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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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.
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 , Herrero-Hernández , J , Pose-García , B , Sevillano-Palmero , M L , 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
Copyright © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
DescriptionThe 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.
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