Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12)

Teresa Sanz-Cuesta, Paloma González-Escobar, Rosario Riesgo-Fuertes, Sofía Garrido-Elustondo, Isabel del Cura-González, Jesús Martín-Fernández, Esperanza Escortell-Mayor, Francisco Rodríguez-Salvanés, Marta García-Solano, Rocío González-González, María Ángeles Martín-de la Sierra-San Agustín, Carmen Olmedo-Lucerón, María Luisa Sevillano Palmero, Carmen Mateo-Ruiz, Beatriz Medina-Bustillo, Antonio Valdivia-Pérez, Francisca García-de Blas-González, José Enrique Mariño-Suárez, Ricardo Rodríguez-Barrientos, Gloria Ariza-Cardiel, Luisa María Cabello-Ballesteros, Elena Polentinos-Castro, Milagros Rico-Blázquez, Ma Teresa Rodríguez-Monje, Sonia Soto-Díaz, Susana Martín-Iglesias, Ramón Rodríguez-González, Irene Bretón-Lesmes, María Vicente-Herrero, Jesús Sánchez-Díaz, Tomás Gómez-Gascón, Mercedes Drake-Canela, Ángel Asúnsolo-del Barco, OB12 Group, Germán Reviriego Jaén, Cristina Montero García, Ana Isabel Sanz Lorente, Ma del Pilar Serrano Simarro, Julián Díaz Sánchez, Irma Ma Ramos Gutiérrez, Josefa Ma San Vicente Rodríguez, Pilar Huelin Martín, Ma Inmaculada González García, Margarita Camarero Shelly, Clarisa Reinares Martínez, Laura Villanova Cuadra, Rosa Ma Gómez del Forcallo, Francisco Endrino Gómez, Ma Rosario Ferreras Eleta, Luis De Vicente Aymat, María Santos Santander Gutiérrez, Alicia Mateo Madurga, Nuria Caballero Ramírez, Ana Morán Escudero, Mercedes Rodríguez Franco, Ma Luz Meiriño Pérez, Ma Mar Zamora Gómez, Francisco Vivas Rubio, María Martín Martín, Rafael Pérez Quero, Ma Isabel Manzano Martín, Raimundo Pastor Sánchez, Alicia Herrero de Dios, Cesar Redondo Luciáñez, Cristina Casado Rodríguez, Luisa María Andrés Arreaza, Pilar Hombrados Gonzalo, Soledad Escolar Llamazares, Francisco López Ortiz, Luz Ma del Rey Moya, Isabel Rodríguez López, Diego Martín Acicoya, Pilar Kloppe Villegas, Isabel García Amor, Magdalena Canals Aracil, José Javier Gómez Marco, Alberto González Álvaro, Fco Javier San Andrés Rebollo, Inés González López, Isabel Herreros Hernanz, Antonio Revuelta Alonso, Nieves Calvo Arrabal, Ma Milagros Jimeno Galán, Rosa García Hernández, Tomás Gómez Gascón, Concepción Vargas-Machuca Cabañero, Ma Isabel Gutiérrez Sánchez, Ma Angeles Fernández Abad, Margarita Beltejar Rodríguez, Javier Martínez Suberviola, Miguel Angel Real Pérez, Carmen Coello Alarcón, Carlos San Andrés Pascua, José Antonio Granados Garrido, Santiago Machín Hamalainen, Raquel Mateo Fernández, Cristina de la Cámara Gonzalez, José D Garcés Ranz, Asunción Prieto Orzanco, Ma Teresa Marín Becerra, Paulino Cubero González, Francisco R Abellán López, Olga Álvarez Montes, Mercedes Canellas Manrique, Ma José San Telesforo Navarro, Ma Mercedes Parrilla Laso, Ma Ángeles Aragoneses Cañas, Angela Auñón Muelas, Esther Valdés Cruz, Consuelo Mayoral Lopez, Teresa Gijon Seco, Francisca Martinez Vallejo, Ana Isabel Menéndez Fernández, Ma del Mar De la Peña González, Ma Ángeles Maroto García, María Sánchez Cristóbal, Ma Carmen Álvarez Orviz, Jesús Herrero Hernández, Ma Veredas González Márquez, Ma Jesús López Rodríguez, Ma de las Maravillas Almarza García, Ma Teresa San Clemente Pastor, Ma Ámparo Corral Rubio, Gonzalo Ruiz Zurita, Ángela Allue Bergua, Marta Cabrera Orozco, Ma del Puerto De Antonio García, Ana Isabel Cerezo Diviu, Inmaculada Solsons Roig, Pilar Gómez de Abia, María Concepción Díaz Laso, Ma Luisa Asensio Ruiz, Carmen Siguero Pérez, Antonio Molina Siguero, Inmaculada Cerrada Puri, Paloma Rodríguez Almagro, Rosa Rosanes González, Ma Carmen Pérez García, Mar Noguerol Álvarez, Ma Ángeles de Miguel Abanto, Ma Lourdes Reyes Martínez, Pilar Gutiérrez Valentín, Jorge Gómez Ciriano, Raquel Calzada Benito, Carolina Torrijos Bravo, David Ferreiro González, Judit León González, Nuria Tomás García, Alberto Alcalá Faúndez, Eva Fernández López, Inés Melero Redondo, Ricardo González Gascón, Jeannet Sánchez Yépez, Mercedes del Pilar Fernández Girón, Beatriz López Serrano, Ma Teresa Rodríguez Monje, Paloma Morso Pelaez, María Cortes Duran, Carolina López Olmeda, Almudena García-Uceda Sevilla, Dolores Serrano González, Inmaculada Santamaría López, Francisca García De Blas González, Alberto López García-Franco, Amaya Azcoaga Lorenzo, Mar Álvarez Villalba, Belén Pose García, Rosa Fernández García, Francisco de Alba Gómez, Antonio Redondo Horcajo, Beatriz Pajuelo Márquez, José Luis Gala Paniagua, Encarnación Cidoncha Calderón, Ángel Delgado Delgado, Ma Jesús Gómez Martín, José Francisco Ávila Tomas, José Enrique Mariño Suárez, José Luis Quintana Gómez, José Antonio González-Posada Delgado, Enrique Revilla Pascual, Esperanza Duralde Rodríguez, Milagros Beamud Lagos, Leonor González Galán, María Verdugo Rosado, Luis Nistal Martín de Serranos, Ma Jesús López Barroso, Mariano Rivera Moreno, Margarita Torres Parras, Ma Reyes Delgado Pulpon, Elena Alcalá Llorente, Sonsoles Muñoz Moreno, Ana María Ribao Verdugo, María Jesús Fidalgo Baz, Isabel Vaquero Turiño, Ana María Jeú Fidalgo Baz, Clementa Sanz Sanchez, Ana María Sánchez Sempere, Javier Martínez Sanz, María Isabel Arratibel Elizondo, Paloma González Escobar, Javier Muñoz Gutiérrez, Raquel Baños Morras, Carmen Molins Santos, Ana María Ibarra Sánchez, Cecilio Gómez Almodóvar, Cristina Cassinello Espinosa, Teresa Sanz-Cuesta, Paloma González-Escobar, Rosario Riesgo-Fuertes, Sofía Garrido-Elustondo, Isabel del Cura-González, Jesús Martín-Fernández, Esperanza Escortell-Mayor, Francisco Rodríguez-Salvanés, Marta García-Solano, Rocío González-González, María Ángeles Martín-de la Sierra-San Agustín, Carmen Olmedo-Lucerón, María Luisa Sevillano Palmero, Carmen Mateo-Ruiz, Beatriz Medina-Bustillo, Antonio Valdivia-Pérez, Francisca García-de Blas-González, José Enrique Mariño-Suárez, Ricardo Rodríguez-Barrientos, Gloria Ariza-Cardiel, Luisa María Cabello-Ballesteros, Elena Polentinos-Castro, Milagros Rico-Blázquez, Ma Teresa Rodríguez-Monje, Sonia Soto-Díaz, Susana Martín-Iglesias, Ramón Rodríguez-González, Irene Bretón-Lesmes, María Vicente-Herrero, Jesús Sánchez-Díaz, Tomás Gómez-Gascón, Mercedes Drake-Canela, Ángel Asúnsolo-del Barco, OB12 Group, Germán Reviriego Jaén, Cristina Montero García, Ana Isabel Sanz Lorente, Ma del Pilar Serrano Simarro, Julián Díaz Sánchez, Irma Ma Ramos Gutiérrez, Josefa Ma San Vicente Rodríguez, Pilar Huelin Martín, Ma Inmaculada González García, Margarita Camarero Shelly, Clarisa Reinares Martínez, Laura Villanova Cuadra, Rosa Ma Gómez del Forcallo, Francisco Endrino Gómez, Ma Rosario Ferreras Eleta, Luis De Vicente Aymat, María Santos Santander Gutiérrez, Alicia Mateo Madurga, Nuria Caballero Ramírez, Ana Morán Escudero, Mercedes Rodríguez Franco, Ma Luz Meiriño Pérez, Ma Mar Zamora Gómez, Francisco Vivas Rubio, María Martín Martín, Rafael Pérez Quero, Ma Isabel Manzano Martín, Raimundo Pastor Sánchez, Alicia Herrero de Dios, Cesar Redondo Luciáñez, Cristina Casado Rodríguez, Luisa María Andrés Arreaza, Pilar Hombrados Gonzalo, Soledad Escolar Llamazares, Francisco López Ortiz, Luz Ma del Rey Moya, Isabel Rodríguez López, Diego Martín Acicoya, Pilar Kloppe Villegas, Isabel García Amor, Magdalena Canals Aracil, José Javier Gómez Marco, Alberto González Álvaro, Fco Javier San Andrés Rebollo, Inés González López, Isabel Herreros Hernanz, Antonio Revuelta Alonso, Nieves Calvo Arrabal, Ma Milagros Jimeno Galán, Rosa García Hernández, Tomás Gómez Gascón, Concepción Vargas-Machuca Cabañero, Ma Isabel Gutiérrez Sánchez, Ma Angeles Fernández Abad, Margarita Beltejar Rodríguez, Javier Martínez Suberviola, Miguel Angel Real Pérez, Carmen Coello Alarcón, Carlos San Andrés Pascua, José Antonio Granados Garrido, Santiago Machín Hamalainen, Raquel Mateo Fernández, Cristina de la Cámara Gonzalez, José D Garcés Ranz, Asunción Prieto Orzanco, Ma Teresa Marín Becerra, Paulino Cubero González, Francisco R Abellán López, Olga Álvarez Montes, Mercedes Canellas Manrique, Ma José San Telesforo Navarro, Ma Mercedes Parrilla Laso, Ma Ángeles Aragoneses Cañas, Angela Auñón Muelas, Esther Valdés Cruz, Consuelo Mayoral Lopez, Teresa Gijon Seco, Francisca Martinez Vallejo, Ana Isabel Menéndez Fernández, Ma del Mar De la Peña González, Ma Ángeles Maroto García, María Sánchez Cristóbal, Ma Carmen Álvarez Orviz, Jesús Herrero Hernández, Ma Veredas González Márquez, Ma Jesús López Rodríguez, Ma de las Maravillas Almarza García, Ma Teresa San Clemente Pastor, Ma Ámparo Corral Rubio, Gonzalo Ruiz Zurita, Ángela Allue Bergua, Marta Cabrera Orozco, Ma del Puerto De Antonio García, Ana Isabel Cerezo Diviu, Inmaculada Solsons Roig, Pilar Gómez de Abia, María Concepción Díaz Laso, Ma Luisa Asensio Ruiz, Carmen Siguero Pérez, Antonio Molina Siguero, Inmaculada Cerrada Puri, Paloma Rodríguez Almagro, Rosa Rosanes González, Ma Carmen Pérez García, Mar Noguerol Álvarez, Ma Ángeles de Miguel Abanto, Ma Lourdes Reyes Martínez, Pilar Gutiérrez Valentín, Jorge Gómez Ciriano, Raquel Calzada Benito, Carolina Torrijos Bravo, David Ferreiro González, Judit León González, Nuria Tomás García, Alberto Alcalá Faúndez, Eva Fernández López, Inés Melero Redondo, Ricardo González Gascón, Jeannet Sánchez Yépez, Mercedes del Pilar Fernández Girón, Beatriz López Serrano, Ma Teresa Rodríguez Monje, Paloma Morso Pelaez, María Cortes Duran, Carolina López Olmeda, Almudena García-Uceda Sevilla, Dolores Serrano González, Inmaculada Santamaría López, Francisca García De Blas González, Alberto López García-Franco, Amaya Azcoaga Lorenzo, Mar Álvarez Villalba, Belén Pose García, Rosa Fernández García, Francisco de Alba Gómez, Antonio Redondo Horcajo, Beatriz Pajuelo Márquez, José Luis Gala Paniagua, Encarnación Cidoncha Calderón, Ángel Delgado Delgado, Ma Jesús Gómez Martín, José Francisco Ávila Tomas, José Enrique Mariño Suárez, José Luis Quintana Gómez, José Antonio González-Posada Delgado, Enrique Revilla Pascual, Esperanza Duralde Rodríguez, Milagros Beamud Lagos, Leonor González Galán, María Verdugo Rosado, Luis Nistal Martín de Serranos, Ma Jesús López Barroso, Mariano Rivera Moreno, Margarita Torres Parras, Ma Reyes Delgado Pulpon, Elena Alcalá Llorente, Sonsoles Muñoz Moreno, Ana María Ribao Verdugo, María Jesús Fidalgo Baz, Isabel Vaquero Turiño, Ana María Jeú Fidalgo Baz, Clementa Sanz Sanchez, Ana María Sánchez Sempere, Javier Martínez Sanz, María Isabel Arratibel Elizondo, Paloma González Escobar, Javier Muñoz Gutiérrez, Raquel Baños Morras, Carmen Molins Santos, Ana María Ibarra Sánchez, Cecilio Gómez Almodóvar, Cristina Cassinello Espinosa

Abstract

Background: The oral administration of vitamin B12 offers a potentially simpler and cheaper alternative to parenteral administration, but its effectiveness has not been definitively demonstrated. The following protocol was designed to compare the effectiveness of orally and intramuscularly administered vitamin B12 in the treatment of patients ≥65 years of age with vitamin B12 deficiency.

Methods/design: The proposed study involves a controlled, randomised, multicentre, parallel, non-inferiority clinical trial lasting one year, involving 23 primary healthcare centres in the Madrid region (Spain), and patients ≥65 years of age. The minimum number of patients required for the study was calculated as 320 (160 in each arm). Bearing in mind an estimated 8-10% prevalence of vitamin B12 deficiency among the population of this age group, an initial sample of 3556 patients will need to be recruited. Eligible patients will be randomly assigned to one of the two treatment arms. In the intramuscular treatment arm, vitamin B12 will be administered as follows: 1 mg on alternate days in weeks 1 and 2, 1 mg/week in weeks 3-8,and 1 mg/month in weeks 9-52. In the oral arm, the vitamin will be administered as: 1 mg/day in weeks 1-8 and 1 mg/week in weeks 9-52. The main outcome variable to be monitored in both treatment arms is the normalisation of the serum vitamin B12 concentration at weeks 8, 26 and 52; the secondary outcome variables include the serum concentration of vitamin B12 (in pg/ml), adherence to treatment, quality of life (EuroQoL-5D questionnaire), patient 3satisfaction and patient preferences. All statistical tests will be performed with intention to treat and per protocol. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in analyses.

Discussion: The results of this study should help establish, taking quality of life into account, whether the oral administration of vitamin B12 is an effective alternative to its intramuscular administration. If this administration route is effective, it should provide a cheaper means of treating vitamin B12 deficiency while inducing fewer adverse effects. Having such an alternative would also allow patient preferences to be taken into consideration at the time of prescribing treatment.

Trial registration: This trial has been registered with ClinicalTrials.gov, number NCT 01476007, and under EUDRACT number 2010-024129-20.

Trial registration: ClinicalTrials.gov NCT01476007.

Figures

Figure 1
Figure 1
Patient recruitment.

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