groups present between baseline and 2 weeks after completion of the 14-day course with Placebo or VE818 (Study arms 2 and 3), which corresponds to the 35th day, +2 from the first dose of oral vancomycin.

The 11 enteropathogen targets will be detected by customized real-time quantitative PCR-based TaqMan Array Cards (TAC-qPCR) and include the following organisms: Aeromonas, Campylobacter coli, Campylobacter jejuni, Campylobacter Pan, Enteroaggregative Escherichia coli (E. coli), Enteropathogenic E. coli, Enterotoxigenic E. coli, Plesiomonas, Shigella\_Enteroinvasive E. coli (EIEC), Salmonella, and Klebsiella pneumoniae

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Women aged 18 years or older in their first or early second trimester of pregnancy (13-17 weeks of gestational age [GA]), living in defined geographical areas of Bangladesh (Matlab), Pakistan, Zambia, and Burkina Faso, where it can be assumed that environmental enteropathy is prevalent

Presence of any 2 out of 11 selected bacterial pathogen targets (Aeromonas, Campylobacter coli, Campylobacter jejuni, Campylobacter Pan, Enteroaggregative Escherichia coli, Enteropathogenic Escherichia coli, Enterotoxigenic Escherichia coli, Plesiomonas, Shigella_EIEC, Salmonella and Klebsiella pneumoniae in fecal samples measured by TAC-qPCR.

Presence of any of the following WASH conditions -

use surface water, unimproved water, or limited water for drinking; OR

Disqualifiers

have MUAC ≥30 cm

are carrying more than one fetus (i.e., multiple pregnancy)

have diarrhea, defined as the passage of three or more loose stools per 24 hours, or have had diarrhea in the preceding 14 days

have fever or an active infection

Trial design

Design model

Parallel

Treatments tested in this trial

Oral Vancomycin
Drug
Oral vancomycin in capsule form will be administered three times daily for 5 days at 250mg per dose. Because oral vancomycin is a non-absorbable antibiotic, the likelihood of systemic absorption is minimal and therefore, it is not associated with the adverse events attributable to the intravenous formulation
VE818
Drug
VE818 is an 11-strain bacterial consortium rationally designed by Vedanta Biosciences Inc., to displace enteropathogens and reduce intestinal inflammation in pregnant women.
Placebo
Drug
Enteric capsules filled with approximately 400mg of microcrystalline cellulose (bulking agent)

Treatment groups

144 Participants

are divided into 3 treatment groups

Group A: Oral vancomycin + VE818Active comparator 2 interventions

Group B: Oral vancomycin + PlaceboPlacebo comparator 2 interventions

Group C: Observation only armNo intervention 0 interventions

Trial outcomes

Primary outcomes

Change in the Mean Count of 11 Selected Fecal Bacterial Pathogen Groups as Measured by TAC-qPCR between enrollment and 2 weeks after completion of the 14-day course with Placebo or VE818

The primary endpoint is the change in the mean count in the number of 11 selected fecal bacterial pathogen groups present between enrollment and 2 weeks after completion of the 14-day course with Placebo or VE818 (Study arms 2 and 3), which corresponds to 35th day, +2 from the first dose of oral vancomycin.

Time frame

Between enrollment and 2 weeks after completion of the 14-day course with Placebo or VE818

Secondary outcomes

Change in prevalence of specific enteropathogens not included in the primary endpoint in pregnant women as Measured by TAC-qPCR

Change in prevalence of specific enteropathogens (i.e., rotavirus, norovirus, Giardia, Cryptosporidium, and bacterial pathogens not included in the primary endpoint) in pregnant women detected in feces by TAC-qPCR between baseline (Day 0), end of oral vancomycin treatment (Day 6) the last dose of the 14-day VE818 intervention (21st day, +2), 14 days after the last dose of VE818 (35th day, +2), 42 days after the last dose of VE818 (63rd day, +2), and 7 day post-partum in the Treatment arm compared to Placebo arm and Observation-only arm.

Time frame

Enrollment, Day 6 (18 weeks gestation), Day 21, Day 35 (23 weeks gestation), Day 63 (28 weeks gestation), and 7 days post-partum.

Engraftment of VE818 strains in pregnant women as Measured by Shotgun Metagenomic Sequencing

Engraftment of VE818 strains in pregnant women as measured by shotgun metagenomic sequencing of fecal samples collected at the end of the 14-day VE818 intervention (21st day, +2), 14 days after the last dose of VE818 (35th day, +2), 42 days after the last dose of VE818 (63rd day, +2) and 7 days post-partum

Time frame

At Day 21, Day 35 (23 weeks gestation), Day 63 (28 weeks gestation), and 7 days post-partum.

Change from Enrollment in the Concentration of a Panel of Plasma Biomarkers as Measured by ELISA

Change in a panel of plasma biomarkers (CRP, AGP, sCD14, LBP, CD163 and iFABP) in pregnant women as measured by ELISA between baseline (Day 0), end of oral vancomycin treatment (Day 6), 14 days after the last dose the of 14-day intervention (35th day, +2) and, 42 days after the last dose of VE818 (63rd day, +2) in the Treatment arm compared to Placebo arm and Observation-only arm.

Time frame

At Enrollment, Day 6 (18 weeks gestation), Day 35 (23 weeks gestation), and Day 63 (28 weeks gestation).

Change from Enrollment in the Concentration of a Panel of Fecal Biomarkers as Measured by ELISA

Change in a panel of fecal biomarkers (myeloperoxidase, neopterin, calprotectin and lipocalin) in pregnant women as measured by ELISA between baseline (Day 0) , end of oral vancomycin treatment (Day 6), the last dose of the 14-day VE818 intervention (21st day, +2), 14 days after the last dose of VE818 (35th day, +2) 42 days after the last dose VE818 (63rd day, +2), and 7 day post-partum in the Treatment arm, compared to Placebo arm and Observation-only arm.

Time frame

At Enrollment, Day 6 (18 weeks gestation), Day 21, Day 35 (23 weeks gestation), Day 63 (28 weeks gestation), and 7 days post-partum

Other outcomes

Difference in the rate of weight gain during the second and third trimester of pregnancy

Difference in the rate of weight gain during the second and third trimester of pregnancy between Treatment arm and Placebo and Observation-only arms

Time frame

Second (13 to 28 weeks of gestation) and third trimester of pregnancy (28 to 40 weeks of gestation)

Difference in fetal growth trajectories

Difference in fetal growth trajectories as measured by serial ultrasound evaluation of intrauterine growth between Treatment arm and Placebo and Observation-only arms

Time frame

At gestational weeks 16, 20, 24, 28, 32, and 36

Difference in placental insufficiency

Difference in placental insufficiency as measured by ultrasound-derived cerebroplacental ratio (CPR) between Treatment arm and Placebo and Observation-only arms

Time frame

At gestational weeks 28, 32, and 36

Difference in placental stress

Difference in placental stress measured through sFlt-1/PlGF ratio between Treatment arm and Placebo and Observation-only arms

Time frame

First (up to 13 weeks of gestation), second (14 to 28 weeks of gestation), and third trimester of pregnancy (28 to 40 weeks of gestation)"

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Aga Khan University

Lead sponsor

Bill and Melinda Gates Foundation

Collaborator

International Centre for Diarrhoeal Disease Research, Bangladesh

Collaborator

University of Zambia

Collaborator

Institut Pasteur de Dakar

Collaborator

Source ClinicalTrials.gov

Apply now