Vitamin B12 Supplementation in Diabetic Neuropathy

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Diabetic Foot; Diabetic Neuropathies; Diabetic Complication
• Intervention / Treatment: Other: Placebo; Dietary supplement: B12 fix 1000mcg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Greece
  • Thessaloniki
    • Thessaloníki, Thessaloniki, Greece, 54621
      • University General Hospital AHEPA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Aristotle University Of Thessaloniki
• Collaborators: University of Sheffield; University Hospital Tuebingen

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2018
• Primary Completion (Actual): February 28, 2020
• Study Completion (Actual): February 28, 2020

Study Registration Dates

• First Submitted: January 9, 2021
• First Submitted That Met QC Criteria: January 11, 2021
• First Posted (Actual): January 12, 2021

Study Record Updates

• Last Update Posted (Actual): January 12, 2021
• Last Update Submitted That Met QC Criteria: January 11, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; peripheral neuropathy; autonomic neuropathy; metformin; diabetic foot; vitamin B12; diabetic neuropathy; SUDOSCAN; painful neuropathy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Skin Diseases; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Neuromuscular Diseases; Foot Ulcer; Diabetes Mellitus; Diabetic Foot; Peripheral Nervous System Diseases; Diabetic Neuropathies; Diabetes Complications; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Vitamin B 12
• Other Study ID Numbers: No42439

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No