The Nutritional Benefits of Metanx in Patients With Diabetic Peripheral Neuropathy (MEDIAN)

Study Overview
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Brief Summary
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The objectives of the MEDIAN study are to evaluate the short-term and long-term safety and nutritional benefits of Metanx® versus placebo in subjects with mild to moderate diabetic peripheral neuropathy (DPN). Short-term effects will be evaluated during the first 16 weeks of treatment, and long-term effects will be evaluated over the duration of a 48 week treatment period.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety and Nutritional Benefits of Metanx® in Subjects With Diabetic Peripheral Neuropathy

Conditions
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Diabetic Peripheral Neuropathy, B Vitamin Deficiency

Intervention / Treatment
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* Other: Metanx
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be male or female between 25 and 80 years of age, inclusive, at the time of consent Have a diagnosis of diabetes mellitus Type 2 as defined by the American Diabetes Association and on stable therapy as defined per the investigator's opinion for at least 1 month before the Screening Visit. Have a diagnosis of DPN established at least 6 months but not greater than 7 years prior to Screening If receiving DPN-related medication, doses must be stable for at least 6 weeks and should be taking only one of the following medications compliant with Exclusion Criterion 7: Alpha-2-delta ligand [e.g., pregabalin (Lyrica) or gabapentin (Neurontin) Anticonvulsant [e.g., carbamazepine, topiramate (Topamax), valproic acid (Depakote) or lamotrigine (Lamictal)] Serotonin-norepinephrine Reuptake Inhibitor (SNRI) [e.g., duloxetine (Cymbalta) or venlafaxine (Effexor)] Tricyclic antidepressant (TCA) [e.g., amitriptyline, nortriptyline, imipramine, and desipramine (Norpramin, Pertofrane)] Have a score between 3 and 6, inclusive, on the Michigan Neuropathy Screening Instrument (MNSI) Part b Have a minimum score of 6 on the NTSS-6 at Screening Have negative urinalysis for drugs of abuse, such as amphetamines, barbiturates, cannabinoids, cocaine, or opiates Have a negative urine pregnancy test at Screening if female and of childbearing potential If female, must be either of nonchildbearing potential (surgically sterile or 2 years postmenopausal) or agree to use two methods of effective contraception such as hormonal contraception, intrauterine device or other mechanical contraception device, or condom plus spermicide during the subject's participation If male, must be surgically sterile or agree to use two methods of effective contraception such as condom plus spermicide during the subject's participation Have the ability to understand the requirements of the study, have provided written informed consent as evidenced by signature on an informed consent form (ICF) approved by an institutional review board (IRB), and agree to abide by the study restrictions and return to the site for the required assessments Have provided written authorization for use and disclosure of protected health information Exclusion Criteria: Be pregnant or lactating Have a history of amputation, skin ulceration, and/or active Charcot of either foot Have a history of previous surgery involving the spine or lower extremity, with residual symptoms of pain or difficulty with movement Have Crohn's disease or a history of any type of bariatric surgery or any surgical resection of all or part of the stomach, duodenum, jejunum, and/or ileum. (Previous surgical resections of the colon that spared the stomach, duodenum, jejunum and ileum are allowed.) Have a history of surgery or hospitalization within 2 months prior to Screening or planned hospitalization at any time during the study Be taking systemic corticosteroids within 2 months prior to Screening, opiates or tramadol hydrochloride within 6 weeks prior to Screening, and/or immunosuppressives, or receiving radiotherapy within 6 months prior to Screening Be taking more than one anticonvulsant, serotonin-norepinephrine reuptake inhibitor (SNRI), or tricyclic antidepressant (TCA) Have ongoing evidence of peripheral vascular disease, including greater than one nonpalpable pulse on either foot, history of claudication, or history of lower extremity vascular bypass surgery or angioplasty Have circulating glycated hemoglobin (HbA1c) exceeding 11% at Screening Have an estimated glomerular filtration rate (eGFR) less than or equal to 40 ml/min using the Modification of Diet in Renal Disease (MDRD) formula at Screening or have end-stage renal disorder requiring hemodialysis Have uncontrolled hypertension defined as sustained systolic blood pressure (SBP) greater than 200 mmHg or diastolic blood pressure (DBP) greater than 110 mmHg at screening Have lung disease (uncontrolled asthma or shortness of breath) within 2 months prior to Screening Use of any of the following supplements within 6 weeks before Screening: evening primrose oil, vitamin B12 injection, greater than 10 mg of vitamin B6, or greater than 800 µg of folate Have previously failed two or more prior therapies for painful DPN Currently abusing alcohol or drugs or have a history of such abuse within the past 3 years. (Alcohol abuse is defined as more than 2 drink units per day for women and more than 3 drink units per day for men. One drink unit is defined as 1.5 oz [45 mL] of distilled spirits, 5 oz [150 mL] of wine, or 12 oz [360 mL] of beer.) Have any nondiabetic cause of peripheral neuropathy Have a history of documented lumbar nerve entrapment or symptoms suggestive of a lumbar nerve entrapment Have a history of systemic lupus erythematosis, rheumatoid arthritis, Sjögren's syndrome, or mixed connective tissue disease If receiving thyroid replacement therapy, should be on a stable dose for at least 6 weeks prior to Screening Have a history of a positive HIV test or active Hepatitis B or C infection. Have a history or presence of malignancy within 10 years prior to Screening except for basal or squamous cell carcinoma of the skin. Records to be submitted to Pamlab for review and approval to randomize. Have prior use of or intolerance to Metanx® or any of its active ingredients Have been dosed or used a medical device in another investigational trial within 60 days prior to Screening. Have any clinically significant existing medical, psychiatric, or nonmedical condition that in the opinion of the investigator places the subject at undue risk, prevents compliance with the study protocol, or potentially jeopardizes the quality of the data to be generated

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metanx<br>Subjects will take 2 Metanx tablets once daily for 48 weeks. | Other: Metanx<br>* Metanx is a prescription medical food.<br>|
| Placebo Comparator: Placebo<br>Subjects will take 2 placebo tablets once daily for 48 weeks. | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma methylmalonic acid (MMA) levels |  | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma 5-methyltetrahydrofolate levels |  | 16 weeks | 
| Change in plasma vitamin B6 levels |  | 16 weeks | 
| Change in plasma vitamin B12 levels |  | 16 weeks | 
| Change in urine microalbumin/creatinine ratio |  | 48 weeks | 
| Change in epidermal nerve fiber density | This neuropathy-specific measure will be evaluated to monitor for signs of disease progression. | 48 weeks | 
| Change in neuropathic disability as measured by the Michigan Neuropathy Screening Instrument part B | This neuropathy-specific measure will be evaluated to monitor for signs of disease progression. | 48 weeks | 
| Change in neuropathic symptoms as measured by the Neuropathy Total Symptom Score-6questionnaire(NTSS-6) | This neuropathy-specific measure will be evaluated to monitor for signs of disease progression. | 16 weeks | 
| Change in neuropathic symptoms as measured by the Neuropathy Total Symptom Score-6 questionnaire (NTSS-6) | This neuropathy-specific measure will be evaluated to monitor for signs of disease progression. | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metanx, B vitamins, neuropathy, nutrition