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Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial


Metaxas, Corina; Mathis, Déborah; Jeger, Cyrill; Hersberger, Kurt Eduard; Arnet, Isabelle; Walter, Philipp (2017). Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised parallel-group trial. Swiss Medical Weekly, 147:w14421.

Abstract

BACKGROUND: Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (i.m.) injection of VB12. Whenever alternative routes of administration exist, patient prefer-ences should be considered when choosing the treatment. We aimed to assess outpatient preferences towards oral or IM VB12 substitution and confirm noninferiority of early biomarker response with oral treat-ment, in a typical primary care population.
METHODS: Prospective randomised nonblinded parallel-group trial. Patients were recruited by their general practitioner and randomly as-signed to oral or IM treatment. Group O-oral was given 28 tablets of 1000 μg cyanocobalamin in a monthly punch card fitted with an elec-tronic monitoring system. Group I-IM received four, weekly injections of 1000 μg hydroxocobalamin. Blood samples were drawn before the first administration and after 1, 2 and 4 weeks of treatment, and ana-lysed for VB12, holotranscobalamin (HoloTc), homocysteine (Hcy) and methylmalonic acid (MMA). For group O-oral, treatment adherence and percentage of days with 2 dosing events were calculated. Before and after 28 days of treatment, patients were asked to fill in a ques-tionnaire about their preference for the therapy options and associ-ated factors.
RESULTS: Between November 2013 and December 2015, 37 patients (age: 49.5 ± 18.5 years; women: 60.5%) were recruited for oral (19) or IM (18) treatment. Baseline values with 95% confidence intervals for serum VB12, HoloTc, Hcy and MMA were 158 pmol/l [145-172], 49.0 pmol/l [40.4-57.5], 14.8 µmol/l [12.0-17.7] and 304 nmol/l [219-390], respective-ly, in group O-oral and 164 pmol/l [154-174], 50.1 pmol/l [38.7-61.6], 13.0 µmol/l [11.0-15.1] and 321 nmol/l [215-427], respectively, in group I-IM (not significant). After 1 month of treatment, levels of VB12 and HoloTc showed a significant increase compared with baseline (group O-oral: VB12 354 pmol/l [298-410] and HoloTc 156 pmol/l [116-196]; group I-IM: VB12 2796 pmol/l [1277-4314] and HoloTc 1269 pmol/l [103-2435]). Hcy and MMA levels showed a significant decrease compared with baseline (group O-oral: Hcy 13.8 µmol/l [10.7-16.8] and MMA 168 nmol/l [134-202]; group I-IM: Hcy 8.5 µmol/l [7.1-9.8] and MMA 156 nmol/l [121-190]). HoloTc and MMA levels were normalised in all patients after 4 weeks of treatment, whereas normalisation of VB12 and Hcy was reached by all patients in group I-IM only. Response of VB12, HoloTc and Hcy was more pronounced in group I-IM (p <0.01) and the primary hypothesis that oral VB12 treatment would be noninfe-rior to IM treatment was rejected. Average adherence to thera-py was 99.6 ± 1.1% and days with 2 dosing events reached 5.6%. Before randomisation, preference was in favour of oral treatment (45.9%, n = 17) over IM administration (21.6%, n = 8). Twelve patients (32.4%) had no preference. Nine (24.3%) patients changed their preference after treatment. Patients who obtained their preferred route of administration main-tained their preference in the case of oral treatment and changed their preference after IM treatment.
CONCLUSIONS: Differences in VB12 levels between groups were higher than expected. Therefore, noninferiority of oral treat-ment had to be rejected. However, normalisation of HoloTc and MMA was reached by all patients after a 1-month treatment period. The clinical benefit of the exaggerated biomarker re-sponse after IM treatment within a typical primary care popula-tion is questionable. Midterm biomarker effects and patient preferences should be considered when a therapeutic scheme is chosen. Initial rating in favour of either IM or oral therapy can change over time and justifies repeated re-evaluation of patient preferences. (ClinicalTrials.gov ID NCT01832129).

Abstract

BACKGROUND: Vitamin B12 (VB12) deficiency can be treated with oral high-dose substitution or intramuscular (i.m.) injection of VB12. Whenever alternative routes of administration exist, patient prefer-ences should be considered when choosing the treatment. We aimed to assess outpatient preferences towards oral or IM VB12 substitution and confirm noninferiority of early biomarker response with oral treat-ment, in a typical primary care population.
METHODS: Prospective randomised nonblinded parallel-group trial. Patients were recruited by their general practitioner and randomly as-signed to oral or IM treatment. Group O-oral was given 28 tablets of 1000 μg cyanocobalamin in a monthly punch card fitted with an elec-tronic monitoring system. Group I-IM received four, weekly injections of 1000 μg hydroxocobalamin. Blood samples were drawn before the first administration and after 1, 2 and 4 weeks of treatment, and ana-lysed for VB12, holotranscobalamin (HoloTc), homocysteine (Hcy) and methylmalonic acid (MMA). For group O-oral, treatment adherence and percentage of days with 2 dosing events were calculated. Before and after 28 days of treatment, patients were asked to fill in a ques-tionnaire about their preference for the therapy options and associ-ated factors.
RESULTS: Between November 2013 and December 2015, 37 patients (age: 49.5 ± 18.5 years; women: 60.5%) were recruited for oral (19) or IM (18) treatment. Baseline values with 95% confidence intervals for serum VB12, HoloTc, Hcy and MMA were 158 pmol/l [145-172], 49.0 pmol/l [40.4-57.5], 14.8 µmol/l [12.0-17.7] and 304 nmol/l [219-390], respective-ly, in group O-oral and 164 pmol/l [154-174], 50.1 pmol/l [38.7-61.6], 13.0 µmol/l [11.0-15.1] and 321 nmol/l [215-427], respectively, in group I-IM (not significant). After 1 month of treatment, levels of VB12 and HoloTc showed a significant increase compared with baseline (group O-oral: VB12 354 pmol/l [298-410] and HoloTc 156 pmol/l [116-196]; group I-IM: VB12 2796 pmol/l [1277-4314] and HoloTc 1269 pmol/l [103-2435]). Hcy and MMA levels showed a significant decrease compared with baseline (group O-oral: Hcy 13.8 µmol/l [10.7-16.8] and MMA 168 nmol/l [134-202]; group I-IM: Hcy 8.5 µmol/l [7.1-9.8] and MMA 156 nmol/l [121-190]). HoloTc and MMA levels were normalised in all patients after 4 weeks of treatment, whereas normalisation of VB12 and Hcy was reached by all patients in group I-IM only. Response of VB12, HoloTc and Hcy was more pronounced in group I-IM (p <0.01) and the primary hypothesis that oral VB12 treatment would be noninfe-rior to IM treatment was rejected. Average adherence to thera-py was 99.6 ± 1.1% and days with 2 dosing events reached 5.6%. Before randomisation, preference was in favour of oral treatment (45.9%, n = 17) over IM administration (21.6%, n = 8). Twelve patients (32.4%) had no preference. Nine (24.3%) patients changed their preference after treatment. Patients who obtained their preferred route of administration main-tained their preference in the case of oral treatment and changed their preference after IM treatment.
CONCLUSIONS: Differences in VB12 levels between groups were higher than expected. Therefore, noninferiority of oral treat-ment had to be rejected. However, normalisation of HoloTc and MMA was reached by all patients after a 1-month treatment period. The clinical benefit of the exaggerated biomarker re-sponse after IM treatment within a typical primary care popula-tion is questionable. Midterm biomarker effects and patient preferences should be considered when a therapeutic scheme is chosen. Initial rating in favour of either IM or oral therapy can change over time and justifies repeated re-evaluation of patient preferences. (ClinicalTrials.gov ID NCT01832129).

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:19 April 2017
Deposited On:16 Jan 2018 10:14
Last Modified:22 Feb 2018 14:29
Publisher:EMH Swiss Medical Publishers
ISSN:0036-7672
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.4414/smw.2017.14421
PubMed ID:28421567

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