治験レーダー

Knowledge gap: To date the focus of research on childhood stunting has been on the young child. It is increasingly appreciated, however, that stunting often begins in utero and the focus has shifted to women's health and pregnancy. Results from rural Bangladesh reveal poor gestational weight gain that ultimately leads to intrauterine growth restriction, low birth weight and ultimately stunting and wasting. Another study recently completed in slum settlements of Dhaka, Bangladesh demonstrated a high prevalence of EED among undernourished women. Intestinal histopathology was abnormal in more than 80% of women. We postulate that growth retardation in utero is a consequence of EED in the mother during pregnancy and lactation. This leads to systemic inflammation, which lead to disadvantageous partitioning of nutrients, and reduced nutrient availability.

Relevance: This trial will explore the conceptual framework that a probiotic or live biotherapeutic product that can improve the composition of gut microbiota, can also displace enteropathogens and reduce biomarkers of intestinal inflammation to promote gut health. This will restore healthy microbial signaling 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 colonized 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 in antenatal clinics and in the community in Matlab in Bangladesh, Bobo-Dioulasso in Burkina Faso, Matiari in Pakistan, and Lusaka in Zambia. 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 randomized into either 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 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 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.

As per WHO recommendations, participants in all 3 arms will receive Multiple Micronutrient Supplements (MMS) as part of routine antenatal care, which they will begin taking at enrollment and continue throughout pregnancy.

Blinding will be implemented for the comparison between the Treatment arm and the Placebo arm. However, it is not feasible to apply blinding to the Observation-only arm as the participants in this group will receive no intervention and the arm solely serves as an observational arm.

After the end of the intervention, pregnant women will be followed up until birth to record birth and pregnancy outcomes. Mother-infant dyads will be sampled 7 days after birth. Maternal and Infant health outcomes will be followed up to 1 month after childbirth to record clinical outcomes during this period.