Study of Metanx® in Subjects With Type 2 Diabetic Peripheral Neuropathy (DPN)

Study Overview
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Brief Summary
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The purpose of this research study is to determine if Metanx improves sensory neuropathy in persons with Type 2 diabetes. Metanx is a medical food available with a prescription from a physician. It consists of L-methylfolate, Pyridoxal 5'-phosphate, and Methylcobalamin, which are the active forms of folate, vitamin B6, and vitamin B12, respectively. Subjects will be randomly assigned to receive either Metanx or placebo for 6 months.

Official Title
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A 24 Week, Double-blind, Placebo-controlled, Multisite Study of Metanx® in Subjects With Type 2 Diabetic Peripheral Neuropathy (DPN)

Conditions
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Type 2 Diabetic Peripheral Neuropathy (DPN)

Intervention / Treatment
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* Other: Metanx (a medical food)
* Other: Metanx placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female between 25 and 80 years of age (inclusive); Documented diabetes mellitus Type 2 (Based upon ADA criteria); Peripheral polyneuropathy: Vibration Perception Threshold (VPT) 25-45 Volts at hallux on either leg. Adequate lower extremity vascular status: Palpable pedal pulse in both feet; No intermittent claudication; No history of lower extremity vascular bypass surgery or angioplasty The subject is able to understand the information in the informed consent form and is willing and able to sign the consent. Exclusion Criteria: Amputation of any kind or an ulceration within the last two (2) years including at Screen; History or active Charcot neuroarthropathy on either foot; Previous surgery to spine or lower extremity with residual symptoms of pain or difficulty with movement; Severe rheumatoid arthritis or osteoarthritis that would cause discomfort during causal walking or stair climbing; Current treatment with systemic steroids, immunosuppressives, or radiotherapy; Peripheral vascular disease defined as any nonpalpable foot pulse, history of claudication, or a history of lower extremity vascular bypass surgery or angioplasty; Glycated hemoglobin (HbA1c) >9 at Screen. Uncontrolled heart (Hypertension: BP > 160/90), or lung disease (uncontrolled asthma or shortness of breath) in the last 2 months prior to Screen; End stage kidney disorder requiring hemodialysis or serum creatinine > 2.5X (normal upper limit); The following supplements within 2 months prior to Screen: alpha lipoic acid; B12 injection; >10mg of B6; or, > 800mcg of folate; Taking either an opiate at any dose or on the maximum dose of any anticonvulsant; Pregnant or nursing; Life expectancy < 12 months; Initiated therapies for Painful Diabetic Neuropathy (pregabalin, gabapentin, duloxetine etc.) in the last 2 months prior to Screen; Initiated new hyperglycemic, insulin, statin or hypertensive therapies within 2 months prior to Screen (dose modifications of current therapies are allowed at the discretion of the investigator); Current alcohol or drug abuse (or history of such abuse within the past 3 years); and, Not willing or able to follow procedures specified by the protocol and/or the instructions of the study personnel.

Ages Eligible for Study
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Minimum Age: 25 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Metanx | Other: Metanx (a medical food)<br>* Metanx one tablet twice a day<br>|
| Placebo Comparator: 2<br>Placebo | Other: Metanx placebo<br>* Metanx placebo one tablet twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Vibration Perception Threshold (VPT) at 24 Weeks | Vibration Perception Threshold (VPT) 25-45 volts at hallux on either leg as measured by VPT meter on the great toe of each foot. Mean VPT averaged across both toes. | VPT was measured a 0 (baseline), and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Neuropathy Total Symptom Score-6 (NTSS-6) | This measure was taken to determine if Metanx® (compared to placebo) changes neuropathic symptoms as evaluated by the Neuropathy Total Symptom Score-6 (NTSS-6) The Neuropathy Total Symptom Score-6 Scale (NTSS-6) is a validated scale that evaluates individual neuropathy sensory symptoms in patients with diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN). This scale was a modified 6 item scale that consists of yes or no questions. Scores range between 0 and 21.96, a higher score indicates greater severity of symptoms. After adjusting for baseline measurements scores are reflected as negative numbers. Negative numbers indicate improvement in symptoms. ie. a change from baseline after 24 weeks of -2 would be a greater improvement than a change in baseline of -1 after 24 weeks. | NTSS-6 scores were taken at 0 (Baseline), 16, and 24 weeks | 
| Change From Baseline in Neuropathy Disability Score (NDS)at Week 16 and 24 | This outcome was taken to determine if Metanx® (compared to placebo) has an effect on clinical examination as determined by the Neuropathy Disability Score (NDS) The Neuropathy Disability Score (NDS) evaluates the severity of individual symptoms of neuropathy. A simple visual numeric distress scale is used that ranges from 0 to 10. The most favorable score is 0, which indicates an absence of symptoms. The most severe symptoms possible would be recorded as a score of 10. | NDS scores were taken at 0 (Baseline), 16, and 24 weeks | 
| Change From Baseline in Plasma Marker Levels of Total Folate and Total Methyl Malonic Acid (MMA) at Week 16 and 24 | To determine if Metanx® (compared to placebo) affects a change in subject's total folate and total methyl malonic acid (MMA) at week 16 and 24 | Change from Baseline in Plasma Marker Levels at 0 (Baseline), 16, and 24 weeks | 
| Change From Baseline in SF-36 MCS and SF-36 PCS at Week 24 | To determine if Metanx® (compared to placebo) affects a subject's quality of life as determined by the SF-36 questionnaire The Short Form- 36 Mental Component Summary (SF-36 MCS) and SF-36 Physical Component Summary (SF-36 PCS) both measure health related quality of life, the MCS quantifying mental health and the PCS quantifying physical function. They are both scored on 100 point scales with 0 representing the worst possible outcome and 100 representing the most optimal possible scoring | SF-36 MCS and SF-36 PCS scores were measured at 0 (Baseline) and 24 weeks | 
| Change From Baseline in 10-point Visual Analog Scale(VAS) at Week 24 | To determine if Metanx® (compared to placebo) affects a subject's lower extremity pain level using a 10-point Visual Analog Scale at Baseline and 24-week evaluation visits. The Visual Analog Scale (VAS) measures a patients sensation of pain. A 10-cm visual analog scale is used. A measurement on the 10 cm analog scale is used to quantify the level of pain indicated with 0 cm indicating no pain and 10 cm indicating the worst pain imaginable. | VAS scores were taken at 0 (Baseline) and 24 weeks | 
| (Exploratory) Change From Baseline in Levels of IL-6 and TNF-α, at Week 24 | (Exploratory) To determine if Metanx® affects a subject's plasma oxidative stress and inflammatory marker levels, including IL-6 and TNF-α | Analyte levels were taken at 0 (Baseline) and 24 weeks | 
| (Exploratory) Change From Baseline in the Hospital Anxiety and Depression Scale (HADS) Question Inventory at Week 24 | The Hospital Anxiety and Depression Scale (HADS) consists of a 14-item questionnaire that provides a measurement of depression. Each item is rated on a 4-point scale, giving a maximum scores of 21 for the most severe depression. Depression was evaluated using the Hospital Anxiety and Depression Scale (HADS) question inventory at Baseline, and 24-week evaluation visits | HADS Scores scores were taken at 0 (Baseline) and 24 weeks | 
| Change From Baseline in Total Homocysteine at Week 16 and 24 | To determine if Metanx® (compared to placebo) affects change in subjects total homocysteine levels | Change from Baseline in Plasma Marker Levels at 0 (Baseline), 16, and 24 weeks | 
| (Exploratory) Change From Baseline in Levels of Hs-CRP at Week 24 | (Exploratory) To determine if Metanx® affects a subject's plasma oxidative stress and inflammatory markers levels including hs-CRP | Analyte levels were taken at 0 (Baseline) and 24 weeks | 
| (Exploratory) Change From Baseline in Levels Potential Antioxidant (PAO) at Week 24 | (Exploratory) To determine if Metanx® affects a subject's plasma oxidative stress and inflammatory markers levels including Potential Antioxidant (PAO) | Analyte levels were taken at 0 (Baseline) and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metanx, diabetes, neuropathy, folic acid, folate, L-methylfolate, vitamin B6, Pyridoxal 5'-phosphate, vitamin B12, methylcobalamin