EAL

NSUP: Vitamin B12 (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine the lowest dose of cyanocobalamin that is required for a maximal reduction in methylmalonic acid (MMA) concentrations in a randomized, double-blind, controlled, dose-finding study in older people with mild vitamin B₁₂deficiency.

Inclusion Criteria:

Serum vitamin B₁₂ concentration between 100pmol and 300pmol per L (135pg tp 406pg per ml)
Serum MMA concentration 0.26μmol per L or greater
Serum creatinine concentration 120μmol per L or less (under 1.4mg per dL).

Exclusion Criteria:

Self-reported anemia
Surgery or diseases of the stomach or small intestine
Any life-threatening diseases
Current use of multi-vitamin supplements containing folic acid, cobalamin or pyridoxine hydrochloride
Currently receiving cobalamin injections.

Description of Study Protocol:

Recruitment

From the Wageningen area of the Netherlands, through a database of individuals who had previously indicated interest in participation in such a trial.

Design

Randomized, double-blind dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B₁₂ deficiency in older people with mild vitamin B₁₂ deficiency, defined as a serum vitamin B₁₂ level of 100pmol to 300pmol per L (135pg to 406pg per ml) and a methylmalonic acid level of 0.26μmol per L or greater
A three- to four-week placebo run-in period before randomization to prove to be compliant (90% intake of capsules).

Blinding Used

Yes.

Intervention

Subjects were randomly assigned to 16 weeks of treatment with daily oral doses of 2.5mcg, 100mcg, 250mcg, 500mcg or 1,000mcg of cyanocobalamin
The researchers did not include a placebo in the study design for ethical reasons
The concomitant use of medications known to affect vitamin B₁₂ absorption (e.g., proton pump inhibitors, H₂ antagonists and metformin) was permitted if the medication had been provided at least three months before enrollment and was scheduled to be continued for the duration of the trial.

Statistical Analysis

Kruskal-Wallis
Mann-Whitney.

Data Collection Summary:

Timing of Measurements

The following data was collected at zero, eight and 16 weeks:

Height and weight
MMA
HoloTC
Hematologic variables (Hct, Hbg, MCV, neutrophils)
Plasma folate.

Dependent Variables

MMA.

Independent Variables

Dose of cyanocobalamin.
The doses selected for this study were based on the recommended dietary allowance of the Netherlands, which was 2.5mcg cobalamin daily at the start of the trial
The 1,000mcg cobalamin dose served as a positive control and was administered in the form of intramuscular injections to treat vitamin B₁₂ deficiency
The 100-, 250- and 500-mcg doses were chosen to provide an optimum dose-response curve.

Description of Actual Data Sample:

Initial N

120
24 received 2.5mcg per day
24 received 100mcg per day
24 received 250mcg per day
24 received 500mcg per day
24 received 1,000mcg per day
117 analyzed (44 males, 73 females).

Attrition

Described.

Age

80±7 years.

Ethnicity

Not described.

Anthropometrics

BMI: 25.3±4.6.

Location

Wageningen, Netherlands.

Summary of Results:

Daily supplementation with 2.5mcg, 100mcg, 250mcg, 500mcg or 1,000mcg of cyanocobalamin resulted in reductions in MMA concentrations to below the reference interval of 0.26μmol per L in 21%, 38%, 52%, 62% and 76% of the participants, respectively
The proportional decreases in MMA and total homocysteine (tHcy) levels and the proportional increases in vitamin B₁₂ and holotranscobalamin (holoTC) concentrations observed with incremental doses of cyanocobalamin after 16 weeks of supplementation
The mean reduction in plasma MMA concentrations after 16 weeks of supplementation, compared with baseline, varied from 16% to 33% in the groups receiving 2.5mcg to 1,000mcg of cyanocobalamin per day.

Author Conclusion:

The lowest dose of oral cyanocobalamin required to normalize biochemical markers of mild vitamin B₁₂ deficiency in older people with a mild vitamin B₁₂ deficiency is more than 200 times greater than the recommended dietary allowance for vitamin B₁₂ of approximately three mcg per day.

Funding Source:

Government:

Industry:

Kellogg's Benelux

Food Company:

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

There is no consensus on the diagnostic criteria for vitamin B₁₂ deficiency
Design not conducive to placebo use
Limited presentation of demographic data
No description of dosing tolerance.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	???
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	N/A
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes