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CTRI Number  CTRI/2020/11/029108 [Registered on: 13/11/2020] Trial Registered Prospectively
Last Modified On: 17/01/2023
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Nutraceutical 
Study Design  Other 
Public Title of Study   Vitamin B12 absorption and its deficiency  
Scientific Title of Study   Evaluation of Vitamin B12 absorption and deficiency, in relation to genetic variants. 
Trial Acronym  B12-ADG 
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Anura V Kurpad 
Designation  Professor 
Affiliation  St. Johns Medical College 
Address  Department of Physiology and Nutrition (3rd floor-old wing) St. Johns Medical college, Sarjapur Road, Koramangala, Bangalore
Department of Physiology and Nutrition (3rd floor-old wing) St. Johns Medical college, Sarjapur Road, Koramangala, Bangalore-560034
Bangalore
KARNATAKA
560034
India 
Phone  9686512233  
Fax    
Email  a.kurpad@sjri.res.in  
 
Details of Contact Person
Scientific Query  
Name  Dr Sarita Devi 
Designation  Lecturer 
Affiliation  St. Johns Research Institute 
Address  Department of Physiology and Nutrition (3rd floor-old wing) St. Johns Medical College and Research Institute, Sarjapur Road, Koramangala, Bangalore
Department of Physiology and Nutrition (3rd floor-old wing) St. Johns Medical college and Research Institute, Sarjapur Road, Koramangala, Bangalore-560034
Bangalore
KARNATAKA
560034
India 
Phone  09986426938  
Fax    
Email  sarita@sjri.res.in  
 
Details of Contact Person
Public Query  
Name  Dr Sarita Devi 
Designation  Lecturer 
Affiliation  St. Johns Research Institute 
Address  Department of Physiology and Nutrition (3rd floor-old wing) St. Johns Medical College and Research Institute, Sarjapur Road, Koramangala, Bangalore
Department of Physiology and Nutrition (3rd floor-old wing) St. Johns Medical college and Research Institute, Sarjapur Road, Koramangala, Bangalore-560034
Bangalore
KARNATAKA
560034
India 
Phone  09986426938  
Fax    
Email  sarita@sjri.res.in  
 
Source of Monetary or Material Support  
DBT/Wellcome Trust India Alliance 
 
Primary Sponsor  
Name  DBTWellcome Trust India Alliance 
Address  The Wellcome Trust, DBT India Alliance Banjara Hills, Hyderabad-500034 Telephone No-91 40 4018 9445 or 6 or 7 Fax-91 40 4018 9449  
Type of Sponsor  Government funding agency 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Anura V Kurpad  St. Johns Medical College  Division of Nutrition, 3rd floor (old wing), Sarjapur Road, Koramangala, Bangalore 560034
Bangalore
KARNATAKA 		 9686512233

a.kurpad@sjri.res.in 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 3  
Name of Committee  Approval Status 
Institutional Ethics Committee  Approved 
Institutional Ethics Committee  Approved 
Institutional Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Healthy Human Volunteers  Healthy adult population with normal clinical history, good general health and with normal blood biochemistry 
 
Intervention / Comparator Agent
Modification(s)  
Type  Name  Details 
Intervention  Stable isotope labelled cyanocobalamin  Stable Isotopically labelled 13C cyanocobalamin (2.0 ug) dose will be orally administered on the study day. Stable isotopically labelled 13C cyanocobalamin (5 ug) will be instilled during colonoscopy to also check for colonic absorption in a separate set of subjects. The colonoscopy administration will be done by a gastroenterologist in participants undergoing colonoscopy in the Department of Gastroenterology of St. John’s Medical College Hospital and found to have normal colon. 
 
Inclusion Criteria
Modification(s)  
Age From  18.00 Year(s)
Age To  70.00 Year(s)
Gender  Both 
Details  Healthy adult individuals with normal clinical history, good general health and with normal blood biochemistry will be recruited. 
 
ExclusionCriteria 
Details  Exclusion criteria are allergies, intolerances, hypersensitivity, severe anemia, medication use, history of infectious diseases, physical or psychiatric or surgical intervention.  
 
Method of Generating Random Sequence   Not Applicable 
Method of Concealment   Not Applicable 
Blinding/Masking   Not Applicable 
Primary Outcome  
Outcome  TimePoints 
Vitamin B12 status and its bioavailability  One time measurement with biospecimen
collection over 12 hrs after the dose administration 
 
Secondary Outcome
Modification(s)  
Outcome  TimePoints 
Genetic variants and their role in understanding the B12 deficiency and colonic absorption of vitamin B12   Baseline for genetic variants and One time measurement with biospecimen collection over 4 hrs after the dose administration for colonic absorption  
 
Target Sample Size
Modification(s)  		 Total Sample Size="138"
Sample Size from India="138" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   N/A 
Date of First Enrollment (India)   17/11/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="5"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   NIL 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary   Introduction: Vitamin B12 is an essential micronutrient that plays a fundamental role in cell division and in one-carbon metabolism (1–4). Chronic vitamin B12 depletion (i.e., prolonged low intake or intestinal malabsorption) results in a state of negative vitamin balance. The nutritional deficiency of vitamin B12 has been linked to many complications including an increased risk of macrocytic anaemia, neuropsychiatric symptoms (5), cardiovascular diseases (6) and the onset of different forms of cancer (7,8). Measuring vitamin B12 bioavailability is particularly important in many countries, including India, where vitamin B12 intake is low (9) with respect to the suggested daily requirement of 2.4 to 4 µg/day (10), leading to widespread deficiency in the population, including pregnant women (11–13). Helicobacter pylori infection (14) and the widespread use of drugs such as proton pump inhibitors and metformin also increase the risk of deficiency. The elderly are also at high risk of developing B12 deficiency due to malabsorption of food-bound cobalamin along with atrophic gastritis (15,16).Oral vitamin B12 supplementation shows a marked inter-individual heterogeneity in response, possibly related to variable bioavailability, which is also dependent on the gastrointestinal absorption (17). This large variation could also be due to genetic factors (18), that may alter vitamin B12 tissue status by affecting the proteins involved in vitamin B12 absorption, cellular uptake and intracellular metabolism (19).At present, genetic studies of vitamin B12 status suggest that B12 deficiency is a multifactorial trait, where several single-nucleotide polymorphisms (SNPs) in multiple genes interact with the environment to cause the altered vitamin B12 status. Most of the SNPs related to vitamin B12 status have been examined using a candidate gene approach (20). Moreover, detection of B12 deficiency by total plasma or serum levels have highly variable sensitivity and specificity (21). Therefore, it is important to evaluate vitamin B12 status (by sensitive method), bioavailability, and genetic variants and their interplay towards understanding this deficiency.
Justification / need for the study: There are two knowledge gaps that still exists; first, the exact requirement (based on daily losses) of vitamin B12 and the variability in absorption profiles of vitamin B12 in healthy Indian population is unknown. The pilot data from our recent study of measuring vitamin B12 absorption by stable isotope based method (22) showed that the absorption in apparently healthy individuals (n=11) is highly variable (from 38.3-79.4%). This large variation could be due to various other factors that were not evaluated in pilot study. Therefore, we aim to evaluate the vitamin B12 absorption profiles in 128 subjects including various genetic factors that are known to be significantly associated with B12 deficiency/absorption. In addition, urinary measurements to the existing method that was developed by us (22), can provide the daily excretion (requirement) term of B12 that needs validation. Secondly, since total plasma/serum B12 levels have a highly variable sensitivity and specificity for detecting B12 deficiency, there is a need for direct and sensitive method for measuring each vitamin B12 form. The direct LCMS/MS measurements by us suggest that the efficiency of re-cyanylation may be varied in different assays and direct measurements of the different forms of B12 provide higher values. It is possible that the unmeasured component of B12 compounds could vary across populations, especially vegetarian and non-vegetarian. Therefore, we aim to fill the gap in existing knowledge by combining a stable and safe method for measuring vitamin B12 absorption and assaying genetic variants that may affect absorption in healthy adult population as well as measuring status by quantifying individual form of vitamin B12 (methyl, ado, hydroxy and cyanocobalamin).
References:  
 1.   Herbert V. Vitamin B-12: plant sources, requirements, and assay. Am J Clin Nutr [Internet]. 1988;48:852–8. Available from: https://academic.oup.com/ajcn/article/48/3/852-858/4716470 
 2.  Alexander D, Ball MJ, Mann J. Nutrient intake and haematological status of vegetarians and age-sex matched omnivores. Eur J Clin Nutr. 1994;48:538–46. 
 3.  Schneede J, Dagnelie PC, Van Staveren WA, Vollset SE, Refsum H, Ueland PM. Methylmalonic Acid and Homocysteine in Plasma as Indicators of Functional Cobalamin Deficiency in Infants on Macrobiotic Diets. Pediatr Res [Internet]. 1994;36:194–201. Available from: http://www.nature.com/doifinder/10.1203/00006450-199408000-00010 
 4.  Herbert V. Staging vitamin B’12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994;59:1213S-1222S.
 5.   Lechner K, Födinger M, Grisold W, Püspök A, Sillaber C. [Vitamin B12 deficiency. New data on an old theme]. Wien Klin Wochenschr [Internet]. 2005;117:579–91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16395986 
 6.   Boushey CJ. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease. JAMA [Internet]. 1995;274:1049. Available from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.1995.03530130055028 
 7.   Arendt JFB, Nexo E. Unexpected high plasma cobalamin. Clinical Chemistry and Laboratory Medicine. 2013. 
 8.   Arendt JFB, Pedersen L, Nexo E, Sørensen HT. Elevated Plasma Vitamin B12 Levels as a Marker for Cancer: A Population-Based Cohort Study. JNCI J Natl Cancer Inst [Internet]. 2013;105:1799–805. Available from: https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/djt315 
 9.   Tata NIN Centre of Excellence in Public Health Nutrition Dashboard. Overview of food and nutrition in India [Internet]. Available from: https://www.dashboard.nintata.res.in/#/dashboard/nutrient-intake
10. Scientific Opinion on Dietary Reference Values for cobalamin (vitamin B12). EFSA J [Internet]. 2015;13. Available from: http://doi.wiley.com/10.2903/j.efsa.2015.4150 
 11. Gonmei Z, Toteja GS. Micronutrient status of Indian population. Indian J Med Res [Internet]. 2018;148:511–21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30666978 
 12. Singh S, Geddam JJB, Reddy GB, Pallepogula DR, Pant HB, Neogi SB, John N, Kolli SR, Doyle P, Kinra S, et al. Folate, vitamin B12, ferritin and haemoglobin levels among women of childbearing age from a rural district in South India. BMC Nutr. 2017; 
 13. Finkelstein JL, Kurpad A V, Thomas T, Srinivasan K, Duggan C. Vitamin B12 status in pregnant women and their infants in South India. Eur J Clin Nutr [Internet]. 2017;71:1046–53. Available from: http://www.nature.com/articles/ejcn201729 
 14. Annibale B, Capurso G, Delle Fave G. Consequences of Helicobacter pylori infection on the absorption of micronutrients. Dig Liver Dis [Internet]. 2002;34:S72–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1590865802801700 
 15. Green R. Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood [Internet]. 2017;129:2603–11. Available from: https://ashpublications.org/blood/article/129/19/2603/36140/Vitamin-B12-deficiency-from-the-perspective-of-a 
 16. Baik HWW, Russell RMM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr [Internet]. 1999;19:357–77. Available from: http://www.annualreviews.org/doi/10.1146/annurev.nutr.19.1.357 
 17. Watanabe F. Vitamin B 12 Sources and Bioavailability. Exp Biol Med [Internet]. 2007;232:1266–74. Available from: http://journals.sagepub.com/doi/10.3181/0703-MR-67 
 18. Nielsen MJ, Rasmussen MR, Andersen CBF, Nexø E, Moestrup SK. Vitamin B 12 transport from food to the body’s cells - A sophisticated, multistep pathway. Nature Reviews Gastroenterology and Hepatology. 2012. 
 19. Quadros E V. Advances in the understanding of cobalamin assimilation and metabolism. Br J Haematol. 2010;148:195–204. 
 20. Haggarty P. B-vitamins, genotype and disease causality. Proc Nutr Soc. 2007; 
 21. Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr [Internet]. 2011;94:666S-672S. Available from: https://academic.oup.com/ajcn/article/94/2/666S/4597978 
 22. Devi S, Pasanna RM, Shamshuddin Z, Bhat K, Sivadas A, Mandal AK, Kurpad A V. Measuring vitamin B-12 bioavailability with [13C]-cyanocobalamin in humans. Am J Clin Nutr [Internet]. 2020; Available from: https://academic.oup.com/ajcn/advance-article/doi/10.1093/ajcn/nqaa221/5897229        
 
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