Cochrane Library

1. [mh "Vitamin B 12"]

2. ((vitamin* or vit or coenzym*) near/1 (b12 or "b 12" or b12? or "b 12?")):ti,ab

3. (cobalamin* or hydrox?cobalamin* or c?anocobalamin* or methylcobalamin* or adenosylcobalamin* or dibencozid* or cobamamid* or cobamid*):ti,ab

4. {or #1‐#3}

5. [mh "Vitamin B 12 Deficiency"]

6. ((b12 or "b 12" or b12? or "b 12?" or cobalamin* or cyanocobalamin) near/3 deficien*):ti,ab

7. #5 or #6

8. #4 and #7 [Publication Year from 2005 to 2017]

MEDLINE (Ovid SP)

1. exp Vitamin B 12/

2. ((vitamin* or vit or coenzym*) adj1 (b12? or "b 12?")).tw.

3. (cobalamin* or hydrox?cobalamin* or c?anocobalamin* or methylcobalamin* or adenosylcobalamin* or dibencozid* or cobamamid* or cobamid*).tw.

4. or/1‐3

5. exp Vitamin B 12 Deficiency/

6. ((b12? or "b 12?" or cobalamin* or cyanocobalamin) adj3 deficien*).tw.

7. or/5‐6

8. 4 and 7

[9‐19: Cochrane Handbook 2008 RCT filter ‐ sensitivity max. version]

9. randomized controlled trial.pt.

10. controlled clinical trial.pt.

11. randomi?ed.ab.

12. placebo.ab.

13. drug therapy.fs.

14. randomly.ab.

15. trial.ab.

16. groups.ab.

17. or/9‐16

18. exp animals/ not humans/

19. 17 not 18

20. 8 and 19

21. (200412?? or 2005* or 2006* or 2007* or 2008* or 2009 or 201*).dc.

22. 20 and 21

Embase (Ovid SP)

1. cobalamin derivative/

2. hydroxocobalamin/

3. methylcobalamin/

4. cyanocobalamin/

5. cobamamide/

6. cobalamin/

7. ((vitamin* or vit or coenzym*) adj1 (b12? or "b 12?")).tw.

8. (cobalamin* or hydrox?cobalamin* or c?anocobalamin* or methylcobalamin* or adenosylcobalamin* or dibencozid* or cobamamid* or cobamid*).tw.

9. or/1‐8

10. cyanocobalamin deficiency/

11. ((b12? or "b 12?" or cobalamin* or cyanocobalamin) adj3 deficien*).tw.

12. or/10‐11

13. 9 and 12

[13Wong 2006"sound treatment studies" filter – BS version]

14. random*.tw. or clinical trial*.mp. or exp health care quality/

15. 13 and 14

16. (200412?? or 2005* or 2006* or 2007* or 2008* or 2009 or 201*).dc.

17. 15 and 16

LILACS (iAHx)

(MH:" Vitamin B 12" OR ((vitamin$ OR coenzym$ OR coenzim$) AND (B12 OR "B 12")) OR (cobalamin$ OR hydroxicobalamin$ OR hydroxocobalamin$ hidroxicobalamin$ OR hidroxocobalamin$ OR cyanocobalamin$ OR cianocobalamin$ OR methylcobalamin$ OR metilcobalamin$ OR adenosylcobalamin$ OR adenosilcobalamin$ OR dibencozid$ OR cobamamid$ OR cobamid$)) AND (MH: "Vitamin B 12 Deficiency" OR ((B12 OR "B 12" OR cobalamin$ OR cyanocobalamin$ OR cianocobalamin$) AND deficien$))

+ Filter "Controlled Clinical Trial"

ClinicalTrials.gov (Expert search)

( hydroxocobalamin OR hydroxicobalamin OR methylcobalamin OR cyanocobalamin OR cobamamide OR cobalamin OR dibencozid OR adenosylcobalamin OR cobamide OR "vitamin B12" OR "vitamin B 12" OR "coenzym B12" OR "coenzym B 12" ) AND ( B12 OR "B 12" OR cobalamin OR cyanocobalamin ) AND ( deficiency OR deficiencies OR deficient ) AND EXACT "Interventional" [STUDY‐TYPES]

ICTRP Search Portal (Standard search)

deficien* AND vitamin B12 OR

deficien* AND vitamin B 12 OR

vitamin B12 deficiency OR

vitamin B 12 deficiency OR

deficien* AND cobalamin* OR

deficien* AND cyanocobalamin*

Trial ID

Intervention(s)
(route, frequency, total dose/day)

Comparator(s)
(route, frequency, total dose/day)

Bolaman 2003

Oral: 1000 µg cyanocobalamin (ampoule mixed with 20 mL fruit juice) self administered once daily for 10 days; after 10 days, once a week for 4 weeks and then once a month for life

Intramuscular: 1000 µg cyanocobalamin (ampoule, injection by a nurse into the gluteus muscle) once daily for 10 days; after 10 days, once a week for 4 weeks and then once a month for life

Kuzminski 1998

Oral: 2000 µg cyanocobalamin (two 1000 µg tablets) with breakfast daily for 4 months

Intramuscular: 1000 µg cyanocobalamin on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 (injection by a nurse)

Saraswathy 2012

Oral: 1000 μg of vitamin B₁₂ daily for 3 months

Intramuscular: 1000 μg of vitamin B₁₂ once daily for a week followed by once a week for 8 weeks

Trial ID

Intervention(s) and comparator(s)

Duration of intervention
(duration of follow‐up)

Description of participants

Trial period
(year to year)

Country

Setting

Ethnic groups
(%)

Duration of vitamin B₁₂ deficiency
(mean years (SD))

Vitamin B₁₂ levels (mean pg/mL (SD))

Bolaman 2003

I: oral vitamin B₁₂

90 days (90 days)

People with megaloblastic anaemia due to vitamin B₁₂ deficiency (defined as serum vitamin B₁₂ level < 160 pg/mL)

1999 to 2003

Turkey

Hospital

‐

‐

72.9 (54.8)

C: intramuscular vitamin B₁₂

90 days (90 days)

70.2 (59.1)

Kuzminski 1998

I: oral vitamin B₁₂

4 months (4 months)

People with newly diagnosed vitamin B₁₂ deficiency (defined as serum vitamin B₁₂ level < 160 pg/mL)

1993 to 1996

USA

Ambulatory care centres

White: 97

Latina: 3

‐

93 (46)

C: intramuscular vitamin B₁₂

90 days (4 months)

95 (92)

Saraswathy 2012

I: oral vitamin B₁₂

3 months (3 months)

Consecutive patients with vitamin B₁₂ deficiency (serum vitamin B₁₂ level < 200 pg/mL)

2009 to 2010

South India

A tertiary care hospital

‐

‐

149.8 (37.6)

C: intramuscular vitamin B₁₂

9 weeks (3 months)

146.0 (42.1)

‐ denotes not reported

C: comparator; I: intervention; SD: standard deviation

Trial ID

Intervention(s) and comparator(s)

Sex
(female %)

Age
(mean years (SD)

MCV (mean fL (SD))

Haemoglobin (mean g/dL (SD))

Total homocysteine (mean μmol/L (SD))

Serum methylmalonic acid (mean nmol/L (SD))

Comedications/Cointerventions

Comorbidities

Bolaman 2003

I: oral vitamin B₁₂

39

60 (15)

112.3 (11.4)

8.4 (2.1)

‐

‐

18/26 participants with upper GI endoscopy

Atrophic gastritis: 5
Chronic antral gastritis: 5
Chronic pangastritis: 3
Enterogastric reflux: 2
Alkaline reflux: 2

C: intramuscular vitamin B₁₂

50

64 (10)

114.8 (10.9)

8.3 (2.3)

‐

‐

27/34 participants with upper GI endoscopy

Atrophic gastritis: 9
Chronic antral gastritis: 2
Chronic pangastritis: 4
Enterogastric reflux: 2
Alkaline reflux: 4
Erosive gastritis: 1

Kuzminski 1998

I: oral vitamin B₁₂

67

72 (11)

100 (12)

‐

37.2 (44.9)

3850 (6930)

‐

Atrophic gastritis: 7 (3 unclear)
Pernicious anaemia: 5
Inadequate dietary protein intake: 3

C: intramuscular vitamin B₁₂

87

71 (15)

102 (11)

‐

40.0 (26.2)

3630 (7040)

‐

Atrophic gastritis: 7
Pernicious anaemia: 2
Inadequate dietary protein intake: 2
Prior ileal resection: 1
Prior gastric stapling: 1

Saraswathy 2012

I: oral vitamin B₁₂

36.7

38.6 (14.8)

92.8 (14.3)

11.7 (2.4)

‐

‐

‐

‐

C: intramuscular vitamin B₁₂

16.7

44.3 (9.3)

89.4 (16.3)

12.4 (2.7)

‐

‐

‐

‐

‐ denotes not reported

C: comparator; GI: gastrointestinal tract; I: intervention; MCV: mean corpuscular volume; SD: standard deviation

Trial ID

Endpoints quoted in trial document(s)
(ClinicalTrials.gov, FDA/EMA document, manufacturer's website, published design paper)^a

Trial results/
publications available
in trial register

Endpoints quoted in publication(s)^b,c

Endpoints quoted in abstract of publication(s)^b,c

Saraswathy 2012

Source: N/T

No full publication

Primary outcome measure: proportion of participants with serum vitamin B₁₂ normalisation (≥ 200 pg/mL) after 60 days of treatment

Secondary outcome measure: compliance: ensured by pill/ampoule count and verification of injection records

Other outcome measure(s): ‐

Bolaman 2003

Source: N/T

Primary outcome measure(s): ‐

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): haemoglobin level, improvements in signs and symptoms of anaemia; response to therapy (detection of reticulocytosis between days 5 and 10, and recovery of the haematologic parameters on complete blood counts and peripheral blood smears at days 10, 30, and 90 of treatment); tolerability ‐ adverse events (assessed by a haematologist at days 0, 30, and 90 using laboratory tests, e.g. serum potassium level, eosinophilia on blood smear, and patient interviews); costs (costs of the study drug and of the injections); serum vitamin B₁₂ levels; serum autoantibodies to gastric parietal cells; cognitive function (Mini‐Mental State Examination); vibration threshold; neurologic sensory assessment (soft‐touch, pinprick examination)

Other outcome measure(s): therapeutic effectiveness (haematologic parameters on days 0, 10, 30, and 90); serum vitamin B₁₂ (on days 0 and 90); cognitive function, vibration threshold; neurologic sensory assessment; tolerability

Kuzminski 1998

Source: N/T

Primary outcome measure(s): ‐

Primary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Secondary outcome measure(s): ‐

Other outcome measure(s): serum vitamin B₁₂ levels, serum folate levels, serum anti‐intrinsic factor antibodies, unsaturated serum cobalamin‐binding capacity, serum methylmalonic acid levels, serum homocysteine levels, serum pepsinogen I levels, neurologic symptoms, haematocrit, mean corpuscular volume

Other outcome measure(s): therapeutic effectiveness: haematologic and neurologic improvement and changes in serum levels of cobalamin (normal: 200 to 900 pg/mL), methylmalonic acid (normal: 73 to 271 nmol/L), and homocysteine (normal: 5.1 to 13.9 µmol/L)

‐ denotes not reported
EMA: European Medicines Agency; FDA: US Food and Drug Administration; N/T: no trial document available

^aTrial document(s) refers to all available information from published design papers and sources other than regular publications (e.g. FDA/EMA documents, manufacturer's websites, trial registers).
^bPublication(s) refers to trial information published in scientific journals (primary reference, duplicate publications, companion documents or multiple reports of a primary trial).
^cOther outcome measures refers to all outcomes not specified as primary or secondary outcome measures.

Trial ID

Outcome

High risk of bias
(category A)^a

High risk of bias
(category D)^b

High risk of bias
(category E)^c

High risk of bias
(category G)^d

Bolaman 2003

Clinical signs and symptoms of vitamin B₁₂ deficiency

No

Yes

No

No

Kuzminski 1998

N/A

Saraswathy 2012

N/A

N/A: not applicable

^aClear that outcome was measured and analysed; trial report states that outcome was analysed but only reports that result was not significant.
(Classification 'A', table 2, Kirkham 2010)
^bClear that outcome was measured and analysed; trial report states that outcome was analysed but no results reported.
(Classification 'D', table 2, Kirkham 2010)
^cClear that outcome was measured; clear that outcome was measured but not necessarily analysed; judgement says likely to have been analysed but not reported due to non‐significant results.
(Classification 'E', table 2, Kirkham 2010)
^dUnclear whether the outcome was measured; not mentioned, but clinical judgement says likely to have been measured and analysed but not reported on the basis of non‐significant results.
(Classification 'G', table 2, Kirkham 2010)

Trial ID

Definition of vitamin B₁₂ deficiency

Therapeutic efficacy

Clinical signs and symptoms of vitamin B₁₂ deficiency

Adverse events

Health‐related quality of life

Acceptability

Socioeconomic effects

Bolaman 2003

Serum vitamin B₁₂ concentrations < 160 pg/mL, megaloblastic anaemia, mean corpuscular volume > 94 fL (IO)

Response to therapy (detection of reticulocytosis between days 5 and 10, and recovery of the haematologic parameters on complete blood counts and peripheral blood smears at days 10, 30, and 90 of treatment)
(IO)

Cognitive function (Mini‐Mental State Examination)

Tolerabilty ‐ adverse events (assessed by a haematologist at days 0, 30, and 90 using laboratory tests, e.g. serum potassium level, eosinophilia on blood smear, and participant interviews)
(IO)

N/I

Tolerabilty ‐ adverse events (assessed by a haematologist at days 0, 30, and 90 using laboratory tests, e.g. serum potassium level, eosinophilia on blood smear, and participant interviews)
(IO)

Costs of the study drug and of the injections
(IO)

Kuzminski 1998

Serum vitamin B₁₂ concentrations < 160 pg/mL
(IO)

Haematologic and neurologic improvement and changes in serum levels of vitamin B₁₂ (normal: 200 to 900 pg/mL), methylmalonic acid (normal: 73 to 271 nmol/L), and homocysteine (normal: 5.1 to 13.9 µmol/L)
(IO)

"Neurologic improvement"
(IO)

N/I

N/I

N/I

N/I

Saraswathy 2012

Serum vitamin B₁₂ concentrations < 200 pg/mL
(IO)

Proportion of participants in each treatment arm in whom vitamin B₁₂ levels were normalised (≥ 200 ng/mL) at 3 months after initial treatment

N/I

N/I

N/I

N/I

N/I

AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; N/I: not investigated; SO: self reported outcome measurement

^aIn addition to definition of endpoint measurement, description of who measured the outcome (AO: adjudicated outcome measurement; IO: investigator‐assessed outcome measurement; SO: self reported outcome measurement).

Trial ID

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Deaths
(N)

Deaths
(%)

Participants with adverse events
(N)

Participants with adverse events
(%)

Participants with severe/serious adverse events
(N)

Participants with severe/serious adverse events
(%)

Bolaman 2003

I: oral vitamin B₁₂

26^a

0

0

0

0

0

0

C: intramuscular vitamin B₁₂

34^a

0

0

0

0

0

0

Kuzminski 1998

I: oral vitamin B₁₂

18^b

0

0

‐

‐

‐

‐

C: intramuscular vitamin B₁₂

15^b

0

0

‐

‐

‐

‐

Saraswathy 2012

I: oral vitamin B₁₂

22^c

0

0

‐

‐

‐

‐

C: intramuscular vitamin B₁₂

27^d

0

0

‐

‐

‐

‐

‐ denotes not reported

C: comparator; I: intervention

^aTen participants in Bolaman 2003 left the trial early, and the group assignment of the 10 participants was not reported ("no treatment related adverse events were reported in either treatment group").

^bFive participants in Kuzminski 1998 were judged to have deficiency of primary folate rather than of cobalamin, therefore they were excluded from the data analysis.

^cEight participants in this group left the trial early due to adverse events (n = 2), loss to follow‐up (n = 4), and lack of subjective improvement (n = 2).

^dThree participants in this group left the trial early due to expired (n = 1) and loss to follow‐up (n = 2).

Trial ID

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Participants discontinuing study due to adverse events
(N)

Participants discontinuing study due to adverse events
(%)

Participants hospitalised
(N)

Participants hospitalised
(%)

Participants with outpatient treatment
(N)

Participants with outpatient treatment
(%)

Bolaman 2003

I: oral vitamin B₁₂

26^a

0

0

‐

‐

‐

‐

C: intramuscular vitamin B₁₂

34^a

0

0

‐

‐

‐

‐

Kuzminski 1998

I: oral vitamin B₁₂

18^b

‐

‐

‐

‐

‐

‐

C: intramuscular vitamin B₁₂

15^b

‐

‐

‐

‐

‐

‐

Saraswathy 2012

I: oral vitamin B₁₂

22^c

2

6.7

‐

‐

‐

‐

C: intramuscular vitamin B₁₂

27^d

0

0

‐

‐

‐

‐

‐ denotes not reported

C: comparator; I: intervention

^aTen participants in Bolaman 2003 left the trial early, and the group assignment of the 10 participants was not reported.

^bFive participants in Kuzminski 1998 were judged to have deficiency of primary folate rather than of cobalamin, therefore they were excluded from the data analysis.

^cEight participants in this group left the trial early due to adverse events (n = 2), loss to follow‐up (n = 4), and lack of subjective improvement (n = 2).

^dThree participants in this group left the trial early due to expired (n = 1) and loss to follow‐up (n = 2).

Trial ID

Intervention(s) and comparator(s)

Participants included in analysis
(N)

Participants with specific adverse events
(description)

Participants with specific adverse events
(N)

Participants with specific adverse events
(%)

Bolaman 2003

I: oral vitamin B₁₂

26^a

‐

‐

‐

C: intramuscular vitamin B₁₂

34^a

‐

‐

‐

Kuzminski 1998

I: oral vitamin B₁₂

18^b

‐

‐

‐

C: intramuscular vitamin B₁₂

15^b

‐

‐

‐

Saraswathy 2012

I: oral vitamin B₁₂

22^c

‐

‐

‐

C: intramuscular vitamin B₁₂

27^d

‐

‐

‐

‐ denotes not reported

C: comparator; I: intervention

^aTen participants in Bolaman 2003 left the trial early, and the group assignment of the 10 participants was not reported.

^bFive participants in Kuzminski 1998 were judged to have deficiency of primary folate rather than of cobalamin, therefore they were excluded from the data analysis.

^cEight participants in this group left the trial early due to adverse events (n = 2), loss to follow‐up (n = 4), and lack of subjective improvement (n = 2).

^dThree participants in this group left the trial early due to expired (n = 1) and loss to follow‐up (n = 2).

Trial ID

Date trial author contacted

Date trial author replied

Date trial author asked for additional information
(short summary)

Date trial author provided data
(short summary)

Bolaman 2003

18 March 2016

No reply

N/A

N/A

Kuzminski 1998

18 March 2016

No reply

N/A

N/A

Saraswathy 2012

23 December 2016

No reply

N/A

N/A

N/A: not applicable

Serum vitamin B₁₂ level

Clinical signs and symptoms of vitamin B₁₂ deficiency

Adverse events

Health‐related quality of life

Acceptability

Socioeconomic effects

Trial limitations
(risk of bias)^a

Was random sequence generation used (i.e. no potential for selection bias)?

Yes

N/R

Unclear

N/R

N/R

Unclear

Was allocation concealment used (i.e. no potential for selection bias)?

Unclear

Unclear

Unclear

Was there blinding of participants and personnel (i.e. no potential for performance bias) or outcome not likely to be influenced by lack of blinding?

Yes

No (↓)

Yes

Was there blinding of outcome assessment (i.e. no potential for detection bias) or was outcome measurement not likely to be influenced by lack of blinding?

Yes

No (↓)

Yes

Was an objective outcome used?

Yes

No (↓)

Yes

Were more than 80% of participants enrolled in trials included in the analysis (i.e. no potential reporting bias)?^e

Yes

Yes

Yes

Were data reported consistently for the outcome of interest (i.e. no potential selective reporting)?

Yes

Unclear

Unclear

No other biases reported (i.e. no potential for other bias)?

N/A

Yes

Yes

Did the trials end as scheduled (i.e. not stopped early)?

Yes

Yes

Yes

Inconsistency^b

Point estimates did not vary widely?

N/A

N/A

N/A

To what extent did confidence intervals overlap (substantial: all confidence intervals overlap at least one of the included studies point estimate; some: confidence intervals overlap but not all overlap at least one point estimate; no: at least one outlier: where the confidence intervals of some
of the studies do not overlap with those of most included studies)?

N/A

N/A

N/A

Was the direction of effect consistent?

N/A

N/A

N/A

What was the magnitude of statistical heterogeneity (as measured by I²): low (I² < 40%), moderate (I² 40% to 60%), high (I² > 60%)?

N/A

N/A

N/A

Was the test for heterogeneity statistically significant (P < 0.1)?

N/A

N/A

N/A

Indirectness^a

Were the populations in the included studies applicable to the decision context?

Yes

Yes

Yes

Were the interventions in the included studies applicable to the decision context?

Highly applicable

Highly applicable

Highly applicable

Was the included outcome not a surrogate outcome?

Yes

Yes

Yes

Was the outcome time frame sufficient?

Sufficient

Sufficient

Sufficient

Were the conclusions based on direct comparisons?

Yes

Yes

Yes

Imprecision^c

Was the confidence interval for the pooled estimate not consistent with benefit and harm?

N/A

N/A

N/A

What is the magnitude of the median sample size (high: 300 participants, intermediate: 100 to 300 participants, low: < 100 participants)?^e

Low (↓)

Low (↓)

Low (↓)

What was the magnitude of the number of included studies (large: > 10 studies, moderate: 5 to 10 studies, small: < 5 studies)?^e

Small (↓)

Small (↓)

Small (↓)

Was the outcome a common event (e.g. occurs more than 1/100)?

N/A

Yes

N/A

Publication bias^d

Was a comprehensive search conducted?

Yes

Yes

Yes

Was grey literature searched?

Yes

Yes

Yes

Were no restrictions applied to study selection on the basis of language?

Yes

Yes

Yes

There was no industry influence on studies included in the review?

Unclear

Unclear

Unclear

There was no evidence of funnel plot asymmetry?

N/A

N/A

N/A

There was no discrepancy in findings between published and unpublished trials?

N/A

N/A

N/A

(↓): key item for possible downgrading the quality of the evidence (GRADE) as shown in the footnotes of the 'Summary of findings' table(s); N/A: not applicable; N/R: not reported

^aQuestions on risk of bias are answered in relation to the majority of the aggregated evidence in the meta‐analysis rather than to individual trials.
^bQuestions on inconsistency are primarily based on visual assessment of forest plots and the statistical quantification of heterogeneity based on I².

^cWhen judging the width of the confidence interval, it is recommended that a clinical decision threshold be used to assess whether the imprecision is clinically meaningful.
^dQuestions address comprehensiveness of the search strategy, industry influence, funnel plot asymmetry, and discrepancies between published and unpublished trials.
^eDepends on the context of the systematic review area.