Probiotic For the Improvement of Environmental Enteropathy in Pregnant Women in Senegal

Environmental Enteric Dysfunction Clinical Trial

— PROFE-Sen  

Official title:

Ability of the Probiotic Vivomixx to Improve Environmental Enteropathy in Pregnant Women: a Proof of Concept Trial in Senegal

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05501470
• Other study ID #: 2022-01
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: December 2022
• Est. completion date: October 2023

Study information

• Verified date: November 2022
• Source: Institut Pasteur de Dakar
• Contact: Ndeye D Drame, MPH
• Phone: +221 77551 35 42
• Email: ndeyedieynaba.drame[@]pasteur.sn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Stunting in young children refers to attenuated linear growth. In the year 2020, 149.2 million children under the age of 5 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 non-communicable 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. 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. This trial will explore the conceptual framework, that a well known probiotic, that can improve the composition of the gut microbiota, can 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.

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 development5 , impaired responses to oral vaccines, and increased risk of non-communicable 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 pathogen-associated 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 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. The primary objective of this trial is to determine if a probiotic, Vivomixx, can reduce inflammation and epithelial damage in pregnant women with environmental enteropathy in the target countries. The secondary objectives of this trial are: To determine if Vivomixx can reduce enteropathogen colonisation To determine if Vivomixx can impact the structure and function of the microbiome To determine if Vivomixx can reduce permeability. To determine if Vivomixx can impact the host metabolome in pregnant woman To evaluate variability in endpoints across geographies and participating laboratories.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 76
• Est. completion date: October 2023
• Est. primary completion date: April 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Women over the age of 18, living in Guediawaye district, Senegal

Exclusion Criteria:

• • 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 non-steroidal anti-inflammatory drugs in the preceding 14 days
• have any illness which in the opinion of the investigator will complicate 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 a plan to leave the study area within the follow-up period but may be enrolled if/when these disqualifiers have expired.

Related Conditions & MeSH terms

• Environmental Enteric Dysfunction
• Intestinal Diseases
• Probiotic

Intervention

Drug:
• VSL#3
VSL#3 (a mixture of Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii subspecies bulgaricus, Streptococcus salivarius subspecies thermophiles, Bifidobacterium breve, Bifidobacterium longum, and Bifidobacterium infantis), as VivomixxAll consenting participants will be randomized into the treatment to control arm, receiving either Vivomixx or a placebo for 8 weeks. During the study, women will visit the healthcare center on a weekly basis to receive sachets of Vivomixx or a placebo according to their trial arm.

Device:
• CapScan®
The only non-standard sample collection instrument is the CapScan® device. The CapScan Collection Capsule ("Capsule") is a non-invasive device that collects gastrointestinal samples along the GI tract that are then analyzed outside the body. Samples collected by the Capsule will be expressed, then undergo DNA sequencing and mass spectrometric analysis to determine the identity and function of the bacterial and host cells in the different regions of the GI tract and compared to similar analyses conducted on concomitantly collected stool samples.

Drug:
• Placebo
The placebo for the experimental drug VSL#3 (Vivomixx) is microcrystalline cellulose. It is similar in appearance to VSL#3.

Locations

Country	Name	City	State
Senegal	Centre de santé de Wakhinane	Guédiawaye	Dakar

Sponsors (5)

Lead Sponsor	Collaborator
Institut Pasteur de Dakar	Aga Khan University, Bill and Melinda Gates Foundation, International Centre for Diarrhoeal Disease Research, Bangladesh, University of Zambia

Country where clinical trial is conducted

Senegal, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	CapScan success rate in delivering an assessment of the microbiome	Recovery of useful data from CapScan; completion of whole gut microbiome profiles	Day 1 and Day 56
Primary	Change in inflammation and epithelial damage in pregnant women with environmental enteropathy	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.	Day 0 (screening) - Day 56
Secondary	Change in enteropathogen colonisation	Change in colonisation with specific enteropathogens (Salmonella, Shigella, Campylobacter, ETEC, EPEC, EAEC, rotavirus, norovirus, Giardia and Cryptosporidium), by qPCR, between baseline and last sample collected after 56 days of treatment, in Vivomixx compared to placebo groups	Day 1 - Day 56
Secondary	Impact on the structure and function of the microbiome	Change in microbiome at community and composition level (as measured by whole-genome shotgun metagenomic sequencing, post versus pre-intervention), in the intervention and placebo groups	Day 1 - Day 56
Secondary	Change in permeability	Change in LR ratio in Vivomixx compared to placebo groups	Day 1 - Day 56
Secondary	Impact of the host metabolome in pregnant woman	Change in metabolome, measured by Nuclear Magnetic Resonance (NMR) spectroscopy in faecal and CAPSCAN samples before and after intervention	Day 1 - Day 56
Secondary	Rate of weight gain in the 2nd trimester of pregnancy	Weight gain velocity in the 2nd trimester of pregnancy	Day 0 (screening) - Day 56
Secondary	Variability in endpoints across geographies and participating laboratories	Measurements of variability, including standard deviations and kappa values; Preliminary work across all sites using identical kits and harmonised SOPs	Beginning of recruitment in the first study site - end of recruitment in the last study site (approximately 12 months)