Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12)

Teresa Sanz-Cuesta; Esperanza Escortell-Mayor; Isabel Cura-Gonzalez; Jesus Martin-Fernandez; Rosario Riesgo-Fuertes; Sofía  Garrido-Elustondo; Jose Enrique  Mariño-Suárez; Mar  Álvarez-Villalba; Tomás  Gómez-Gascón; Inmaculada  González-García; Paloma González-Escobar; Concepción  Vargas-Machuca Cabañero; Mar  Noguerol-Álvarez; Francisca  García de Blas-González; Raquel  Baños-Morras; Concepción  Díaz-Laso; Nuria  Caballero-Ramírez; Alicia Herrero de-Dios; Rosa  Fernández-García; Jesús  Herrero-Hernández; Belen Pose-García; María Luisa Sevillano-Palmero; Carmen  Mateo-Ruiz; Beatriz  Medina-Bustillo; Monica  Aguilar-Jiménez; OB12 Group; Amaya Azcoaga-Lorenzo

doi:10.1136/bmjopen-2019-033687

Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12)

Teresa Sanz-Cuesta, Esperanza Escortell-Mayor, Isabel Cura-Gonzalez, Jesus Martin-Fernandez, Rosario Riesgo-Fuertes, Sofía Garrido-Elustondo, Jose Enrique Mariño-Suárez, Mar Álvarez-Villalba, Tomás Gómez-Gascón, Inmaculada González-García, Paloma González-Escobar, Concepción Vargas-Machuca Cabañero, Mar Noguerol-Álvarez, Francisca García de Blas-González, Raquel Baños-Morras, Concepción Díaz-Laso, Nuria Caballero-Ramírez, Alicia Herrero de-Dios, Rosa Fernández-García, Jesús Herrero-HernándezBelen Pose-García, María Luisa Sevillano-Palmero, Carmen Mateo-Ruiz, Beatriz Medina-Bustillo, Monica Aguilar-Jiménez, OB12 Group, Amaya Azcoaga-Lorenzo

Research output: Contribution to journal › Article › peer-review

Abstract

Objectives To compare the effectiveness of oral versus intramuscular (IM) vitamin B₁₂ (VB12) in patients aged ≥65 years with VB12 deficiency.

Design Pragmatic, randomised, non-inferiority, multicentre trial in 22 primary healthcare centres in Madrid (Spain).

Participants 283 patients ≥65 years with VB12 deficiency were randomly assigned to oral (n=140) or IM (n=143) treatment arm.

Interventions The IM arm received 1 mg VB12 on alternate days in weeks 1–2, 1 mg/week in weeks 3–8 and 1 mg/month in weeks 9–52. The oral arm received 1 mg/day in weeks 1–8 and 1 mg/week in weeks 9–52.

Main outcomes Serum VB12 concentration normalisation (≥211 pg/mL) at 8, 26 and 52 weeks. Non-inferiority would be declared if the difference between arms is 10% or less. Secondary outcomes included symptoms, adverse events, adherence to treatment, quality of life, patient preferences and satisfaction.

Results The follow-up period (52 weeks) was completed by 229 patients (80.9%). At week 8, the percentage of patients in each arm who achieved normal B₁₂ levels was well above 90%; the differences in this percentage between the oral and IM arm were −0.7% (133 out of 135 vs 129 out of 130; 95% CI: −3.2 to 1.8; p>0.999) by per-protocol (PPT) analysis and 4.8% (133 out of 140 vs 129 out of 143; 95% CI: −1.3 to 10.9; p=0.124) by intention-to-treat (ITT) analysis. At week 52, the percentage of patients who achieved normal B₁₂ levels was 73.6% in the oral arm and 80.4% in the IM arm; these differences were −6.3% (103 out of 112 vs 115 out of 117; 95% CI: −11.9 to −0.1; p=0.025) and −6.8% (103 out of 140 vs 115 out of 143; 95% CI: −16.6 to 2.9; p=0.171), respectively. Factors affecting the success rate at week 52 were age, OR=0.95 (95% CI: 0.91 to 0.99) and having reached VB12 levels ≥281 pg/mL at week 8, OR=8.1 (95% CI: 2.4 to 27.3). Under a Bayesian framework, non-inferiority probabilities (Δ>−10%) at week 52 were 0.036 (PPT) and 0.060 (ITT). Quality of life and adverse effects were comparable across groups. 83.4% of patients preferred the oral route.

Conclusions Oral administration was no less effective than IM administration at 8 weeks. Although differences were found between administration routes at week 52, the probability that the differences were below the non-inferiority threshold was very low.

Original language	English
Article number	e033687
Number of pages	11
Journal	BMJ Open
Volume	10
Issue number	8
DOIs	https://doi.org/10.1136/bmjopen-2019-033687
Publication status	Published - 20 Aug 2020

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Sanz-Cuesta, T., Escortell-Mayor, E., Cura-Gonzalez, I., Martin-Fernandez, J., Riesgo-Fuertes, R., Garrido-Elustondo, S., Mariño-Suárez, J. E., Álvarez-Villalba, M., Gómez-Gascón, T., González-García, I., González-Escobar, P., Vargas-Machuca Cabañero, C., Noguerol-Álvarez, M., García de Blas-González, F., Baños-Morras, R., Díaz-Laso, C., Caballero-Ramírez, N., Herrero de-Dios, A., Fernández-García, R., ... Azcoaga-Lorenzo, A. (2020). Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12). BMJ Open, 10(8), Article e033687. https://doi.org/10.1136/bmjopen-2019-033687

@article{99771fd45bcf456a9edc8d6cdcce68c7,

title = "Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12)",

abstract = "Objectives To compare the effectiveness of oral versus intramuscular (IM) vitamin B12 (VB12) in patients aged ≥65 years with VB12 deficiency.Design Pragmatic, randomised, non-inferiority, multicentre trial in 22 primary healthcare centres in Madrid (Spain).Participants 283 patients ≥65 years with VB12 deficiency were randomly assigned to oral (n=140) or IM (n=143) treatment arm.Interventions The IM arm received 1 mg VB12 on alternate days in weeks 1–2, 1 mg/week in weeks 3–8 and 1 mg/month in weeks 9–52. The oral arm received 1 mg/day in weeks 1–8 and 1 mg/week in weeks 9–52.Main outcomes Serum VB12 concentration normalisation (≥211 pg/mL) at 8, 26 and 52 weeks. Non-inferiority would be declared if the difference between arms is 10% or less. Secondary outcomes included symptoms, adverse events, adherence to treatment, quality of life, patient preferences and satisfaction.Results The follow-up period (52 weeks) was completed by 229 patients (80.9%). At week 8, the percentage of patients in each arm who achieved normal B12 levels was well above 90%; the differences in this percentage between the oral and IM arm were −0.7% (133 out of 135 vs 129 out of 130; 95% CI: −3.2 to 1.8; p>0.999) by per-protocol (PPT) analysis and 4.8% (133 out of 140 vs 129 out of 143; 95% CI: −1.3 to 10.9; p=0.124) by intention-to-treat (ITT) analysis. At week 52, the percentage of patients who achieved normal B12 levels was 73.6% in the oral arm and 80.4% in the IM arm; these differences were −6.3% (103 out of 112 vs 115 out of 117; 95% CI: −11.9 to −0.1; p=0.025) and −6.8% (103 out of 140 vs 115 out of 143; 95% CI: −16.6 to 2.9; p=0.171), respectively. Factors affecting the success rate at week 52 were age, OR=0.95 (95% CI: 0.91 to 0.99) and having reached VB12 levels ≥281 pg/mL at week 8, OR=8.1 (95% CI: 2.4 to 27.3). Under a Bayesian framework, non-inferiority probabilities (Δ>−10%) at week 52 were 0.036 (PPT) and 0.060 (ITT). Quality of life and adverse effects were comparable across groups. 83.4% of patients preferred the oral route.Conclusions Oral administration was no less effective than IM administration at 8 weeks. Although differences were found between administration routes at week 52, the probability that the differences were below the non-inferiority threshold was very low.",

author = "Teresa Sanz-Cuesta and Esperanza Escortell-Mayor and Isabel Cura-Gonzalez and Jesus Martin-Fernandez and Rosario Riesgo-Fuertes and Sof{\'i}a Garrido-Elustondo and Mari{\~n}o-Su{\'a}rez, {Jose Enrique} and Mar {\'A}lvarez-Villalba and Tom{\'a}s G{\'o}mez-Gasc{\'o}n and Inmaculada Gonz{\'a}lez-Garc{\'i}a and Paloma Gonz{\'a}lez-Escobar and {Vargas-Machuca Caba{\~n}ero}, Concepci{\'o}n and Mar Noguerol-{\'A}lvarez and {Garc{\'i}a de Blas-Gonz{\'a}lez}, Francisca and Raquel Ba{\~n}os-Morras and Concepci{\'o}n D{\'i}az-Laso and Nuria Caballero-Ram{\'i}rez and {Herrero de-Dios}, Alicia and Rosa Fern{\'a}ndez-Garc{\'i}a and Jes{\'u}s Herrero-Hern{\'a}ndez and Belen Pose-Garc{\'i}a and Sevillano-Palmero, {Mar{\'i}a Luisa} and Carmen Mateo-Ruiz and Beatriz Medina-Bustillo and Monica Aguilar-Jim{\'e}nez and {OB12 Group} and Amaya Azcoaga-Lorenzo",

note = "The trial was financed by Ministerio de Sanidad y Consumo Espa{\~n}ol through their call for independent clinical research, Orden Ministerial SAS/2377, 2010 (EC10-115, EC10-116, EC10-117, EC10-119, EC10-122); CAIBER—Spanish Clinical Research Network, Instituto de Salud Carlos III (ISCIII) (CAI08/010044); and Gerencia Asistencial de Atenci{\'o}n Primaria de Madrid. This study is also supported by the Spanish Clinical Research Network (SCReN), funded by ISCIII-Subdirecci{\'o}n General de Evaluaci{\'o}n y Fomento de la Investigaci{\'o}n, project number PT13/0002/0007, within the National Research Program I+D+I 2013-2016 and co-funded with European Union ERDF funds (European Regional Development Fund). This project received a grant for the translation and publication of this article from the Foundation for Biomedical Research and Innovation in Primary Care (FIIBAP) Call 2017 for grants to promote research programs.",

year = "2020",

month = aug,

day = "20",

doi = "10.1136/bmjopen-2019-033687",

language = "English",

volume = "10",

journal = "BMJ Open",

issn = "2044-6055",

publisher = "BMJ Publishing Group Ltd",

number = "8",

}

Sanz-Cuesta, T, Escortell-Mayor, E, Cura-Gonzalez, I, Martin-Fernandez, J, Riesgo-Fuertes, R, Garrido-Elustondo, S, Mariño-Suárez, JE, Álvarez-Villalba, M, Gómez-Gascón, T, González-García, I, González-Escobar, P, Vargas-Machuca Cabañero, C, Noguerol-Álvarez, M, García de Blas-González, F, Baños-Morras, R, Díaz-Laso, C, Caballero-Ramírez, N, Herrero de-Dios, A, Fernández-García, R, Herrero-Hernández, J, Pose-García, B, Sevillano-Palmero, ML, Mateo-Ruiz, C, Medina-Bustillo, B, Aguilar-Jiménez, M, OB12 Group & Azcoaga-Lorenzo, A 2020, 'Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12)', BMJ Open, vol. 10, no. 8, e033687. https://doi.org/10.1136/bmjopen-2019-033687

TY - JOUR

T1 - Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care

T2 - a pragmatic, randomised, non-inferiority clinical trial (OB12)

AU - Sanz-Cuesta, Teresa

AU - Escortell-Mayor, Esperanza

AU - Cura-Gonzalez, Isabel

AU - Martin-Fernandez, Jesus

AU - Riesgo-Fuertes, Rosario

AU - Garrido-Elustondo, Sofía

AU - Mariño-Suárez, Jose Enrique

AU - Álvarez-Villalba, Mar

AU - Gómez-Gascón, Tomás

AU - González-García, Inmaculada

AU - González-Escobar, Paloma

AU - Vargas-Machuca Cabañero, Concepción

AU - Noguerol-Álvarez, Mar

AU - García de Blas-González, Francisca

AU - Baños-Morras, Raquel

AU - Díaz-Laso, Concepción

AU - Caballero-Ramírez, Nuria

AU - Herrero de-Dios, Alicia

AU - Fernández-García, Rosa

AU - Herrero-Hernández, Jesús

AU - Pose-García, Belen

AU - Sevillano-Palmero, María Luisa

AU - Mateo-Ruiz, Carmen

AU - Medina-Bustillo, Beatriz

AU - Aguilar-Jiménez, Monica

AU - OB12 Group

AU - Azcoaga-Lorenzo, Amaya

N1 - The trial was financed by Ministerio de Sanidad y Consumo Español through their call for independent clinical research, Orden Ministerial SAS/2377, 2010 (EC10-115, EC10-116, EC10-117, EC10-119, EC10-122); CAIBER—Spanish Clinical Research Network, Instituto de Salud Carlos III (ISCIII) (CAI08/010044); and Gerencia Asistencial de Atención Primaria de Madrid. This study is also supported by the Spanish Clinical Research Network (SCReN), funded by ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, project number PT13/0002/0007, within the National Research Program I+D+I 2013-2016 and co-funded with European Union ERDF funds (European Regional Development Fund). This project received a grant for the translation and publication of this article from the Foundation for Biomedical Research and Innovation in Primary Care (FIIBAP) Call 2017 for grants to promote research programs.

PY - 2020/8/20

Y1 - 2020/8/20

N2 - Objectives To compare the effectiveness of oral versus intramuscular (IM) vitamin B12 (VB12) in patients aged ≥65 years with VB12 deficiency.Design Pragmatic, randomised, non-inferiority, multicentre trial in 22 primary healthcare centres in Madrid (Spain).Participants 283 patients ≥65 years with VB12 deficiency were randomly assigned to oral (n=140) or IM (n=143) treatment arm.Interventions The IM arm received 1 mg VB12 on alternate days in weeks 1–2, 1 mg/week in weeks 3–8 and 1 mg/month in weeks 9–52. The oral arm received 1 mg/day in weeks 1–8 and 1 mg/week in weeks 9–52.Main outcomes Serum VB12 concentration normalisation (≥211 pg/mL) at 8, 26 and 52 weeks. Non-inferiority would be declared if the difference between arms is 10% or less. Secondary outcomes included symptoms, adverse events, adherence to treatment, quality of life, patient preferences and satisfaction.Results The follow-up period (52 weeks) was completed by 229 patients (80.9%). At week 8, the percentage of patients in each arm who achieved normal B12 levels was well above 90%; the differences in this percentage between the oral and IM arm were −0.7% (133 out of 135 vs 129 out of 130; 95% CI: −3.2 to 1.8; p>0.999) by per-protocol (PPT) analysis and 4.8% (133 out of 140 vs 129 out of 143; 95% CI: −1.3 to 10.9; p=0.124) by intention-to-treat (ITT) analysis. At week 52, the percentage of patients who achieved normal B12 levels was 73.6% in the oral arm and 80.4% in the IM arm; these differences were −6.3% (103 out of 112 vs 115 out of 117; 95% CI: −11.9 to −0.1; p=0.025) and −6.8% (103 out of 140 vs 115 out of 143; 95% CI: −16.6 to 2.9; p=0.171), respectively. Factors affecting the success rate at week 52 were age, OR=0.95 (95% CI: 0.91 to 0.99) and having reached VB12 levels ≥281 pg/mL at week 8, OR=8.1 (95% CI: 2.4 to 27.3). Under a Bayesian framework, non-inferiority probabilities (Δ>−10%) at week 52 were 0.036 (PPT) and 0.060 (ITT). Quality of life and adverse effects were comparable across groups. 83.4% of patients preferred the oral route.Conclusions Oral administration was no less effective than IM administration at 8 weeks. Although differences were found between administration routes at week 52, the probability that the differences were below the non-inferiority threshold was very low.

AB - Objectives To compare the effectiveness of oral versus intramuscular (IM) vitamin B12 (VB12) in patients aged ≥65 years with VB12 deficiency.Design Pragmatic, randomised, non-inferiority, multicentre trial in 22 primary healthcare centres in Madrid (Spain).Participants 283 patients ≥65 years with VB12 deficiency were randomly assigned to oral (n=140) or IM (n=143) treatment arm.Interventions The IM arm received 1 mg VB12 on alternate days in weeks 1–2, 1 mg/week in weeks 3–8 and 1 mg/month in weeks 9–52. The oral arm received 1 mg/day in weeks 1–8 and 1 mg/week in weeks 9–52.Main outcomes Serum VB12 concentration normalisation (≥211 pg/mL) at 8, 26 and 52 weeks. Non-inferiority would be declared if the difference between arms is 10% or less. Secondary outcomes included symptoms, adverse events, adherence to treatment, quality of life, patient preferences and satisfaction.Results The follow-up period (52 weeks) was completed by 229 patients (80.9%). At week 8, the percentage of patients in each arm who achieved normal B12 levels was well above 90%; the differences in this percentage between the oral and IM arm were −0.7% (133 out of 135 vs 129 out of 130; 95% CI: −3.2 to 1.8; p>0.999) by per-protocol (PPT) analysis and 4.8% (133 out of 140 vs 129 out of 143; 95% CI: −1.3 to 10.9; p=0.124) by intention-to-treat (ITT) analysis. At week 52, the percentage of patients who achieved normal B12 levels was 73.6% in the oral arm and 80.4% in the IM arm; these differences were −6.3% (103 out of 112 vs 115 out of 117; 95% CI: −11.9 to −0.1; p=0.025) and −6.8% (103 out of 140 vs 115 out of 143; 95% CI: −16.6 to 2.9; p=0.171), respectively. Factors affecting the success rate at week 52 were age, OR=0.95 (95% CI: 0.91 to 0.99) and having reached VB12 levels ≥281 pg/mL at week 8, OR=8.1 (95% CI: 2.4 to 27.3). Under a Bayesian framework, non-inferiority probabilities (Δ>−10%) at week 52 were 0.036 (PPT) and 0.060 (ITT). Quality of life and adverse effects were comparable across groups. 83.4% of patients preferred the oral route.Conclusions Oral administration was no less effective than IM administration at 8 weeks. Although differences were found between administration routes at week 52, the probability that the differences were below the non-inferiority threshold was very low.

U2 - 10.1136/bmjopen-2019-033687

DO - 10.1136/bmjopen-2019-033687

M3 - Article

SN - 2044-6055

VL - 10

JO - BMJ Open

JF - BMJ Open

IS - 8

M1 - e033687

ER -

Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12)

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