Vitamin B12, Neurodevelopment and Growth in Nepal

NCT ID: NCT02272842

Last Updated: 2023-09-18

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 600 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-20
• Study Completion Date: 2024-12-28

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.

Conditions

Development; Vitamin Deficiency; Malnutrition

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

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)

Group Type: EXPERIMENTAL

Vitamin B12

Intervention Type: DIETARY_SUPPLEMENT

Vitamin B12 in a multivitamin paste.

Placebo

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)

Group Type: PLACEBO_COMPARATOR

Vitamin B12

Intervention Type: DIETARY_SUPPLEMENT

Vitamin B12 in a multivitamin paste.

Interventions

Vitamin B12

Vitamin B12 in a multivitamin paste.

Intervention Type: DIETARY_SUPPLEMENT

Other Intervention Names

Cobalamin

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.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 11 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tribhuvan University, Nepal

OTHER

Sponsor Role: collaborator

NORCE Norwegian Research Centre AS

OTHER

Sponsor Role: collaborator

Centre For International Health

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Prakash S Shrestha, MD

Role: PRINCIPAL_INVESTIGATOR

Tribhuvan University, Nepal

Tor A Strand, MD/PhD

Role: PRINCIPAL_INVESTIGATOR

Innlandet Hospital Trust / University of Bergen

Locations

Siddhi Memorial Hospital (SMH),Bhelukhel, Bhimsensthan

Bhaktapur, , Nepal

Countries

Nepal

References

Taneja S, Strand TA, Kumar T, Mahesh M, Mohan S, Manger MS, Refsum H, Yajnik CS, Bhandari N. Folic acid and vitamin B-12 supplementation and common infections in 6-30-mo-old children in India: a randomized placebo-controlled trial. Am J Clin Nutr. 2013 Sep;98(3):731-7. doi: 10.3945/ajcn.113.059592. Epub 2013 Jul 31.

Reference Type: BACKGROUND

PMID: 23902779 (View on PubMed)

Strand TA, Taneja S, Ueland PM, Refsum H, Bahl R, Schneede J, Sommerfelt H, Bhandari N. Cobalamin and folate status predicts mental development scores in North Indian children 12-18 mo of age. Am J Clin Nutr. 2013 Feb;97(2):310-7. doi: 10.3945/ajcn.111.032268. Epub 2013 Jan 2.

Reference Type: BACKGROUND

PMID: 23283502 (View on PubMed)

Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull. 2008 Jun;29(2 Suppl):S126-31. doi: 10.1177/15648265080292S117.

Reference Type: BACKGROUND

PMID: 18709887 (View on PubMed)

Black MM. Micronutrient deficiencies and cognitive functioning. J Nutr. 2003 Nov;133(11 Suppl 2):3927S-3931S. doi: 10.1093/jn/133.11.3927S.

Reference Type: BACKGROUND

PMID: 14672291 (View on PubMed)

Ulak M, Kvestad I, Chandyo RK, Schwinger C, Basnet S, Shrestha M, Ranjitkar S, Nguyen LV, Corona-Perez D, De Vivo I, Ueland PM, McCann A, Strand TA. The Effect of Vitamin B12 Supplementation on Leukocyte Telomere Length in Mildly Stunted Nepalese Children: A Secondary Outcome of a Randomized Controlled Trial. J Nutr. 2024 Aug;154(8):2543-2550. doi: 10.1016/j.tjnut.2023.10.015. Epub 2023 Oct 31.

Reference Type: DERIVED

PMID: 37918674 (View on PubMed)

Chandyo RK, Schwinger C, Kvestad I, Ulak M, Ranjitkar S, Shrestha M, Nguyen LV, Corona-Perez D, DeVivo I, Shrestha L, Strand TA. The association between household biomass fuel use and leukocyte telomere length among toddlers in Bhaktapur, Nepal. J Expo Sci Environ Epidemiol. 2023 May;33(3):448-454. doi: 10.1038/s41370-022-00474-1. Epub 2022 Sep 22.

Reference Type: DERIVED

PMID: 36138138 (View on PubMed)

Hysing M, Strand TA, Chandyo RK, Ulak M, Ranjitkar S, Schwinger C, Shrestha M, Kvestad I. The effect of vitamin B12-supplementation on actigraphy measured sleep pattern; a randomized control trial. Clin Nutr. 2022 Feb;41(2):307-312. doi: 10.1016/j.clnu.2021.11.040. Epub 2021 Dec 6.

Reference Type: DERIVED

PMID: 34999324 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33259482 (View on PubMed)

Strand TA, Ulak M, Chandyo RK, Kvestad I, Hysing M, Shrestha M, Basnet S, Ranjitkar S, Shrestha L, Shrestha PS. The effect of vitamin B12 supplementation in Nepalese infants on growth and development: study protocol for a randomized controlled trial. Trials. 2017 Apr 21;18(1):187. doi: 10.1186/s13063-017-1937-0.

Reference Type: DERIVED

PMID: 28431557 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.thrasherresearch.org/SitePages/current-grants-all.aspx

Link to the founding source.

Other Identifiers

U1111-1161-5187

Identifier Type: OTHER

Identifier Source: secondary_id

808734

Identifier Type: -

Identifier Source: org_study_id