Clinical trial NCT03851120: Brain Probiotic and LC-PUFA Intervention for Optimum Early Life
Official title: Promotion of Maternal Gut Microbiota and Psychological Stimulation on Child Cognitive Development at 6 Months of Age
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Maternal Exposure
Health Behavior
Infant Development
Child Development
Lead sponsor: Indonesia University
Sponsor class: OTHER
Collaborators: name: Grand Challenges Canada
First posted: 2019-02-22
Enrollment: 314
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Combination product: Probiotics and LC-PUFA The product will be given to 314 pregnant women, 157 pregnant women as an intervention group, and 157 pregnant women as a control group
Primary purpose: PREVENTION

Brief summary: Probiotics is suggested to play several roles in promoting health, including alleviating disease symptoms, protection against atopic disease, and modulating the immune system by improving the beneficial gut microbiota colonization. The discovery of the gut microbiota-brain axis suggested that there is a reciprocal influence between the brain and the gut through a constant communication. This bi-directional axis enables signals to be transferred from brain to influence sensory, motor, and secretory modalities of the GI tract, also permits signal from the gut to influence brain function. The establishment of intestinal microbiota during early neurodevelopmental period suggests the colonization and maturation of gut microbiota may influence brain development. Several studies have shown there is an association between shifts in the gut microbiota composition in children with neurodevelopmental disorders. This study aims to investigate how maternal probiotic + LC-PUFA supported with government program supplements, healthy eating, and psychosocial stimulation could affect fetal brain development and later child brain functions and cognitive development. Intervention would be delivered to pregnant women for 9 months, starting at the end of second trimester of gestational period.

Detailed description: Health and well-being at all ages is one of the goal set in the Sustainable Development Goals. Starting as early as possible has been considered to be an effective strategy for better investation in achieving healthy population. Therefore, the prevention and promotion of health and well being is starting to target population at younger age, starting as early as possible. Accordingly, the early life period of individuals has been considered as a critical period, especially in terms of the brain and cognitive development. The phases of brain development starts very early, starting from the fetal development in the uterus. The development process extends from early in the beginning of fetal development and lasted to the end, finishing last. The brain undergoes a period of rapid growth during the last trimester of fetal life and the first 2 years of childhood. Therefore, quality of pregnancy as well as quality of early life is important to the fetal brain development as well as later child brain function and cognitive development. In line with that notion, there are many studies suggesting that gut microbiota could affect CNS development through several ways, i.e. alteration of microbial composition, activation of immune system, changes in signaling via neural pathways, affecting tryptophan metabolism, modulating gut hormonal response and affecting hormonal signaling pathway, and releasing metabolites that could stimulate sympathetic nervous system. In particular, these studies have found bi-directional communication between the brain and the gut microbiota, referred to as the microbiota-gut-brain axis. The animal study showed that the gut microbiota regulates the development and function of the brain. Unfortunately, the study on human was still lacking.

This study is a randomized clinical trial (RCT) and placebo parallel controlled study, followed by a follow-up study at 2 years old. The research will be conducted in eight public hospitals / health care facilities in Indonesia, Jakarta.

In light of COVID-19 outbreak, if face-to-face activities are permitted by (1) national government (Indonesian Ministry of Health), (2) local government (DKI Jakarta), (3) the university, (4) Data Safety Monitoring Board, and (5) by consent of the subject, then the activities need to be strictly adjusted with the COVID-19 prevention measures for both personnel and subjects. All personnel and subjects who will be involved in the activities are required to fill out the COVID-19 symptom screening form prior to the visit.

Some adjustments for the project field implementation have been conducted during the outbreak, including:

1. Following Good Clinical Practice, for the safety of the subjects and all the team members, we are now ensuring that the subjects gain benefits from their involvement in the BRAVE project by implementing routine COVID-19 screening, providing adequate PPE for the fieldworkers, and educating them about the prevention measures.
2. Supplement delivery: Because we could not visit to the houses anymore due to staff restriction regulations, the bottles of the supplement are delivered using online motorcycle taxi services, and this includes the weighing scale for monthly monitoring. We have also developed a protocol to ensure the safety of supplement bottle transfer from the research personnel to the motorcycle taxi driver, and from the driver to the mothers, including safe distancing and disinfection procedures. We will also educate, provide a thermometer for self-temperature screening and provide the disinfectant to the mothers.
3. Outcome assessment: As per March 19, MRI assessment and blood sample collection remained implemented at a non-COVID-19 referral hospital and laboratory, with strict safety procedures for the subjects and personnel. For mothers who do not feel comfortable visiting the hospital/laboratory, they are free to refuse these procedures.
4. Compliance: Online system to promote and assess compliance. To maintain the quality, we cross-check mothers' activities by online assessment, interactive short message service (sms), and phone calls.
5. New Subject Recruitment are less priority right now or potentially stop for the time being until the situation is getting better.

Eligibility criteria: Inclusion Criteria:

Each pregnant woman must meet all of the following criteria to be enrolled in this study:

1. Indonesian pregnant women in the 2nd trimester of gestational period 2. healthy pregnancy (as measured by hemoglobin level, pregnancy status, pregnancy history) 3. Having a normal blood pressure 4. Planning to stay in the study area until the child is 6 months old 5. Willing to sign informed consent 5. Having a legally acceptable representative who is capable to understand the informed consent document and providing consent on the subject's behalf

Exclusion Criteria:

Each pregnant women meeting any of the following criteria will be excluded from the study:

1. Having foreign objects in the body due to trauma, artificial heart value, metal objects or ferromagnetic (plate, screw, clip, prosthetic), and electronic device (pacemaker, cochlear implant, insulin pump), and being claustrophobic
2. Having history of previous gestational diabetes or been diagnosed to have gestational diabetes
3. Having history of type 1 and type 2 diabetes
4. Severe anemia

Inclusion Criteria for Follow-up at 24 months:

1. Child age above 24 months from the BRAVE intervention project
2. Having a legally acceptable representative who is capable to understand the informed consent document and providing consent on the subject's behalf

Exclusion Criteria for Follow-up at 24 months:

1. Child being hospitalized during the study/data collection

Primary outcomes:
measure: Total brain volume
timeFrame: 1 year
measure: Fetal brain development
timeFrame: 1 year
measure: Child cognitive at 4 months of age
timeFrame: 1 year
measure: Brain function at 4 months of age
timeFrame: 1 year
measure: Eye tracking tasks at 6 months of age
timeFrame: 1 year
measure: Child cognitive at 6 months of age
timeFrame: 1 year
Secondary outcomes:
measure: Mother depression scale
timeFrame: 1 year
measure: Birth weight
timeFrame: 4 month
measure: Child's Growth
timeFrame: 6 months
measure: Child's linear growth
timeFrame: 6 months
measure: Head circumference
timeFrame: 6 months
measure: Child nutritional status
timeFrame: 6 months
measure: Quality of interaction with parents
timeFrame: 1 year
measure: Maternal blood micronutrient & macronutrient status
timeFrame: 1 year
measure: Incidence of gestational diabetes
timeFrame: 1 year
measure: Incidence of pre-eclampsia
timeFrame: 1 year
measure: Incidence of preterm birth
timeFrame: 4 month
measure: Mother's dietary quality
timeFrame: 1 year
measure: Maternal fecal microbiota composition
timeFrame: 1 year
measure: Child fecal microbiota composition
timeFrame: 4 months
measure: Maternal omega-3 level in breast milk at 4 months of age
timeFrame: 1 year
measure: Human milk oligosaccharides at 6 months of age
timeFrame: 1 year
measure: Maternal glucagon-like peptide-1 (GLP-1) profile
timeFrame: 1 year
measure: Maternal peptide-YY (PYY) profile
timeFrame: 1 year
measure: Maternal fecal short chain fatty acids (SCFAs)
timeFrame: 1 year
measure: Child fecal short chain fatty acids
timeFrame: 1 year
measure: Post-partum weight retention
timeFrame: 1 year
measure: Maternal weight circumference
timeFrame: 1 year
measure: Gestational weight gain
timeFrame: 1 year
measure: Head circumference
timeFrame: 25 months
measure: Mid-Upper Arm Circumference
timeFrame: 25 months
measure: Toddler Body Weight
timeFrame: 25 months
measure: Toddler Height
timeFrame: 25 months
measure: Mother Body weight
timeFrame: 1 year
measure: Mother Depression Test
timeFrame: 1 year
measure: Mother Quality of Life
timeFrame: 1 year
measure: Maternal History of COVID-19 during follow-up
timeFrame: 2 years
measure: Maternal Occurrence of COVID-19 during intervention period
timeFrame: 1 year
measure: Child cognitive at 25-28 months of age
timeFrame: 1 year
measure: Eye tracking tasks at 25-28 months of age
timeFrame: 1 year
measure: Mother Height
timeFrame: 1 year
measure: Mother Fat Percentage
timeFrame: 1 year
Other outcomes:
Locations:
city: Jakarta Pusat
country: Indonesia
facility: Human Nutrition Research Center, Indonesian Medical Education Research Institute; and Department of Nutrition, Faculty of Medicine, Universitas Indonesia
state: DKI Jakarta
Study officials:
affiliation: Human Nutrition Research Center, IMERI; Dep of Nutrition, Fac.of Medicine UI
name: Rina Agustina, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sheridan PO, Bindels LB, Saulnier DM, Reid G, Nova E, Holmgren K, O'Toole PW, Bunn J, Delzenne N, Scott KP. Can prebiotics and probiotics improve therapeutic outcomes for undernourished individuals? Gut Microbes. 2014 Jan-Feb;5(1):74-82. doi: 10.4161/gmic.27252. Epub 2013 Dec 16.
citation: Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. The Central Nervous System and the Gut Microbiome. Cell. 2016 Nov 3;167(4):915-932. doi: 10.1016/j.cell.2016.10.027.
citation: Naaktgeboren, C. Effect of maternal probiotic exposure during pregnancy and lactation on the mother and infant. International Journal of Probiotics and Prebiotics 5: 113-124, 2010
citation: Ramakrishnan, U. A review of the benefits of nutrients supplements during pregnancy: from iron -folic-acid to long-chain polyunsaturated fatty acids to probiotics. Annales Nestle (English Ed): 29-40, 2010