BACKGROUND: Vitamin B(12) deficiency is routinely treated with parenteral dosing and less often with high-dose oral vitamin B(12). Oral vitamin B(12) formulations have low bioavailability in patients with malabsorption and are considered less reliable than parenteral treatments. OBJECTIVE: The objective of this study was to compare the efficacy and safety profile of a new proprietary oral vitamin B(12) formulation (oral B(12)) with intramuscular (IM) vitamin B(12) (IM B(12)) in restoring normal serum B(12) concentrations in patients with low cobalamin levels (<350 pg/mL). METHODS: Patients were recruited from 5 centers and randomly assigned to receive oral B(12) 1000 μg, taken daily for 90 days, or IM B(12) 1000 μg, given on study days 1, 3, 7, 10, 14, 21, 30, 60, and 90. The patients were aged ≥60 years or aged ≥18 years and had gastrointestinal abnormalities or were on a restricted diet. The primary efficacy outcome compared the proportion of patients in each treatment arm in whom cobalamin levels were normalized (≥350 ng/mL) following 60 days of treatment. Secondary objectives included comparing the efficacy of the 2 formulations after 90 days of treatment, assessing time to normalization of B(12) levels, and evaluating the changes in the levels of biomarkers methylmalonic acid (MMA) and homocysteine (HC). The effect on holotranscobalamin II (active B(12)) levels was assessed as an exploratory end point and correlated to serum cobalamin levels in both treatment groups. Blood samples were collected at baseline (day 1) and on days 15, 31, 61, and 91. RESULTS:Fifty patients were recruited. Forty-eight patients (96.0%) completed the study (22 patients [91.7%] in the oral B(12) group and 26 patients [100%] in the IM B(12) group). All patients (100%) in both treatment groups and in both populations had a cobalamin level ≥350 pg/mL on day 61 and maintained it on day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance (P < 0.05) for mean percent change from baseline (PCFB) in serum cobalamin levels on day 61 and day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in serum MMA levels on day 61. There was a statistical difference between the IM and oral treatment groups for mean PCFB in serum MMA levels on day 91 (P = 0.033), with lower values in the oral B(12) group. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in plasma HC levels on day 61 and day 91. All patients in each treatment group achieved normalization of serum cobalamin levels by day 15. All patients in both treatment groups and in both populations had plasma holotranscobalamin levels ≥40 pmol/L on day 61 and on day 91. No statistical analysis was planned or performed for safety end points, which were reported only descriptively. Most observed adverse effects were considered mild or moderate in intensity. All adverse effects that were considered severe in intensity were also considered by the investigator to be not related to the study drug. CONCLUSIONS: In this selected study population comprising individuals with low cobalamin levels but who otherwise were in good health, patients received oral B(12) (1000 μg/d) or IM B(12) (1000 μg in 9 injections over 3 months) for a total of 3 months. Both the oral and IM formulations were effective in restoring normal levels of serum cobalamin in all patients studied (100%). Both formulations used in this study were well tolerated at the dose studied. ClinicalTrials.gov identifier: NCT01312831.
RCT Entities:
BACKGROUND:Vitamin B(12) deficiency is routinely treated with parenteral dosing and less often with high-dose oral vitamin B(12). Oral vitamin B(12) formulations have low bioavailability in patients with malabsorption and are considered less reliable than parenteral treatments. OBJECTIVE: The objective of this study was to compare the efficacy and safety profile of a new proprietary oral vitamin B(12) formulation (oral B(12)) with intramuscular (IM) vitamin B(12) (IM B(12)) in restoring normal serum B(12) concentrations in patients with low cobalamin levels (<350 pg/mL). METHODS:Patients were recruited from 5 centers and randomly assigned to receive oral B(12) 1000 μg, taken daily for 90 days, or IM B(12) 1000 μg, given on study days 1, 3, 7, 10, 14, 21, 30, 60, and 90. The patients were aged ≥60 years or aged ≥18 years and had gastrointestinal abnormalities or were on a restricted diet. The primary efficacy outcome compared the proportion of patients in each treatment arm in whom cobalamin levels were normalized (≥350 ng/mL) following 60 days of treatment. Secondary objectives included comparing the efficacy of the 2 formulations after 90 days of treatment, assessing time to normalization of B(12) levels, and evaluating the changes in the levels of biomarkers methylmalonic acid (MMA) and homocysteine (HC). The effect on holotranscobalamin II (active B(12)) levels was assessed as an exploratory end point and correlated to serum cobalamin levels in both treatment groups. Blood samples were collected at baseline (day 1) and on days 15, 31, 61, and 91. RESULTS: Fifty patients were recruited. Forty-eight patients (96.0%) completed the study (22 patients [91.7%] in the oral B(12) group and 26 patients [100%] in the IM B(12) group). All patients (100%) in both treatment groups and in both populations had a cobalamin level ≥350 pg/mL on day 61 and maintained it on day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance (P < 0.05) for mean percent change from baseline (PCFB) in serum cobalamin levels on day 61 and day 91. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in serum MMA levels on day 61. There was a statistical difference between the IM and oral treatment groups for mean PCFB in serum MMA levels on day 91 (P = 0.033), with lower values in the oral B(12) group. The difference between the IM and oral treatment groups did not reach the planned level of statistical significance for mean PCFB in plasma HC levels on day 61 and day 91. All patients in each treatment group achieved normalization of serum cobalamin levels by day 15. All patients in both treatment groups and in both populations had plasma holotranscobalamin levels ≥40 pmol/L on day 61 and on day 91. No statistical analysis was planned or performed for safety end points, which were reported only descriptively. Most observed adverse effects were considered mild or moderate in intensity. All adverse effects that were considered severe in intensity were also considered by the investigator to be not related to the study drug. CONCLUSIONS: In this selected study population comprising individuals with low cobalamin levels but who otherwise were in good health, patients received oral B(12) (1000 μg/d) or IM B(12) (1000 μg in 9 injections over 3 months) for a total of 3 months. Both the oral and IM formulations were effective in restoring normal levels of serum cobalamin in all patients studied (100%). Both formulations used in this study were well tolerated at the dose studied. ClinicalTrials.gov identifier: NCT01312831.
Authors: Fernando Gomollón; Carla J Gargallo; Jose Fernando Muñoz; Raquel Vicente; Alberto Lue; Alberto Mir; Marta García-Alvarado; Marta Gracia; Santiago García-López Journal: Nutrients Date: 2017-03-20 Impact factor: 5.717