Clinical trial NCT02272842: Vitamin B12, Neurodevelopment and Growth in Nepal
Official title: The Effect of Vitamin B12 Supplementation in Nepali Infants on Growth and Development
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Development
Vitamin Deficiency
Malnutrition
Keywords: Nepal
Cobalamin
Neurodevelopment
Stunting
Growth
Lead sponsor: Centre For International Health
Sponsor class: OTHER
Collaborators: name: Tribhuvan University, Nepal
name: NORCE Norwegian Research Centre AS
First posted: 2014-10-23
Enrollment: 600
Sex: ALL
Minimum age (years): 6
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Rationale: Globally, vitamin B12 deficiency is one of the most common micronutrient deficiencies. The only relevant source of Vitamin B12 is animal-source foods. Vitamin B12 is crucial for normal cell division and is necessary for brain growth as well as for the maintenance of its normal function. Deficiency is also associated with impaired growth. In a previous study, we demonstrated that vitamin B12 administration over a period of six months enhanced growth, and scores on a neuro-developmental test in young Indian children. However, the overall effect was small and, for the developmental scores significant only in those that were malnourished at the start of the study.

Our findings need to be verified in trials targeting younger, malnourished children and with longer supplementation time.

Hypothesis: This proposed study will test three hypotheses; to measure to what extent 2 recommended daily allowances (RDA) of vitamin B12 administration for one year to stunted children improves; 1) growth, 2) neurodevelopment, and 3) hemoglobin concentration.

Study design: Randomized placebo-controlled trial. Half of the children will receive a paste containing vitamin B12, the other half the same paste but without vitamin B12.

Study participants and site: 600 malnourished infants in Bhaktapur municipality in Nepal. In this population we have demonstrated that vitamin B12 deficiency and poor growth is common in early childhood.

Intervention: Daily administration of a paste containing vitamin B12 or placebo for 12 months

Data: The main outcomes of this study are scores on developmental assessments tools and growth measured every month for 12 months.

Detailed description: Scientific basis: Globally, vitamin B12 deficiency is one of the most common micronutrient deficiencies. The only relevant source of vitamin B12 is animal-source foods. Vitamin B12 is crucial for normal cell division and differentiation and is necessary for the development and initial myelination of the central nervous system as well as for the maintenance of its normal function. Deficiency is also associated with impaired infant and child growth.

In a previous clinical trial, we demonstrated that vitamin B12 administration over a period of six months enhanced growth and neurodevelopment in young Indian children. The overall effect on growth was significant but small. We saw an effect on both ponderal (weight for age z scores) and linear (height for age z scores) growth. However, the overall effects were driven by the effects in the subgroups of children who were wasted, underweight or stunted at baseline, and no effect in the children who were not malnourished at baseline. This effect modification was significant for all three (stunting, wasting, and underweight) baseline variables. Similarly, the effect of the intervention on neurodevelopmental scores was also strongest in the subgroup of children that were stunted.

We have for the last 15 years undertaken studies on dietary intake and status in women and children in Bhaktapur, Nepal. In this site, vitamin B12 deficiency is very common. The objective of the proposed study is to measure to what extent administration of 2 RDA of vitamin B12 to stunted children from the last half of infancy and for 12 months affect neurodevelopment, growth and hemoglobin concentration.

Hypothesis: Daily supplementation of 2 RDA of vitamin B12 in young Nepali children for 12 months improves neurodevelopment, growth and hemoglobin concentration.

Study design: Individually randomized placebo controlled, double blind trial. Children will be identified in the community and stunted children will be randomized to daily receive a paste containing vitamin B12 or a placebo paste. The paste will be delivered by trained field workers every day and by the caregivers on Saturdays and public holidays.

Study participants and site: 600 stunted children aged 6 to 11 months in Bhaktapur municipality and surrounding areas.

Intervention: Daily administration of a paste containing vitamin B12 or placebo for 12 months.

Comparator: Placebo, identical to the vitamin B12 supplements.

Data: Primary outcomes: (i) neurodevelopmental scores measured by Bayley Scales of Infant and Toddler Development 3rd edition and the Ages and Stages Questionnaire 3rd edition after 6 and 12 months of supplementation (ii) growth measured by change in height for age, weight for age and weight for height z-score from study start to end study and growth velocity z scores during the six first and six last months of supplementation (iii) hemoglobin concentration after 12 months of supplementation. Secondary: (i) cognitive development in children measured approximately 3 and 6 years after enrollment, (ii) linear and ponderal growth measured 2 and 3 years after enrollment, (iii) hemoglobin concentration measured 2 and 3 years after enrollment. All secondary outcomes require additional funding.

Relevance for programs and public health: Improved learning ability and growth in young malnourished children. If the supplementation is effective this will have consequences for dietary recommendation to malnourished children worldwide. In contrast to most other relevant nutritional interventions, vitamin B12 is inexpensive and our body has the ability to store vitamin B12, up to years. Thus, improving the status of this nutrient for a limited time period may have impact on learning and productivity beyond the time of administration and help to lift poor children out of the vicious cycle of poverty and malnutrition.

Eligibility criteria: Inclusion Criteria:

* Age 6 to 11 months
* Stunted
* Availability of informed verbal consent
* Plan to reside in the area for the next 12 months

Exclusion Criteria:

* Severe systemic illness requiring hospitalization
* Severe malnutrition, i.e. weight for height \< -3 z of the WHO standard for this age group. For ethical reasons these children require micronutrient supplementation and adequate medical care.
* Lack of consent
* Taking B vitamin supplements that include vitamin B12.
* Severe anemia (Hb \< 7 g/dL). This would be a temporary exclusion and the children will be enrolled if they are successfully treated.
* Ongoing acute infection with fever or infection that requires medical treatment. This would be a temporary exclusion and the children will be enrolled after recovery.

Primary outcomes:
measure: The Bayley Scales of Infant Development Version 3
timeFrame: 12 months
measure: Hemoglobin Concentration
timeFrame: 12 months
Secondary outcomes:
measure: Growth Velocity Over the First Six Months of Supplementation
timeFrame: 12 months
measure: Predictors for Neurodevelopment in Young Nepali Children
timeFrame: 12 months
measure: Identify Subgroups of Children Who Benefit From Vitamin B12 Supplementation
timeFrame: 12 months
measure: The Effect of Vitamin B12 Supplementation on Markers of Vitamin B Status
timeFrame: 12 months
measure: Neurodevelopment Measured by Other Tools.
timeFrame: 12 months
measure: Immediate Adverse Effects of the Intervention
timeFrame: 12 months
measure: Leucocyte Telomere Length
timeFrame: 12 months
measure: Sleep Duration
timeFrame: 12 months
Other outcomes:
measure: Extended Followup: Neurodevelopment (IQ)
timeFrame: 3 years
measure: Surrogate Markers for Neurodevelopment
timeFrame: 2 years
Locations:
city: Bhaktapur
country: Nepal
facility: Siddhi Memorial Hospital (SMH),Bhelukhel, Bhimsensthan
Study officials:
affiliation: Tribhuvan University, Nepal
name: Prakash S Shrestha, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Innlandet Hospital Trust / University of Bergen
name: Tor A Strand, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Strand TA, Ulak M, Hysing M, Ranjitkar S, Kvestad I, Shrestha M, Ueland PM, McCann A, Shrestha PS, Shrestha LS, Chandyo RK. Effects of vitamin B12 supplementation on neurodevelopment and growth in Nepalese Infants: A randomized controlled trial. PLoS Med. 2020 Dec 1;17(12):e1003430. doi: 10.1371/journal.pmed.1003430. eCollection 2020 Dec.
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