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Vitamin B12 Supplementation in Diabetic Neuropathy

Primary Purpose

Diabetes Mellitus, Diabetic Neuropathies, Diabetic Complication

Status
Completed
Phase
Not Applicable
Locations
Greece
Study Type
Interventional
Intervention
B12 fix 1000mcg
Placebo
Sponsored by
Aristotle University Of Thessaloniki
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus focused on measuring diabetic neuropathy, vitamin B12, SUDOSCAN, metformin, diabetic foot, Diabetes Mellitus, autonomic neuropathy, peripheral neuropathy, painful neuropathy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University General Hospital AHEPA

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active treatment group

Placebo group

Arm Description

Patients were given oral dispersible tablet with 1000μg of vitamin B12 daily for 12 months.

Patients were given placebo tablet similar to the tablet given to the active group once a day for 12 months.

Outcomes

Primary Outcome Measures

Change in Sural Nerve Function measured by conduction velocity
Sural Nerve conduction velocity measured as m/s
Change in Sural Nerve Function measured by amplitude
Sural Nerve conduction amplitude measured as μV
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.
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. )
Change in Electrochemical Skin Conductance
Electrochemical Skin Conductance in hands and feet measured by SUDOSCAN
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)
Change in Vibration perception threshold
Vibration perception threshold was measured using a Biothesiometer
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.
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)
serum vitamin B12 levels
serum vitamin B12 levels

Secondary Outcome Measures

Adverse events
report of any adverse events

Full Information

First Posted
January 9, 2021
Last Updated
January 11, 2021
Sponsor
Aristotle University Of Thessaloniki
Collaborators
University of Sheffield, University Hospital Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT04706377
Brief Title
Vitamin B12 Supplementation in Diabetic Neuropathy
Official Title
Vitamin B12 Supplementation in Diabetic Neuropathy :1-year Double Blind Randomized Placebo-Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
February 1, 2018 (Actual)
Primary Completion Date
February 28, 2020 (Actual)
Study Completion Date
February 28, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Aristotle University Of Thessaloniki
Collaborators
University of Sheffield, University Hospital Tuebingen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Diabetic Neuropathies, Diabetic Complication, Diabetic Foot
Keywords
diabetic neuropathy, vitamin B12, SUDOSCAN, metformin, diabetic foot, Diabetes Mellitus, autonomic neuropathy, peripheral neuropathy, painful neuropathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Double Blind Placebo Controlled Randomized Clinical Trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The tablets containing B12 and placebo had a similar appearance and were packed in similar containers. Patients and health care providers did not know what each package contained.
Allocation
Randomized
Enrollment
90 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Active treatment group
Arm Type
Active Comparator
Arm Description
Patients were given oral dispersible tablet with 1000μg of vitamin B12 daily for 12 months.
Arm Title
Placebo group
Arm Type
Placebo Comparator
Arm Description
Patients were given placebo tablet similar to the tablet given to the active group once a day for 12 months.
Intervention Type
Dietary Supplement
Intervention Name(s)
B12 fix 1000mcg
Other Intervention Name(s)
vitamin B12
Intervention Description
oral dispersible tablet with vitamin B12 1000mcg
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo tablet
Primary Outcome Measure Information:
Title
Change in Sural Nerve Function measured by conduction velocity
Description
Sural Nerve conduction velocity measured as m/s
Time Frame
12 months
Title
Change in Sural Nerve Function measured by amplitude
Description
Sural Nerve conduction amplitude measured as μV
Time Frame
12 months
Title
Change in Michigan Neuropathy Screening Instrument Questionnaire
Description
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.
Time Frame
12 months
Title
Change in Michigan Neuropathy Screening Instrument Examination
Description
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. )
Time Frame
12 months
Title
Change in Electrochemical Skin Conductance
Description
Electrochemical Skin Conductance in hands and feet measured by SUDOSCAN
Time Frame
12 months
Title
Change in Cardiovascular Autonomic Reflex Tests (CARTs)
Description
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)
Time Frame
12 months
Title
Change in Vibration perception threshold
Description
Vibration perception threshold was measured using a Biothesiometer
Time Frame
12 months
Title
Change in level of pain with painDETECT questionnaire
Description
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.
Time Frame
12 months
Title
Change in quality of life score
Description
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)
Time Frame
12 months
Title
serum vitamin B12 levels
Description
serum vitamin B12 levels
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Adverse events
Description
report of any adverse events
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
University General Hospital AHEPA
City
Thessaloníki
State/Province
Thessaloniki
ZIP/Postal Code
54621
Country
Greece

12. IPD Sharing Statement

Plan to Share IPD
No

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Vitamin B12 Supplementation in Diabetic Neuropathy

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