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Brain Probiotic and LC-PUFA Intervention for Optimum Early Life (BRAVE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03851120
Recruitment Status : Not yet recruiting
First Posted : February 22, 2019
Last Update Posted : February 25, 2019
Grand Challenges Canada
Information provided by (Responsible Party):
Rina Agustina, Indonesia University

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 early third semester of gestational period.

Condition or disease Intervention/treatment Phase
Maternal Exposure Health Behavior Infant Development Dietary Supplement: Probiotic and LC-PUFA Dietary Supplement: Placebo Behavioral: Psychosocial stimulation and healthy eating education Phase 2

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. The research will be conducted in eight public hospitals / health care facilities in Indonesia, Jakarta.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Combination product: Probiotics and LC-PUFA Product will be given to 400 pregnant women, 200 pregnant women as an intervention group and 200 pregnant women as a control group
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Participant, care provider, investigator, and outcomes assessor do not know which one is the intervention product or placebo.
Primary Purpose: Prevention
Official Title: Promotion of Maternal Gut Microbiota and Psychological Stimulation on Child Cognitive Development at 6 Months of Age
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2022

Arm Intervention/treatment
Experimental: Intervention
200 pregnant women will be given Probiotic and LC-PUFA, psychosocial stimulation, and healthy eating education
Dietary Supplement: Probiotic and LC-PUFA
Probiotic and LC-PUFA

Behavioral: Psychosocial stimulation and healthy eating education
Psychosocial stimulation and healthy eating education

Placebo Comparator: Control
200 pregnant women will be given placebo, psychosocial stimulation, and healthy eating education
Dietary Supplement: Placebo

Behavioral: Psychosocial stimulation and healthy eating education
Psychosocial stimulation and healthy eating education

Primary Outcome Measures :
  1. Total brain volume [ Time Frame: 1 year ]
    measured in parenchymal and cortical regions

  2. Fetal brain development [ Time Frame: 1 year ]
    Myelination index

  3. Child cognitive and brain function at 3 months of age [ Time Frame: 1 year ]
    Looking time (s) as a response to stimuli differentiation at 3 months of age

  4. Child cognitive at 6 months of age [ Time Frame: 1 month ]

  5. Brain function at 6 months of age [ Time Frame: 1 month ]

Secondary Outcome Measures :
  1. Mother depression scale [ Time Frame: 1 year ]
    Edinburgh Postnatal Depression Scale (EPDS)

  2. Cognitive development and brain function at 3-months of age [ Time Frame: 1 year ]
    Visual acuity

  3. Birth weight [ Time Frame: 1 month ]
    Baby weighing scale

  4. Child's Growth [ Time Frame: 6 months ]
    Change in weight-for-age z-score

  5. Child's linear growth [ Time Frame: 6 months ]
    Change in Length-for-age z-score

  6. Head circumference [ Time Frame: 6 months ]
    Change in Head-circumference-for-age

  7. Child nutritional status [ Time Frame: 6 months ]
    Change in weight-for-length z score

  8. Quality of interaction with parents [ Time Frame: 1 year ]
    Maternal involvement using HOME inventory questionnaires

  9. Maternal micronutrient status [ Time Frame: 1 year ]
    Zinc, iron, folate blood level

  10. Gestational diabetes [ Time Frame: 1 year ]
    Blood glucose

  11. Pre-eclampsia [ Time Frame: 1 year ]
    Diagnosed by doctor

  12. Preterm birth [ Time Frame: 1 year ]
    Gestational age

  13. Mother's dietary quality [ Time Frame: 1 year ]
    actual dietary intake, dietary pattern and quality

  14. Fecal microbiota composition [ Time Frame: 1 year ]
    Microbiota composition by S16rRNA analysis

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   20 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pregnant women
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03851120

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Contact: Rina Agustina, PhD +62 21 291 891 60 ext 201052
Contact: Rahyussalim Rahyussalim, PhD +62 21 291 891 60 ext 201908

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Human Nutrition Research Center, Indonesian Medical Education Research Institute; and Department of Nutrition, Faculty of Medicine, Universitas Indonesia Not yet recruiting
Jakarta Pusat, DKI Jakarta, Indonesia, 13420
Contact: Hanifa Hanifa, MBiomed    +622129189160 ext 201052   
Principal Investigator: Rina Agustina, MD, MSc, PhD         
Sub-Investigator: Ali Sungkar, MD,ObGyn,PhD         
Sponsors and Collaborators
Indonesia University
Grand Challenges Canada
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Principal Investigator: Rina Agustina, PhD Human Nutrition Research Center, IMERI; Dep of Nutrition, Fac.of Medicine UI

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
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

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Responsible Party: Rina Agustina, Principal Investigator, Indonesia University Identifier: NCT03851120     History of Changes
Other Study ID Numbers: BRAVE
First Posted: February 22, 2019    Key Record Dates
Last Update Posted: February 25, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No