EAL

NSUP: Vitamin B12 (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the effects of oral vitamin B₁₂ supplementation alone or in combination with folic acid for 24 weeks, on cognitive function in older persons with mild vitamin B₁₂ deficiency with no to moderate cognitive impairment.

Inclusion Criteria:

Individuals who fulfilled the criteria for mild vitamin B₁₂ deficiency, defined as
1. A serum vitamin B₁₂ concentration between 100μmol and 200μmol per L
2. Or a serum vitamin B₁₂ concentration between 200μmol and 300μmol per L and a plasma MMA concentration over 0.32μmol per L.
Medications interfering with B₁₂ absorption were permitted if prescribed three months before initial study screening.

Exclusion Criteria:

History of cobalamin deficiency
Use of cobalamin
Use of folic acid supplementation or injections
Surgery or diseases of the stomach or small intestine
Anemia
Dementia
Life-threatening diseases
Severe hearing or visual problems
Measured amounts of cobalamin (over 50mcg per day) and folic acid (over 200mcg per day)
MMSE score under 19
Serum creatinine concentration up to 120µmol per L (impaired renal function).

Description of Study Protocol:

Recruitment: Free-living older persons and older persons living in carefacility homes aged >70 years old were recruited from different parts of the Netherlands via mailed health questionnaires
Design: Randomized placebo controlled study of 195 elderly patients to either placebo, oral vitamin B-12 supplementation alone, or in combination with folic acid for 24 weeks.
Blinding used: Yes

Intervention

Individuals with mild vitamin B₁₂ deficiency took a placebo for two weeks before randomization (run-in period)
During the run-in period, subjects were excluded from further participation if they ingested under 90% of the capsules or if they scored less than 19 points on the Mini-Mental State Examination (MMSE)
Eligible participants were randomly assigned to receive 24 weeks of treatment in a parallel group design with daily oral doses of:
1. 1,000mcg vitamin B₁₂
2. A combination of 1,000mcg vitamin B₁₂ and 400mcg folic acid
3. Or a placebo.
Vitamin B₁₂ was administered as cyanocobalamin
Participants were asked to maintain their regular diet and to record in a diary their daily intake of capsules, use of medication and occurrence of any new illnesses during the trial
Compliance was checked by counting the number of unused capsules remaining in capsule dispensers and by verifying pill counts in the participants’ diaries
Nurses were asked to monitor the daily capsule intake of the institutionalized participants.

Statistical Analysis

ANOVA
Chi-squared
Tukey’s post-hoc and two-factor repeated measures.

Data Collection Summary:

Timing of Measurements

The following data was collected at baseline and randomization visits at 12 and 24 weeks:
- Height and weight
- MMA
- HoloTC
- Plasma folate.
The following data was collected at baseline:
- MMSE
- CDR
- GDS.
Collected at randomization visits only: Hematologic variables (Hct, Hbg, MCV, Neutrophils, RBC folate).

Dependent Variables

MMA.

Independent Variables

Dose of B₁₂
B12 plus folic acid.

Description of Actual Data Sample:

Initial N: 195 (64 received B₁₂, 66 received B₁₂ plus folic acid, 65 recieved placebo)
Attrition (final N): 162 for all data analyzed
Age: Over 70 years
Ethnicity: Not described
Anthropometrics: Not described
Location: Wageningen, Netherlands.

Summary of Results:

Supplementation with B₁₂ showed a significant time x treatment interaction for B₁₂, MMA, holoTC, tHcy and RBC folate
B₁₂ and B₁₂ plus folic acid decreased tHcy by 16% and 37%, respectively
MMA and tHcy concentrations remained stable between Weeks 12 and 24 for B₁₂ plus folic acid treatment group, however B₁₂ treatment alone further increased holoTC and RBC folate during the last 12 weeks
Treatment with B₁₂ or B₁₂ plus folic acid showed no improvement in cognitive function.

Author Conclusion:

Oral supplementation with vitamin B₁₂ alone or in combination with folic acid for 24 weeks does not improve cognitive function.

Funding Source:

Reviewer Comments:

Included rigorous methods to assess cognitive function
There is no consensus on the diagnostic criteria for vitamin B₁₂ deficiency including severity
Limited anthropometrics
Limited presentation of demographic data.

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?	No
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.)	N/A
	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?		???
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	???
	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.)	???
	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?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	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?	N/A
	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?	No
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
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