EAL

NSUP: Vitamin B12 (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess the effects and cost of oral vs. intramuscular cobalamin treatment in patients with megaloblastic anemia due to cobalamin deficiency.

Inclusion Criteria:

Age of 16 years and up
Serum cobalamin concentration less than 160pg per ml
Megaloblastic anemia
Mean corpuscular volume (MCV) greater than 94fL (normal value 80fL to 94fL).

Exclusion Criteria:

Vomiting or diarrhea
Alcohol use greater than 40g per day
Incapacity to provide informed consent
History of malignancy
Folate deficiency
Inability to ingest oral medication
Use of medication that might interfere with folate metabolism (colchicines, methotrexate)
Pregnancy
Possible pregnancy
Breastfeeding women
Any woman of childbearing age that was not using an effective method of birth control.

Description of Study Protocol:

Recruitment: Patients aged 16 years and up with megaloblastic anemia due to cobalamin deficiency, at the Division of Hematology, Department of Internal Medicine, Adnan Menderes University Research and Practice Hospital (Aydin, Turkey) between January 1999 and January 2003
Design: Prospective, randomized, open-label study
Blinding used: N/A.

Intervention

Patients received one of two treatments:

A 1,000mcg ampule of cobalamin mixed with 20ml fruit juice was self-administered p.o. once daily for 10 days
A 1,000mcg ampule cobalamin injection into the gluteus muscle was administered once daily for 10 days.

After 10 days, both treatments were administered once a week for four weeks and then once a month for life.

Statistical Analysis

Wilcoxon-Mann-Whitney U-tests were used to compare the oral and parenteral treatment arms
Pre-treatment and post-treatment values were compared using the two-paired test
Nominal variables were compared using the Yates chi-square test
P-values less than 0.05 were considered statistically significant
The Statistical Package for Social Services, version 10.0 (SPSS, Inc., Chicago, Illinois), was used to calculate the data.

Data Collection Summary:

Timing of Measurements

Hematologic parameters were assessed at Days Zero, 10, 30 and 90
Serum vitamin B₁₂ concentration was measured on Days Zero and 90.

Patients received one of two treatments:

A 1,000mcg ampule of cobalamin mixed with 20ml fruit juice was self-administered p.o. once daily for 10 days
A 1,000mcg ampule cobalamin injection into the gluteus muscle was administered once daily for 10 days.

After 10 days, both treatments were administered once a week for four weeks and then once a month for life.

Dependent Variables

Serum cobalamin concentration (using chemiluminescence assay) at Days Zero and 90
GI endoscopy was performed on patients that could tolerate it
Gastric atrophy
Reticulocyte counts
Mini-Mental State Examination
Vibration threshold testing
Neurologic sensory assessment (including soft-touch and pinprick examinations) was used to identify neuropathy.

Independent Variables

Use of IM or p.o. cobalamin.

Control Variables

Injections administered by an experienced nurse.

Description of Actual Data Sample:

Initial N

70.

Attrition (Final N)

60 total
26 patients in the p.o. group
34 patients in the IM group.

Age

P.o. group
- Mean age, 60 years
- SD age, 15 years
- Range, 32 to 84 years.
IM group
- Mean age, 64 years
- SD age, 10 years
- Range, 36 to 87 years.

Other Relevant Demographics

PO group: 16 men, 10 women
IM group: 17 men, 17 women.

Anthropometrics

The age, sex, pre-treatment Hb level, platelet and white blood cell (WBC) counts, MCV and serum cobalamin and folate levels were not significantly different between the IM and PO groups.

Location

Aydin, Turkey
Division of Hematology, Department of Internal Medicine, Adnan Menderes University Research and Practice Hospital.

Summary of Results:

Parameter	PO Group (N=26) Measures and Confidence Intervals	IM Group (N=34) Measures and Confidence Intervals
Serum B₁₂ Concentration Day 90 Mean (SD), pg/ml (NV 160-950)	213.8 (30.2)	225.5 (40.2)
Hb Level Mean (SD) g/dL (NV 14.0 -17.5) on Day 90	13.8 (0.7)	13.7 (0.9)
MCV, fL (NV 80-94) on Day 90	86.9 (3.9)	86.7 (4.1)

Author Conclusion:

A moderate dose p.o. cobalamin treatment was as effective as IM cobalamin treatment
P.o. treatment was also better tolerated and less expensive, compared with IM treatment.

Funding Source:

University/Hospital:

Adnan Menderes University Medical School (Turkey)

Reviewer Comments:

No control group
Small sample size
Very short-term study.

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?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
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.)	No
	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?	???
	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?	N/A
	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?	N/A
	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?	No
	6.6.	Were extra or unplanned treatments described?	No
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	Yes
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?	Yes
	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