Clinical trial NCT06196450: Maternal Probiotic Intervention to Improve Gut Health
Official title: Ability of the Probiotic Vivomixx to Improve Environmental Enteropathy in Pregnant Women: a Proof of Concept Trial in Bangladesh, Pakistan, Senegal and Zambia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Environmental Enteric Dysfunction
Gut Microbiota Dysbiosis
Keywords: probiotic
gut health
GWG
fetal growth
perinatal outcome
Lead sponsor: International Centre for Diarrhoeal Disease Research, Bangladesh
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2024-01-09
Enrollment: 76
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-site phase II randomised controlled trial (Proof of concept study)
Primary purpose: SUPPORTIVE_CARE

Brief summary: This trial will determine if a well-established probiotic, Vivomixx, can modulate maternal microbiota and ameliorate maternal environmental enteropathy which compromises growth in the first 1000 days. The probiotic Vivomixx has been used in many thousands of people including pregnant women, both within and outside a research context. This trial is the first in a proposed series of proof-of-concept intervention studies which are intended to provide data to enable a rational selection of interventions to be evaluated at scale in future large scale trials in which birth outcomes and postnatal growth will be key endpoints.

Detailed description: Stunting in young children refers to attenuated linear growth. In the year 2020, 149.2 million children under the age of 5 years of age were stunted, accounting for 22% of stunting globally. Stunting has short- and long-term consequences of increased morbidity and mortality, impairment of neurocognitive development, impaired responses to oral vaccines, and increased risk of noncommunicable diseases. Stunting is partly driven by Environmental Enteric Dysfunction (EED), an enteropathic condition characterised by altered gut permeability, infiltration of immune cells and changes in villous architecture and cell differentiation. EED may help explain why nutritional supplementation either during pregnancy or early childhood has minimal value in correcting childhood stunting. Indeed, EED is believed to be responsible for 40% of childhood stunting.

Disruption in intestinal barrier function affects gut immune homeostasis, nutrient flows, and consequently dysbiosis in the gut microbiome. The gut microbiota consists of 100 trillion bacteria which interact with epithelial cells, the mucus layer and the mucosal immune system that balances tolerance and effector functions. Thus, the gut microbiome has an important role in shaping the responsiveness of the gut immune system. The mucus barrier and the normal gut microbiota limit enteropathogen colonisation. Influx of bacteria from the lumen to the systemic circulation represents microbial translocation and initiation of systemic of inflammatory process through recognition of pathogenassociated molecular patterns (PAMPs) by Pattern Recognition Receptors (PRRs) present on Antigen Presenting Cells (APCs). Three fundamental processes drive the epithelial damage which is so important in EED: infection, undernutrition, and immune dysfunction. Multiple clinical trials show that efforts to correct malnutrition through conventional therapies and improving hygiene and sanitation do not overcome growth deficits by more than about 10%. There is increasing interest in the use of probiotics which may allow pathogen decolonization, improve barrier function and restore overall gut homeostasis. Such therapies are at early stage of trials but may have potential in addressing the global burden of EED, by improving barrier function and gut pathophysiology.

Colonization of gut by enteropathogens is common in children with EED. These include ETEC, Campylobacter, Shigella and Salmonella species. Consistent data from Bangladesh and Zambia show that children with refractory stunting carry over four pathogens on average, whilst controls carry less than two. There is also clear evidence of altered composition of the microbiota in children with EED.

Probiotics may serve to overcome the problem of EED through all mechanisms of pathogenicity, by providing additional bacteria that may help in intestinal decolonization of pathogenic microorganisms (changing the microbiological niche), promoting epithelial healing, improving nutrient absorption, and restoration of an appropriate immune balance between tolerance and responsiveness.

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. For example, the Lancet 2021 Series on maternal and child undernutrition states that "Investments to reduce undernutrition in women are important not only for women's own health but also for the health and nutrition of their children". Results from rural Bangladesh reveal poor gestational weight gain that ultimately leads to intrauterine growth restriction, low birth weight and ultimately stunting and wasting. Furthermore, 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 leads to disadvantageous partitioning of nutrients, and reduced nutrient availability.

This trial will explore the conceptual framework that a well-known probiotic, that can improve the composition of the gut microbiota, can also reduce biomarkers of intestinal inflammation and 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.

Eligibility criteria: Inclusion Criteria:

* Women aged 18 years or older in the first trimester or early second trimester of pregnancy, living in defined geographical areas of Bangladesh (Matlab), Pakistan, Senegal and Zambia, where it can be assumed that environmental enteropathy is universal

Exclusion Criteria:

* Potential participants will not be enrolled if they:

  * have had diarrhea, defined as the passage of three or more loose stools per 24 hours, in the preceding 14 days
  * have taken antibiotics or probiotics in the preceding 14 days
  * have taken steroids or non-steroidal anti-inflammatory drugs in the preceding 14 days
  * have severe pallor (hemoglobin concentration \<8g/dl)
  * have any chronic disease, illness or condition which in the opinion of the investigator will complicate the assessment of safety or efficacy
  * have any gastrointestinal contraindication to ingestion of a capsule (known or suspected gastrointestinal obstruction, stricture, fistula, gastroparesis, or any swallowing disorder)
  * have the plan to observe fast at any time during the intervention period
  * have the plan to leave the study area within the follow-up period
  * are included in any other intervention trial
  * belong to a household from which another woman is already enrolled in the study

but may be enrolled if/when these disqualifiers have expired

Primary outcomes:
measure: Percentage change (mean, unweighted) in a multiple panel of biomarkers between baseline and last sample collected after 56 days of treatment, compared to control group
timeFrame: 56 days
Secondary outcomes:
measure: Reduction in colonisation
timeFrame: 56 days
measure: Change in microbiome
timeFrame: 56 days
measure: Change in untargeted metabolome
timeFrame: 56 days
measure: Reduction in intestinal permeability
timeFrame: 56 days
measure: Change in weight gain velocity in the 2nd trimester of pregnancy
timeFrame: 14 weeks
Other outcomes:
measure: Recovery of useful data from CapScan
timeFrame: 56 days
measure: Diversity, centroids and distributions of microbial taxa from sequenced CapScan samples
timeFrame: 56 days
measure: Fetal growth
timeFrame: 6 months
measure: Stillbirth
timeFrame: At birth
measure: Neonatal death
timeFrame: From birith to 28 days after birth
measure: Preterm birth
timeFrame: At birth
measure: Apgar score
timeFrame: At birth
measure: Birth weight
timeFrame: At birth/7 days within birth
measure: Birth length
timeFrame: At birth/7 days within birth
measure: Birth head circumference
timeFrame: At birth/7 days within birth
measure: Low birth weight
timeFrame: At birth/7 days within birth
measure: Small for gestational age
timeFrame: At birth/7 days within birth
measure: Women's mental health
timeFrame: 2 years
measure: Women's postpartum weight loss/retention
timeFrame: 1 year
measure: Infant weight
timeFrame: 1 year
measure: Infant length
timeFrame: 1 year
measure: Infant morbidity
timeFrame: 1 year
Locations:
city: Chandpur
country: Bangladesh
facility: International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)
Study officials:
affiliation: Nutrition Research Division, icddr,b
name: S. M. Tafsir Hasan, MBBS, MS
role: PRINCIPAL_INVESTIGATOR
References: