Vitamin B12 Supplementation in Diabetic Neuropathy

Study Overview
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Brief Summary
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This prospective double-blind placebo-controlled trial aims to investigate the safety and efficacy of oral dispersible tablet of vitamin B12 for 1 year, in 90 patients with diabetes mellitus type 2 and neuropathy.

Detailed Description
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In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin treatment for at least four years, and both peripheral and autonomic diabetic neuropathy were randomized to an active treatment group (n=44) receiving B12, and a control group (n=46) receiving placebo. All patients had B12 levels less than 400 pmol/L. Subjects underwent measurement of sural nerve conduction velocity and amplitude, vibration perception threshold, and performed cardiovascular autonomic reflex tests (CARTs: Mean Circular Resultant, Valsalva test, postural index and orthostatic hypotension]). Sudomotor function was assessed with the SUDOSCAN that measures electrochemical skin conductance in hands and feet. The Michigan Neuropathy Screening Instrument Questionnaire and Examination and questionnaires to evaluate quality of life and level of pain were also used.

Official Title
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Vitamin B12 Supplementation in Diabetic Neuropathy :1-year Double Blind Randomized Placebo-Controlled Trial

Conditions
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Diabetes Mellitus, Diabetic Neuropathies, Diabetic Complication, Diabetic Foot

Intervention / Treatment
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* Dietary Supplement: B12 fix 1000mcg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adults (>18 years old) with Diabetes Mellitus 2 established Diabetic neuropathy, both peripheral and autonomic (Diabetic Peripheral Neuropathy and Diabetic Autonomic Neuropathy). (Diagnosis was made with a)two or more Cardiovascular Autonomic Reflex Tests abnormal, b)abnormal nerve conduction velocity, c)abnormal Michigan Neuropathy Screening Instrument Questionnaire and Michigan Neuropathy Screening Instrument Examination ). good glycemic control (HbA1c between 6.5 and 7.5 %), stable in the last year before participating in the study metformin treatment for at least 4 years low vitamin B12 levels according to suggested normal values for DM2 patients over 60 years old (<400 pmol/L) Exclusion Criteria: pernicious anemia, alcoholism gastrectomy gastric bypass surgery pancreatic insufficiency malabsorption syndromes chronic giardiasis acute infection in the last 6 months cardiovascular event in the last 6 months surgery involving small intestine or Human Immunodeficiency Virus infection. Patients with estimated Glomerular Filtration Rate <50 mL/min/1.73m2 taking multivitamins or B12 supplements in the last 12 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double Blind Placebo Controlled Randomized Clinical Trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active treatment group<br>Patients were given oral dispersible tablet with 1000μg of vitamin B12 daily for 12 months. | Dietary Supplement: B12 fix 1000mcg<br>* oral dispersible tablet with vitamin B12 1000mcg<br>* Other names: vitamin B12;|
| Placebo Comparator: Placebo group<br>Patients were given placebo tablet similar to the tablet given to the active group once a day for 12 months. | Other: Placebo<br>* Placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sural Nerve Function measured by conduction velocity | Sural Nerve conduction velocity measured as m/s | 12 months | 
| Change in Sural Nerve Function measured by amplitude | Sural Nerve conduction amplitude measured as μV | 12 months | 
| Change in Michigan Neuropathy Screening Instrument Questionnaire | Michigan Neuropathy Screening Instrument questionnaire (The Michigan Neuropathy Screening Instrument (MNSI) includes two separate assessments, a 15-item self-administered questionnaire and a lower extremity examination. the questionnaire is scored by summing abnormal responses. Responses are added to obtain a total score. 'Yes' responses to questions 1-3, 5-6, 8-9, 11-12, 14-15 are each counted as one point. 'No' responses to questions 7 and 13 each count as one point. Question 4 was considered to be a measure of impaired circulation and question 10 a measure of general asthenia and were not included in the published scoring algorithm. A score of ≥ 7 was considered abnormal. | 12 months | 
| Change in Michigan Neuropathy Screening Instrument Examination | Michigan Neuropathy Screening Instrument Examination (The Michigan Neuropathy Screening Instrument (MNSI) includes two separate assessments, a 15-item self-administered questionnaire that is scored by summing abnormal responses, and a lower extremity examination that includes inspection and assessment of vibratory sensation and ankle reflexes and is scored by assigning points for abnormal findings.A score ≥ 2 was considered abnormal. Abnormality in each item is graded between 0.5 and 1 and at least more than 2 abnormal items are needed to reach the score of neuropathy. ) | 12 months | 
| Change in Electrochemical Skin Conductance | Electrochemical Skin Conductance in hands and feet measured by SUDOSCAN | 12 months | 
| Change in Cardiovascular Autonomic Reflex Tests (CARTs) | CARTs were performed with Autonomic Nervous System Reader and included R-R variation during deep breathing [Mean Circular Resultant , Valsalva maneuver , 30:15 ratio expressed as postural index, and blood pressure response to standing (orthostatic hypotension) | 12 months | 
| Change in Vibration perception threshold | Vibration perception threshold was measured using a Biothesiometer | 12 months | 
| Change in level of pain with painDETECT questionnaire | painDETECT questionnaire consists of seven questions that address the quality of neuropathic pain symptoms; it is completed by the patient and no physical examination is required. The first five questions ask about the gradation of pain, scored from 0 to 5 (never = 0, hardly noticed = 1, slightly = 2; moderately = 3, strongly = 4, very strongly = 5). Question 6 asks about the pain course pattern, scored from -1 to 2, depending on which pain course pattern diagram is selected. The final score between -1 and 38, indicates the likelihood of a neuropathic pain component. A score of ≤ 12 indicates that pain is unlikely to have a neuropathic component (< 15%), while a score of ≥ 19 suggests that pain is likely to have a neuropathic component (> 90%). A score between these values indicates that the result is uncertain and a more detailed examination is required. | 12 months | 
| Change in quality of life score | Diabetes Quality of Life Brief Clinical Inventory (ThE DQOL questionnaire we used is a 15-items, brief-focused version of the Diabetes Quality of Life (DQOL) questionnaire developed in the DCCT and lowest score means worse quality of life whereas higher values indicate better quality of life) | 12 months | 
| serum vitamin B12 levels | serum vitamin B12 levels | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | report of any adverse events | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetic neuropathy, vitamin B12, SUDOSCAN, metformin, diabetic foot, Diabetes Mellitus, autonomic neuropathy, peripheral neuropathy, painful neuropathy