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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).

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

SUBMITTER: Sanz-Cuesta T

PROVIDER: S-EPMC3403849 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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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).

Sanz-Cuesta Teresa T González-Escobar Paloma P Riesgo-Fuertes Rosario R Garrido-Elustondo Sofía S del Cura-González Isabel I Martín-Fernández Jesús J Escortell-Mayor Esperanza E Rodríguez-Salvanés Francisco F García-Solano Marta M González-González Rocío R Martín-de la Sierra-San Agustín María Ángeles MÁ Olmedo-Lucerón Carmen C Sevillano Palmero María Luisa ML Mateo-Ruiz Carmen C Medina-Bustillo Beatriz B Valdivia-Pérez Antonio A García-de Blas-González Francisca F Mariño-Suárez José Enrique JE Rodríguez-Barrientos Ricardo R Ariza-Cardiel Gloria G Cabello-Ballesteros Luisa María LM Polentinos-Castro Elena E Rico-Blázquez Milagros M Rodríguez-Monje Ma Teresa MT Soto-Díaz Sonia S Martín-Iglesias Susana S Rodríguez-González Ramón R Bretón-Lesmes Irene I Vicente-Herrero María M Sánchez-Díaz Jesús J Gómez-Gascón Tomás T Drake-Canela Mercedes M Asúnsolo-del Barco Ángel Á

BMC public health 20120531

<h4>Background</h4>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.<h4>Methods/design</h4>The proposed study involves a controlled, randomised, multicentre, parallel, non ...[more]

PMID: 22650964

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Project 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 (?>-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:NCT01476007; EUDRACT (2010-024129-20).

Project description:The fertility of dairy cows is challenged during early lactation and better nutritional strategies need to be developed to address this issue. Combined supplementation of folic acid and vitamin B12 improves energy metabolism in the dairy cow during early lactation. Therefore, the present study was undertaken to explore the effects of this supplement on gene expression in granulosa cells from the dominant follicle during the postpartum period. Multiparous Holstein cows received weekly intramuscular injection of 320 mg folic acid and 10 mg vitamin B12 (treated group) beginning 24 (SD 4) d before calving until 56 d after calving, whereas the control group received saline. The urea plasma concentration was significantly decreased during the pre-calving period, and the concentration of both folate and vitamin B12 were increased in treated animals. Milk production and dry matter intake were not significantly different between the two groups. Plasma concentrations of folates and vitamin B12 were increased in vitamin-treated animals. Daily dry matter intake was not significantly different between the 2 groups before (13.5 kg SE 0.5) and after (23.6 kg SE 0.9) calving. Average energy-corrected milk tended to be greater in vitamin-treated cows, 39.7 (SE 1.4) and 38.1 (SE 1.3) kg/d for treated and control cows, respectively. After calving, average plasma concentration of BHBA tended to be lower in cows injected with the vitamin supplement, 0.47 (SE 0.04) vs. 0.55 (SE 0.03) for treated and control cows, respectively. The ovarian follicle ? 12 mm in diameter was collected by ovarian pick-up after estrus synchronization. Recovered follicular fluid volumes were greater in the vitamin-treated group. A microarray platform was used to investigate the impact of treatment on gene expression of granulosa cells. Lower expression of genes involved in the cell cycle and higher expression of genes associated with granulosa cell differentiation prior to ovulation were observed. Selected candidate genes were analyzed by reverse transcription quantitative polymerase chain reaction. Although the effects of intramuscular injections of folic acid and vitamin B12 on lactational performance and metabolic status of animals were limited, Ingenuity Pathway Analysis of gene expression in granulosa cells suggests a stimulation of cell differentiation in vitamin-treated cows, which may be the result of an increase in LH secretion. Two conditions experiment (Control and Treated). Granulosa cells from the 66h post second PGF2alpha injection. Biological replicates: 3 from each time point. Two technical replicates for each comparison (dye-swap).

Project description:BackgroundCobalamin (cbl)-related remethylation disorders are a heterogeneous group of inherited disorders comprising the remethylation of homocysteine to methionine and affecting multiple organ systems, most prominently the nervous system and the bone marrow. To date, the parenteral, generally intramuscular, lifelong administration of hydroxycobalamin (OHCbl) is the mainstay of therapy in these disorders. The dosage and frequency of OHCbl is titrated in each patient to the minimum effective dose in order to account for the painful injections. This may result in undertreatment, a possible risk factor for disease progression and disease-related complications.ResultsWe describe parenteral administration of OHCbl using a subcutaneous catheter together with a portable infusion pump in a home therapy setting in four pediatric patients with remethylation disorders, two patients with cblC, one patient with cblG, and one patient with cblE deficiency, in whom intramuscular injections were not or no longer feasible. The placement of the subcutaneous catheters and handling of the infusion pump were readily accomplished and well accepted by the patients and their families. No adverse events occurred. The use of a small, portable syringe driver pump allowed for a most flexible administration of OHCbl in everyday life. The concentrations of total homocysteine levels were determined at regular patient visits and remained within the therapeutic target range. This approach allowed for the continuation of OHCbl therapy or the adjustment of therapy required to improve metabolic control in our patients.ConclusionsSubcutaneous infusion using a subcutaneous catheter system and a portable pump for OHCbl administration in combined and isolated remethylation disorders is safe, acceptable, and effective. It decreases disease burden in preventing frequent single injections and providing patient independence. Thus, it may promote long-term adherence to therapy in patients and parents.

Project description:BACKGROUND:Test ventilating prior to administration of neuromuscular blockade (NMB) in order to avoid a cannot intubate-cannot ventilate situation is a classic anesthesia teaching. The primary aim of our study was to show that facemask ventilation (FMV) after NMB was not inferior to FMV prior to NMB with respect to exhaled gas volumes before and after their administration. METHODS:This study was approved by the University of Washington Human Subjects Division (Seattle, Washington, USA). Written informed consent was obtained from all patients. Measurements of tidal volume (Vte) as well as other respiratory parameters during FMV were made for 60 s after induction of anesthesia and again after NMB. Difficult, impossible, inadequate, and dead-space only mask ventilation was graded using published definitions. Difficult intubation was defined as >2 attempts at intubation. The primary outcome was non-inferiority in Vte during both study periods defined as a mean difference of <50 mL. Multivariate analysis was performed to assess for interaction between operator experience, patient risk factors for difficult mask ventilation, exhaled volumes, and use of airway adjuncts. RESULTS:Two-hundred and ten patients were studied. Overall, FMV improved after NMBD. The mean (SD) Vte in mL/breath increased from 399 (169) to 428 (166) (mean dif. 30 mL, p = 0.001) and the minute ventilation in L/min from 5.6 (2.5) to 6.3 (2.5) (mean dif. 0.6, p < 0.001). No patient who was difficult to ventilate after induction became impossible after NMB. DISCUSSION:In patients at risk for or judged to be a difficult FMV by clinical grading scales, tidal volumes improved after administration of NMBDs. None of these patients exhibited a decline in ventilation or became impossible to ventilate after NMBDs. Several limitations are noted, including the use of hand-delivered breaths and inability to account for time-related changes in ventilation conditions independent of NMBDs. CONCLUSION:We conclude that FMV is no worse after NMB than before and is likely to improve airway conditions. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02237443 . Registered August 28, 2014.

Dataset Information

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).

Publications

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).

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