Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12)
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 VB...
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2020-08-01
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| Series: | BMJ Open |
| Online Access: | https://bmjopen.bmj.com/content/10/8/e033687.full |
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| author | 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 Isabel Gutiérrez-Sánchez Ángeles Fernández-Abad José Antonio Granados-Garrido Javier Martínez-Suberviola Margarita Beltejar-Rodríguez Carmen Coello-Alarcón Susana Diez-Arjona Ana Ballarín-González Ignacio Iscar-Valenzuela José Luis Quintana-Gómez José Antonio González-Posada-Delgado Enrique Revilla-Pascual Esther Gómez-Suarez Yolanda Fernández-Fernández Fernanda Morales-Ortiz Isabel Ferrer-Zapata Esperanza Duralde-Rodríguez Milagros Beamud-Lagos Mª del Pilar Serrano-Simarro Cristina Montero-García María Domínguez-Paniagua Sofía Causín-Serrano Josefa San Vicente-Rodríguez Germán Reviriego-Jaén Margarita Camarero-Shelly Rosa Gómez-del Forcallo María Ángeles Miguel-Abanto Lourdes Reyes-Martínez Alejandro Rabanal-Basalo Carolina Torrijos-Bravo Pilar Gutiérrez-Valentín Jorge Gómez-Ciriano Susana Parra Román Judit León-González Mª José Nebril-Manzaneque Juana Caro-Berzal Alberto López-García-Franco Sonia Redondo de-Pedro Juan Carlos García-Álvarez Elisa Viñuela-Beneitez Marisa López-Martín Nuria Sanz-López Ana María Ibarra-Sánchez Cecilio Gómez-Almodóvar Javier Muñoz-Gutiérrez Carmen Molins-Santos Cristina Cassinello-Espinosa Antonio Molina-Siguero Rafael Sáez-Jiménez Paloma Rodríguez-Almagro Eva María Rey-Camacho María Carmen Pérez-García Antonio Redondo-Horcajo Beatriz Pajuelo-Márquez Encarnación Cidoncha-Calderón Jesús Galindo Rubio RosaAna Escriva Ferrairo José Francisco Ávila-Tomas Francisco De-Alba-Gómez Mª Jesús Gómez-Martín Alma María Fernández-Martínez Rosa Feijoó-Fernández José Vizcaíno-Sánchez-Rodrigo Victoria Díaz-Puente Felisa Núñez-Sáez Luisa Asensio-Ruiz Agustín Sánchez-Sánchez Orlando Enríquez-Dueñas Silvia Fidel-Jaimez Rafael Ruiz-Morote-Aragón Asunción Pacheco-Pascua Belén Soriano-Hernández Eva Álvarez-Carranza Carmen Siguero-Pérez Ana Morán-Escudero María Martín-Martín Francisco Vivas-Rubio Rafael Pérez-Quero Mª Isabel Manzano-Martín César Redondo-Luciáñez Nuria Tomás-García Carlos Díaz-Gómez-Calcerrada Julia Isabel Mogollo-García Inés Melero-Redondo Ricardo González-Gascón María Carmen Álvarez-Orviz María Veredas González-Márquez Teresa SanClemente-Pastor Amparo Corral-Rubio Asunción Prieto-Orzanco Cristina dela Cámara-Gonzalez Mercedes Parrilla-Laso Mercedes Canellas-Manrique Maria Eloisa Rogero-Blanco Paulino Cubero-González Sara Sanchez-Barreiro Mª Ángeles Aragoneses-Cañas Ángela Auñón-Muelas Olga Álvarez Montes Petra María Cortes-Duran Pilar Tardaguila-Lobato Mar Escobar Gallegos Antonia Pérez-de-Colosia-Zuil Jaime Inneraraty-Martínez María Jesús Bedoya-Frutos María Teresa López-López Nelly Álvarez-Fernández Teresa Fontova-Cemeli Josefa Marruedo-Mateo Josefa Díaz-Serrano Beatriz Pérez-Vallejo Pilar Hombrados-Gonzalo Marta Quintanilla-Santamaría Yolanda González-Pascual Luisa María Andrés-Arreaza Soledad Escolar-Llamazares Cristina Casado-Rodríguez Luzdel Rey-Moya Jesús Fernández-Valderrama Alejandro Medrán-López Julia Alonso-Arcas Alejandra Rabanal-Carrera Araceli Garrido-Barral Milagros Velázquez-García Azucena Sáez-Berlanga Pilar Pérez-Egea Pablo Astorga-Díaz Carlos Casanova-García Ana Isabel Román-Ruiz Carmen Belinchón-Moya Margarita Encinas-Sotillo Virtudes Enguita-Pérez Ester Valdés-Cruz Consuelo Mayoral-López Teresa Gijón-Seco Francisca Martínez-Vallejo Jesica Colorado-Valera Ana Sosa-Alonso Jeannet Sánchez-Yépez Dolores Serrano-González Beatriz López-Serrano Inmaculada Santamaría-López Paloma Morso-Peláez Carolina López-Olmeda Almudena García-Uceda-Sevilla Mercedes delPilar Fernández-Girón Leonor González-Galán Mariano Rivera-Moreno Luis Nistal Martín-de-Serranos Mª Jesús López-Barroso Margarita Torres-Parras María Verdugo-Rosado Mª Reyes Delgado-Pulpón Elena Alcalá-Llorente Sonsoles Muñoz-Moreno Isabel Vaquero-Turiño Ana María Sánchez-Sempere FranciscoJavier Martínez-Sanz Clementa Sanz-Sanchez AnaMaría Arias-Esteso Diego Martín-Acicoya Pilar Kloppe-Villegas Francisco Javier San-Andrés-Rebollo Magdalena Canals-Aracil Isabel García-Amor Nieves Calvo-Arrabal María Milagros Jimeno-Galán Gloriade la Sierra-Ocaña María Mercedes Araujo-Calvo Julia Timoner-Aguilera María Santos Santander-Gutiérrez Alicia Mateo-Madurga Ricardo Rodríguez-Barrientos Milagros Rico-Blázquez Juan Carlos Gil-Moreno Mariel Morey-Montalvo Amaya Azcoaga Lorenzo Gloria Ariza-Cardiel Elena Polentinos-Castro Sonia Soto-Díaz Mª Teresa Rodríguez-Monje Susana Martín-Iglesias Francisco Rodríguez-Salvanés Marta García-Solano Rocío González-González María Vicente Herrero Ramón Rodríguez-González Irene Bretón-Lesmes Martadel Alamo Camuñas Anabel Sánchez Espadas Marisa Serrano Olmeda Mª Angeles Gálvez Múgica |
| author_facet | 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 Isabel Gutiérrez-Sánchez Ángeles Fernández-Abad José Antonio Granados-Garrido Javier Martínez-Suberviola Margarita Beltejar-Rodríguez Carmen Coello-Alarcón Susana Diez-Arjona Ana Ballarín-González Ignacio Iscar-Valenzuela José Luis Quintana-Gómez José Antonio González-Posada-Delgado Enrique Revilla-Pascual Esther Gómez-Suarez Yolanda Fernández-Fernández Fernanda Morales-Ortiz Isabel Ferrer-Zapata Esperanza Duralde-Rodríguez Milagros Beamud-Lagos Mª del Pilar Serrano-Simarro Cristina Montero-García María Domínguez-Paniagua Sofía Causín-Serrano Josefa San Vicente-Rodríguez Germán Reviriego-Jaén Margarita Camarero-Shelly Rosa Gómez-del Forcallo María Ángeles Miguel-Abanto Lourdes Reyes-Martínez Alejandro Rabanal-Basalo Carolina Torrijos-Bravo Pilar Gutiérrez-Valentín Jorge Gómez-Ciriano Susana Parra Román Judit León-González Mª José Nebril-Manzaneque Juana Caro-Berzal Alberto López-García-Franco Sonia Redondo de-Pedro Juan Carlos García-Álvarez Elisa Viñuela-Beneitez Marisa López-Martín Nuria Sanz-López Ana María Ibarra-Sánchez Cecilio Gómez-Almodóvar Javier Muñoz-Gutiérrez Carmen Molins-Santos Cristina Cassinello-Espinosa Antonio Molina-Siguero Rafael Sáez-Jiménez Paloma Rodríguez-Almagro Eva María Rey-Camacho María Carmen Pérez-García Antonio Redondo-Horcajo Beatriz Pajuelo-Márquez Encarnación Cidoncha-Calderón Jesús Galindo Rubio RosaAna Escriva Ferrairo José Francisco Ávila-Tomas Francisco De-Alba-Gómez Mª Jesús Gómez-Martín Alma María Fernández-Martínez Rosa Feijoó-Fernández José Vizcaíno-Sánchez-Rodrigo Victoria Díaz-Puente Felisa Núñez-Sáez Luisa Asensio-Ruiz Agustín Sánchez-Sánchez Orlando Enríquez-Dueñas Silvia Fidel-Jaimez Rafael Ruiz-Morote-Aragón Asunción Pacheco-Pascua Belén Soriano-Hernández Eva Álvarez-Carranza Carmen Siguero-Pérez Ana Morán-Escudero María Martín-Martín Francisco Vivas-Rubio Rafael Pérez-Quero Mª Isabel Manzano-Martín César Redondo-Luciáñez Nuria Tomás-García Carlos Díaz-Gómez-Calcerrada Julia Isabel Mogollo-García Inés Melero-Redondo Ricardo González-Gascón María Carmen Álvarez-Orviz María Veredas González-Márquez Teresa SanClemente-Pastor Amparo Corral-Rubio Asunción Prieto-Orzanco Cristina dela Cámara-Gonzalez Mercedes Parrilla-Laso Mercedes Canellas-Manrique Maria Eloisa Rogero-Blanco Paulino Cubero-González Sara Sanchez-Barreiro Mª Ángeles Aragoneses-Cañas Ángela Auñón-Muelas Olga Álvarez Montes Petra María Cortes-Duran Pilar Tardaguila-Lobato Mar Escobar Gallegos Antonia Pérez-de-Colosia-Zuil Jaime Inneraraty-Martínez María Jesús Bedoya-Frutos María Teresa López-López Nelly Álvarez-Fernández Teresa Fontova-Cemeli Josefa Marruedo-Mateo Josefa Díaz-Serrano Beatriz Pérez-Vallejo Pilar Hombrados-Gonzalo Marta Quintanilla-Santamaría Yolanda González-Pascual Luisa María Andrés-Arreaza Soledad Escolar-Llamazares Cristina Casado-Rodríguez Luzdel Rey-Moya Jesús Fernández-Valderrama Alejandro Medrán-López Julia Alonso-Arcas Alejandra Rabanal-Carrera Araceli Garrido-Barral Milagros Velázquez-García Azucena Sáez-Berlanga Pilar Pérez-Egea Pablo Astorga-Díaz Carlos Casanova-García Ana Isabel Román-Ruiz Carmen Belinchón-Moya Margarita Encinas-Sotillo Virtudes Enguita-Pérez Ester Valdés-Cruz Consuelo Mayoral-López Teresa Gijón-Seco Francisca Martínez-Vallejo Jesica Colorado-Valera Ana Sosa-Alonso Jeannet Sánchez-Yépez Dolores Serrano-González Beatriz López-Serrano Inmaculada Santamaría-López Paloma Morso-Peláez Carolina López-Olmeda Almudena García-Uceda-Sevilla Mercedes delPilar Fernández-Girón Leonor González-Galán Mariano Rivera-Moreno Luis Nistal Martín-de-Serranos Mª Jesús López-Barroso Margarita Torres-Parras María Verdugo-Rosado Mª Reyes Delgado-Pulpón Elena Alcalá-Llorente Sonsoles Muñoz-Moreno Isabel Vaquero-Turiño Ana María Sánchez-Sempere FranciscoJavier Martínez-Sanz Clementa Sanz-Sanchez AnaMaría Arias-Esteso Diego Martín-Acicoya Pilar Kloppe-Villegas Francisco Javier San-Andrés-Rebollo Magdalena Canals-Aracil Isabel García-Amor Nieves Calvo-Arrabal María Milagros Jimeno-Galán Gloriade la Sierra-Ocaña María Mercedes Araujo-Calvo Julia Timoner-Aguilera María Santos Santander-Gutiérrez Alicia Mateo-Madurga Ricardo Rodríguez-Barrientos Milagros Rico-Blázquez Juan Carlos Gil-Moreno Mariel Morey-Montalvo Amaya Azcoaga Lorenzo Gloria Ariza-Cardiel Elena Polentinos-Castro Sonia Soto-Díaz Mª Teresa Rodríguez-Monje Susana Martín-Iglesias Francisco Rodríguez-Salvanés Marta García-Solano Rocío González-González María Vicente Herrero Ramón Rodríguez-González Irene Bretón-Lesmes Martadel Alamo Camuñas Anabel Sánchez Espadas Marisa Serrano Olmeda Mª Angeles Gálvez Múgica |
| author_sort | Teresa Sanz-Cuesta |
| collection | DOAJ |
| description | 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.Trial registration numbers NCT 01476007; EUDRACT (2010-024129-20). |
| format | Article |
| id | doaj-art-0d8b7b39469a4d5c8a24dbac85559f50 |
| institution | Kabale University |
| issn | 2044-6055 |
| language | English |
| publishDate | 2020-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open |
| spelling | doaj-art-0d8b7b39469a4d5c8a24dbac85559f502024-12-02T15:30:08ZengBMJ Publishing GroupBMJ Open2044-60552020-08-0110810.1136/bmjopen-2019-033687Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12)Teresa Sanz-Cuesta0Esperanza Escortell-Mayor1Isabel Cura-Gonzalez2Jesus Martin-Fernandez3Rosario Riesgo-Fuertes4Sofía Garrido-Elustondo5Jose Enrique Mariño-Suárez6Mar Álvarez-Villalba7Tomás Gómez-Gascón8Inmaculada González-García9Paloma González-Escobar10Concepción Vargas-Machuca Cabañero11Mar Noguerol-Álvarez12Francisca García de Blas-González13Raquel Baños-Morras14Concepción Díaz-Laso15Nuria Caballero-Ramírez16Alicia Herrero de-Dios17Rosa Fernández-García18Jesús Herrero-Hernández19Belen Pose-García20María Luisa Sevillano-Palmero21Carmen Mateo-Ruiz22Beatriz Medina-Bustillo23Monica Aguilar-Jiménez24Isabel Gutiérrez-SánchezÁngeles Fernández-AbadJosé Antonio Granados-GarridoJavier Martínez-SuberviolaMargarita Beltejar-RodríguezCarmen Coello-AlarcónSusana Diez-ArjonaAna Ballarín-GonzálezIgnacio Iscar-ValenzuelaJosé Luis Quintana-GómezJosé Antonio González-Posada-DelgadoEnrique Revilla-PascualEsther Gómez-SuarezYolanda Fernández-FernándezFernanda Morales-OrtizIsabel Ferrer-ZapataEsperanza Duralde-RodríguezMilagros Beamud-LagosMª del Pilar Serrano-SimarroCristina Montero-GarcíaMaría Domínguez-PaniaguaSofía Causín-SerranoJosefa San Vicente-RodríguezGermán Reviriego-JaénMargarita Camarero-ShellyRosa Gómez-del ForcalloMaría Ángeles Miguel-AbantoLourdes Reyes-MartínezAlejandro Rabanal-BasaloCarolina Torrijos-BravoPilar Gutiérrez-ValentínJorge Gómez-CirianoSusana Parra RománJudit León-GonzálezMª José Nebril-ManzanequeJuana Caro-BerzalAlberto López-García-FrancoSonia Redondo de-PedroJuan Carlos García-ÁlvarezElisa Viñuela-BeneitezMarisa López-MartínNuria Sanz-LópezAna María Ibarra-SánchezCecilio Gómez-AlmodóvarJavier Muñoz-GutiérrezCarmen Molins-SantosCristina Cassinello-EspinosaAntonio Molina-SigueroRafael Sáez-JiménezPaloma Rodríguez-AlmagroEva María Rey-CamachoMaría Carmen Pérez-GarcíaAntonio Redondo-HorcajoBeatriz Pajuelo-MárquezEncarnación Cidoncha-CalderónJesús Galindo RubioRosaAna Escriva FerrairoJosé Francisco Ávila-TomasFrancisco De-Alba-GómezMª Jesús Gómez-MartínAlma María Fernández-MartínezRosa Feijoó-FernándezJosé Vizcaíno-Sánchez-RodrigoVictoria Díaz-PuenteFelisa Núñez-SáezLuisa Asensio-RuizAgustín Sánchez-SánchezOrlando Enríquez-DueñasSilvia Fidel-JaimezRafael Ruiz-Morote-AragónAsunción Pacheco-PascuaBelén Soriano-HernándezEva Álvarez-CarranzaCarmen Siguero-PérezAna Morán-EscuderoMaría Martín-MartínFrancisco Vivas-RubioRafael Pérez-QueroMª Isabel Manzano-MartínCésar Redondo-LuciáñezNuria Tomás-GarcíaCarlos Díaz-Gómez-CalcerradaJulia Isabel Mogollo-GarcíaInés Melero-RedondoRicardo González-GascónMaría Carmen Álvarez-OrvizMaría Veredas González-MárquezTeresa SanClemente-PastorAmparo Corral-RubioAsunción Prieto-OrzancoCristina dela Cámara-GonzalezMercedes Parrilla-LasoMercedes Canellas-ManriqueMaria Eloisa Rogero-BlancoPaulino Cubero-GonzálezSara Sanchez-BarreiroMª Ángeles Aragoneses-CañasÁngela Auñón-MuelasOlga Álvarez MontesPetra María Cortes-DuranPilar Tardaguila-LobatoMar Escobar GallegosAntonia Pérez-de-Colosia-ZuilJaime Inneraraty-MartínezMaría Jesús Bedoya-FrutosMaría Teresa López-LópezNelly Álvarez-FernándezTeresa Fontova-CemeliJosefa Marruedo-MateoJosefa Díaz-SerranoBeatriz Pérez-VallejoPilar Hombrados-GonzaloMarta Quintanilla-SantamaríaYolanda González-PascualLuisa María Andrés-ArreazaSoledad Escolar-LlamazaresCristina Casado-RodríguezLuzdel Rey-MoyaJesús Fernández-ValderramaAlejandro Medrán-LópezJulia Alonso-ArcasAlejandra Rabanal-CarreraAraceli Garrido-BarralMilagros Velázquez-GarcíaAzucena Sáez-BerlangaPilar Pérez-EgeaPablo Astorga-DíazCarlos Casanova-GarcíaAna Isabel Román-RuizCarmen Belinchón-MoyaMargarita Encinas-SotilloVirtudes Enguita-PérezEster Valdés-CruzConsuelo Mayoral-LópezTeresa Gijón-SecoFrancisca Martínez-VallejoJesica Colorado-ValeraAna Sosa-AlonsoJeannet Sánchez-YépezDolores Serrano-GonzálezBeatriz López-SerranoInmaculada Santamaría-LópezPaloma Morso-PeláezCarolina López-OlmedaAlmudena García-Uceda-SevillaMercedes delPilar Fernández-GirónLeonor González-GalánMariano Rivera-MorenoLuis Nistal Martín-de-SerranosMª Jesús López-BarrosoMargarita Torres-ParrasMaría Verdugo-RosadoMª Reyes Delgado-PulpónElena Alcalá-LlorenteSonsoles Muñoz-MorenoIsabel Vaquero-TuriñoAna María Sánchez-SempereFranciscoJavier Martínez-SanzClementa Sanz-SanchezAnaMaría Arias-EstesoDiego Martín-AcicoyaPilar Kloppe-VillegasFrancisco Javier San-Andrés-RebolloMagdalena Canals-AracilIsabel García-AmorNieves Calvo-ArrabalMaría Milagros Jimeno-GalánGloriade la Sierra-OcañaMaría Mercedes Araujo-CalvoJulia Timoner-AguileraMaría Santos Santander-GutiérrezAlicia Mateo-MadurgaRicardo Rodríguez-BarrientosMilagros Rico-BlázquezJuan Carlos Gil-MorenoMariel Morey-MontalvoAmaya Azcoaga LorenzoGloria Ariza-CardielElena Polentinos-CastroSonia Soto-DíazMª Teresa Rodríguez-MonjeSusana Martín-IglesiasFrancisco Rodríguez-SalvanésMarta García-SolanoRocío González-GonzálezMaría Vicente HerreroRamón Rodríguez-GonzálezIrene Bretón-LesmesMartadel Alamo CamuñasAnabel Sánchez EspadasMarisa Serrano OlmedaMª Angeles Gálvez MúgicaResearch Unit. Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainResearch Unit. Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainResearch Unit. Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealth Services Research on Chronic Patients Network (REDISSEC), Instituto de Salud Carlos III, Madrid, SpainHealth Services Research on Chronic Patients Network (REDISSEC), Instituto de Salud Carlos III, Madrid, Spain11 Centre Family and Community Care Teaching Multiprofessional Unit, Comunidad de Madrid Consejeria de Sanidad, Madrid, SpainHealthcare Centre El Greco, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealth Services Research on Chronic Patients Network (REDISSEC), Instituto de Salud Carlos III, Madrid, SpainHealth Services Research on Chronic Patients Network (REDISSEC), Instituto de Salud Carlos III, Madrid, SpainHealthcare Centre Barajas, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Buenos Aires, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Guayaba, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Cuzco, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealth Services Research on Chronic Patients Network (REDISSEC), Instituto de Salud Carlos III, Madrid, SpainHealthcare Centre Buenos Aires, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Fuentelarreina, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Juncal, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Miguel de Cervantes, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Santa Isabel, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Lavapiés, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainHealthcare Centre Mendiguchía Carriche, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainPharmacy Department, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainPharmacy Department, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainPharmacy Department, Gerencia Asistencial Atención Primaria, Servicio Madrileno de Salud, Madrid, SpainUICEC Hospital Ramón y Cajal. Plataforma SCReN, Hospital Ramón y Cajal; Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS, Madrid, SpainObjectives 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.Trial registration numbers NCT 01476007; EUDRACT (2010-024129-20).https://bmjopen.bmj.com/content/10/8/e033687.full |
| spellingShingle | 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 Isabel Gutiérrez-Sánchez Ángeles Fernández-Abad José Antonio Granados-Garrido Javier Martínez-Suberviola Margarita Beltejar-Rodríguez Carmen Coello-Alarcón Susana Diez-Arjona Ana Ballarín-González Ignacio Iscar-Valenzuela José Luis Quintana-Gómez José Antonio González-Posada-Delgado Enrique Revilla-Pascual Esther Gómez-Suarez Yolanda Fernández-Fernández Fernanda Morales-Ortiz Isabel Ferrer-Zapata Esperanza Duralde-Rodríguez Milagros Beamud-Lagos Mª del Pilar Serrano-Simarro Cristina Montero-García María Domínguez-Paniagua Sofía Causín-Serrano Josefa San Vicente-Rodríguez Germán Reviriego-Jaén Margarita Camarero-Shelly Rosa Gómez-del Forcallo María Ángeles Miguel-Abanto Lourdes Reyes-Martínez Alejandro Rabanal-Basalo Carolina Torrijos-Bravo Pilar Gutiérrez-Valentín Jorge Gómez-Ciriano Susana Parra Román Judit León-González Mª José Nebril-Manzaneque Juana Caro-Berzal Alberto López-García-Franco Sonia Redondo de-Pedro Juan Carlos García-Álvarez Elisa Viñuela-Beneitez Marisa López-Martín Nuria Sanz-López Ana María Ibarra-Sánchez Cecilio Gómez-Almodóvar Javier Muñoz-Gutiérrez Carmen Molins-Santos Cristina Cassinello-Espinosa Antonio Molina-Siguero Rafael Sáez-Jiménez Paloma Rodríguez-Almagro Eva María Rey-Camacho María Carmen Pérez-García Antonio Redondo-Horcajo Beatriz Pajuelo-Márquez Encarnación Cidoncha-Calderón Jesús Galindo Rubio RosaAna Escriva Ferrairo José Francisco Ávila-Tomas Francisco De-Alba-Gómez Mª Jesús Gómez-Martín Alma María Fernández-Martínez Rosa Feijoó-Fernández José Vizcaíno-Sánchez-Rodrigo Victoria Díaz-Puente Felisa Núñez-Sáez Luisa Asensio-Ruiz Agustín Sánchez-Sánchez Orlando Enríquez-Dueñas Silvia Fidel-Jaimez Rafael Ruiz-Morote-Aragón Asunción Pacheco-Pascua Belén Soriano-Hernández Eva Álvarez-Carranza Carmen Siguero-Pérez Ana Morán-Escudero María Martín-Martín Francisco Vivas-Rubio Rafael Pérez-Quero Mª Isabel Manzano-Martín César Redondo-Luciáñez Nuria Tomás-García Carlos Díaz-Gómez-Calcerrada Julia Isabel Mogollo-García Inés Melero-Redondo Ricardo González-Gascón María Carmen Álvarez-Orviz María Veredas González-Márquez Teresa SanClemente-Pastor Amparo Corral-Rubio Asunción Prieto-Orzanco Cristina dela Cámara-Gonzalez Mercedes Parrilla-Laso Mercedes Canellas-Manrique Maria Eloisa Rogero-Blanco Paulino Cubero-González Sara Sanchez-Barreiro Mª Ángeles Aragoneses-Cañas Ángela Auñón-Muelas Olga Álvarez Montes Petra María Cortes-Duran Pilar Tardaguila-Lobato Mar Escobar Gallegos Antonia Pérez-de-Colosia-Zuil Jaime Inneraraty-Martínez María Jesús Bedoya-Frutos María Teresa López-López Nelly Álvarez-Fernández Teresa Fontova-Cemeli Josefa Marruedo-Mateo Josefa Díaz-Serrano Beatriz Pérez-Vallejo Pilar Hombrados-Gonzalo Marta Quintanilla-Santamaría Yolanda González-Pascual Luisa María Andrés-Arreaza Soledad Escolar-Llamazares Cristina Casado-Rodríguez Luzdel Rey-Moya Jesús Fernández-Valderrama Alejandro Medrán-López Julia Alonso-Arcas Alejandra Rabanal-Carrera Araceli Garrido-Barral Milagros Velázquez-García Azucena Sáez-Berlanga Pilar Pérez-Egea Pablo Astorga-Díaz Carlos Casanova-García Ana Isabel Román-Ruiz Carmen Belinchón-Moya Margarita Encinas-Sotillo Virtudes Enguita-Pérez Ester Valdés-Cruz Consuelo Mayoral-López Teresa Gijón-Seco Francisca Martínez-Vallejo Jesica Colorado-Valera Ana Sosa-Alonso Jeannet Sánchez-Yépez Dolores Serrano-González Beatriz López-Serrano Inmaculada Santamaría-López Paloma Morso-Peláez Carolina López-Olmeda Almudena García-Uceda-Sevilla Mercedes delPilar Fernández-Girón Leonor González-Galán Mariano Rivera-Moreno Luis Nistal Martín-de-Serranos Mª Jesús López-Barroso Margarita Torres-Parras María Verdugo-Rosado Mª Reyes Delgado-Pulpón Elena Alcalá-Llorente Sonsoles Muñoz-Moreno Isabel Vaquero-Turiño Ana María Sánchez-Sempere FranciscoJavier Martínez-Sanz Clementa Sanz-Sanchez AnaMaría Arias-Esteso Diego Martín-Acicoya Pilar Kloppe-Villegas Francisco Javier San-Andrés-Rebollo Magdalena Canals-Aracil Isabel García-Amor Nieves Calvo-Arrabal María Milagros Jimeno-Galán Gloriade la Sierra-Ocaña María Mercedes Araujo-Calvo Julia Timoner-Aguilera María Santos Santander-Gutiérrez Alicia Mateo-Madurga Ricardo Rodríguez-Barrientos Milagros Rico-Blázquez Juan Carlos Gil-Moreno Mariel Morey-Montalvo Amaya Azcoaga Lorenzo Gloria Ariza-Cardiel Elena Polentinos-Castro Sonia Soto-Díaz Mª Teresa Rodríguez-Monje Susana Martín-Iglesias Francisco Rodríguez-Salvanés Marta García-Solano Rocío González-González María Vicente Herrero Ramón Rodríguez-González Irene Bretón-Lesmes Martadel Alamo Camuñas Anabel Sánchez Espadas Marisa Serrano Olmeda Mª Angeles Gálvez Múgica Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12) BMJ Open |
| title | Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12) |
| title_full | Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12) |
| title_fullStr | Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12) |
| title_full_unstemmed | Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12) |
| title_short | Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12) |
| title_sort | oral versus intramuscular administration of vitamin b12 for vitamin b12 deficiency in primary care a pragmatic randomised non inferiority clinical trial ob12 |
| url | https://bmjopen.bmj.com/content/10/8/e033687.full |
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oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT maisabelmanzanomartin oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT cesarredondolucianez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT nuriatomasgarcia oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT carlosdiazgomezcalcerrada oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT juliaisabelmogollogarcia oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT inesmeleroredondo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT ricardogonzalezgascon oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariacarmenalvarezorviz oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariaveredasgonzalezmarquez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT teresasanclementepastor oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT amparocorralrubio oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT asuncionprietoorzanco oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT cristinadelacamaragonzalez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mercedesparrillalaso oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mercedescanellasmanrique oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariaeloisarogeroblanco oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT paulinocuberogonzalez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT sarasanchezbarreiro oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT maangelesaragonesescanas oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT angelaaunonmuelas oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT olgaalvarezmontes oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT petramariacortesduran oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT pilartardaguilalobato oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT marescobargallegos oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT antoniaperezdecolosiazuil oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT jaimeinneraratymartinez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariajesusbedoyafrutos oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariateresalopezlopez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT nellyalvarezfernandez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT teresafontovacemeli oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT josefamarruedomateo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT josefadiazserrano oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT beatrizperezvallejo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT pilarhombradosgonzalo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT martaquintanillasantamaria oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT yolandagonzalezpascual oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT luisamariaandresarreaza oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT soledadescolarllamazares oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT cristinacasadorodriguez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT luzdelreymoya oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT jesusfernandezvalderrama oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT alejandromedranlopez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT juliaalonsoarcas oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT alejandrarabanalcarrera oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT araceligarridobarral oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT milagrosvelazquezgarcia oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT azucenasaezberlanga oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT pilarperezegea oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT pabloastorgadiaz oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT carloscasanovagarcia oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT anaisabelromanruiz oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT carmenbelinchonmoya oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT margaritaencinassotillo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT virtudesenguitaperez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT estervaldescruz oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT consuelomayorallopez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT teresagijonseco oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT franciscamartinezvallejo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT jesicacoloradovalera oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT anasosaalonso oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT jeannetsanchezyepez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT doloresserranogonzalez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT beatrizlopezserrano oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT inmaculadasantamarialopez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT palomamorsopelaez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT carolinalopezolmeda oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT almudenagarciaucedasevilla oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mercedesdelpilarfernandezgiron oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT leonorgonzalezgalan oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT marianoriveramoreno oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT luisnistalmartindeserranos oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT majesuslopezbarroso oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT margaritatorresparras oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariaverdugorosado oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mareyesdelgadopulpon oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT elenaalcalallorente oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT sonsolesmunozmoreno oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT isabelvaqueroturino oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT anamariasanchezsempere oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT franciscojaviermartinezsanz oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT clementasanzsanchez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT anamariaariasesteso oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT diegomartinacicoya oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT pilarkloppevillegas oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT franciscojaviersanandresrebollo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT magdalenacanalsaracil oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT isabelgarciaamor oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT nievescalvoarrabal oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariamilagrosjimenogalan oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT gloriadelasierraocana oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariamercedesaraujocalvo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT juliatimoneraguilera oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariasantossantandergutierrez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT aliciamateomadurga oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT ricardorodriguezbarrientos oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT milagrosricoblazquez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT juancarlosgilmoreno oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT marielmoreymontalvo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT amayaazcoagalorenzo oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT gloriaarizacardiel oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT elenapolentinoscastro oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT soniasotodiaz oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT materesarodriguezmonje oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT susanamartiniglesias oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT franciscorodriguezsalvanes oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT martagarciasolano oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT rociogonzalezgonzalez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT mariavicenteherrero oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT ramonrodriguezgonzalez oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT irenebretonlesmes oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT martadelalamocamunas oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT anabelsanchezespadas oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT marisaserranoolmeda oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 AT maangelesgalvezmugica oralversusintramuscularadministrationofvitaminb12forvitaminb12deficiencyinprimarycareapragmaticrandomisednoninferiorityclinicaltrialob12 |