Vitamin B12, Neurodevelopment and Growth in Nepal

Phase 2

Active, not recruiting

Conditions: Development
Vitamin Deficiency
Malnutrition

Interventions: Dietary Supplement: Vitamin B12

Registration Number: NCT02272842

Lead Sponsor: Centre For International Health

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 600

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vitamin B12	Vitamin B12	A paste containing vitamin B12 2µg per 10 mL administered every day. The paste also contains 1 RDA of several other vitamins. The paste is produced by Compact (Norway / India)
Placebo	Vitamin B12	A paste containing no vitamin administered every day. The paste also contains 1 RDA of several vitamins, but no vitamin B12. The paste is produced by Compact (Norway / India)

Primary Outcome Measures

Name	Time	Method
The Bayley Scales of Infant Development Version 3	12 months	Cognitive, Fine Motor, Gross Motor, Receptive language, and Expressive language scaled scores of the Bayley Scales of Infant Development version 3. This scale measures different aspects of neurodevelopment. The mean (SD) scores are usually 100 (15), and 95% of the population has scores between 70 and 130 (theoretical max/means 0/200). The higher scores, the better neurodevelopment; the scale is normalized on age.
Hemoglobin Concentration	12 months	Change in hemoglobin concentration from baseline to end study.

Secondary Outcome Measures

Name	Time	Method
Identify Subgroups of Children Who Benefit From Vitamin B12 Supplementation	12 months	Based on selected baseline variables we will identify subgroups who benefit from vitamin B12 supplementation
The Effect of Vitamin B12 Supplementation on Markers of Vitamin B Status	12 months	We will draw a blood sample at study start and at end study to measure to what extent vitamin status is altered.
Immediate Adverse Effects of the Intervention	12 months	We will investigate side effects such as pain, nausea, vomiting, regurgitation, allergic reactions and others after each dose of the intervention.
Sleep Duration	12 months	Using actigraph and a structured questionaire on all children at baseline and at end of study measure the extent to which the intervention affects sleep.
Growth Velocity Over the First Six Months of Supplementation	12 months	length and weight growth velocity z scores during supplementation z-scores, growth velocity. theoretical values -10 to 10 The higher the value, the faster the growth.
Predictors for Neurodevelopment in Young Nepali Children	12 months	Using the collected data, identify morbidity, stimulation, nutrition, socioeconomic related predictors for neurodevelopment.
Neurodevelopment Measured by Other Tools.	12 months	We will measure to what extent vitamin B12 supplementation improves neurodevelopment measured by other tools such as the Ages and Stages Questionnaire (version 3) and the NEPSY II test.
Leucocyte Telomere Length	12 months	Relative leucocyte telomere length at end of the study period. Estimated by real-time PCR analysis