Phase 3 Gene Therapy for Painful Diabetic Neuropathy

Study Description

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Brief Summary:

The purpose of this study is to determine the safety and efficacy of bilateral intramuscular injections of VM202 versus placebo in the treatment of painful diabetic neuropathy.

A total of 477 subjects will be randomized in a 2:1 ratio to one of two treatment groups:

Treatment - VM202 - 318 subjects Control - Placebo (VM202 vehicle) - 159 subjects

Randomization will be stratified by current use of gabapentin and/or pregabalin.

Condition or disease	Intervention/treatment	Phase
Painful Diabetic Neuropathy; Diabetic Neuropathy, Painful	Genetic: VM202; Genetic: placebo	Phase 3

Detailed Description:

Peripheral neuropathy is a serious complication of diabetes. This form of neuropathy carries a high risk of pain, trophic changes and autonomic dysfunction. Treatment of diabetic peripheral neuropathy (DPN) is based on either pathogenetic mechanisms or symptomatic relief. A number of clinical trials have established symptomatic treatment but for pathogenetic mechanisms, the only proven treatment strategy is strict glycemic control. Clearly, it would be desirable to prevent, impede, or reverse the disrupting and often life-threatening manifestations of peripheral neuropathy by stimulating growth or regeneration of peripheral nerve axons. The results from previous studies suggest that VM202 provides the same magnitude of pain relief as reported with pregabalin or gabapentin.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	477 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of VM202 in Subjects With Painful Diabetic Peripheral Neuropathy
Study Start Date :	April 2016
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	June 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: VM202; Subjects randomized to the VM202 treatment arm will receive the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 / calf; Day 14 - 16 injections of 0.5mL of VM202 / calf; Day 90 - 16 injections of 0.5mL of VM202 / calf; Day 104 - 16 injections of 0.5mL of VM202 / calf	Genetic: VM202; gene therapy
Placebo Comparator: Placebo; Subjects in the placebo control group will receive the following intramuscular injections in each calf: Day 0 - 16 injections of 0.5mL of VM202 vehicle / calf; Day 14 - 16 injections of 0.5mL of VM202 vehicle / calf; Day 90 - 16 injections of 0.5mL of VM202 vehicle / calf; Day 104 - 16 injections of 0.5mL of VM202 vehicle / calf	Genetic: placebo

Outcome Measures

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Primary Outcome Measures :

1. Change in the average pain score [ Time Frame: Baseline to three month follow up ]
   Subjects complete a Daily Pain and Sleep Interference diary at Screening (following wash-out of prohibited medications), and Day 90
2. Outcome of at least 50% reduction in average pain score [ Time Frame: Baseline to three month follow up ]
   Subjects complete a Daily Pain and Sleep Interference diary at Screening (following wash-out of prohibited medications), and Day 90

Secondary Outcome Measures :

1. Change in the average pain score [ Time Frame: Baseline to Six month follow up ]
   Subjects complete a Daily Pain and Sleep Interference diary at Screening (following wash-out of prohibited medications), Day 90, Day 180
2. Outcome of at least 50% reduction in average pain score [ Time Frame: Baseline to Six month follow up ]
   Subjects complete a Daily Pain and Sleep Interference diary at Screening (following wash-out of prohibited medications), Day 90, and Day 180

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Age ≥ 18 years to 75 years;
2. Documented history of Type I or II diabetes with current treatment control (glycosylated hemoglobin A1c of ≤ 10.0% at Screening) and currently on oral medication and / or insulin;
3. No significant changes anticipated in diabetes medication regimen;
4. No new symptoms associated with diabetes within the last 3 months prior to study entry;
5. Diagnosis of painful diabetic peripheral neuropathy in both lower extremities;
6. Lower extremity pain for at least 6 months;
7. Visual analog scale (VAS) score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100 mm very severe pain);
8. Symptoms from the Brief Pain Neuropathy Screening (BPNS) is ≤ 5 point difference between legs at Initial Screening;
9. The average daily pain intensity score of the Daily Pain and Sleep Interference Diary completed after medication wash-out is ≥ 4 with a standard deviation ≤ 2;
10. The physical examination component of the Michigan Neuropathy Screening Instrument Score (MNSI) is ≥ 3 at Initial Screening;
11. Subjects on gabapentin (Neurontin), pregabalin (Lyrica), duloxetine (Cymbalta) for painful DPN at study entry must be on stable regimen of these treatments for at least 3 months prior to study entry; and
12. If female of childbearing potential, negative urine pregnancy test at screening and using acceptable method of birth control during the study.

Exclusion Criteria:

1. Peripheral neuropathy caused by condition other than diabetes;
2. Other pain more severe than neuropathic pain that would prevent assessment of DPN;
3. Progressive or degenerative neurological disorder;
4. Myopathy;
5. Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as Buerger's disease);
6. Active infection;
7. Chronic inflammatory disease (e.g., Crohn's disease, rheumatoid arthritis);
8. Positive HIV or HTLV at Screening;
9. Active Hepatitis B or C as determined by Hepatitis B core antibody (HBcAb), antibody to Hepatitis B surface antigen (IgG and IgM; HBsAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV) at Screening;
10. Subjects with known immunosuppression or currently receiving immunosuppressive drugs, chemotherapy or radiation therapy;
11. Stroke or myocardial infarction within last 3 months;
12. Specific laboratory values at Screening including: Hemoglobin < 8.0 g/dL, WBC < 3,000 cells per microliter, platelet count <75,000/mm3, Creatinine > 2.0 mg/dL; AST and/or ALT > 3 times the upper limit of normal or any other clinically significant lab abnormality which in the opinion of the investigator should be exclusionary;
13. Ophthalmologic conditions pertinent to proliferative retinopathy or conditions that preclude standard ophthalmologic examination;
14. Uncontrolled hypertension defined as sustained systolic blood pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 110 mmHg at Screening;
15. Subjects with a recent history (< 5 years) of or new screening finding of malignant neoplasm except basal cell carcinoma or squamous cell carcinoma of the skin (if excised and no evidence of recurrence for one year); subjects with family history of colon cancer in any first degree relative are excluded unless they have undergone a colonoscopy in the last 12 months with negative findings;

16. Use of the following drugs / therapeutics is PROHIBITED. Subjects may participate in the study if they are willing to discontinue use of these drugs / therapeutics 7 days prior to starting the 7 Day Daily Pain and Sleep Interference Diary. Subjects must refrain from taking these drugs or undergoing these therapies for the duration of the study:

    • skeletal muscle relaxants, opioids, benzodiazepines (except for stable bedtime dose),
    • capsaicin, local anesthetic creams and patches, isosorbide dinitrate (ISDN) spray,
    • transcutaneous electrical nerve stimulation (TENS), acupuncture
17. If not using gabapentin (Neurontin) or pregabalin (Lyrica), subjects must agree not to start these drugs for the first 6 months of the study. Subjects on these medications at study entry must maintain a stable dose for the first 6 months of the study;

18. If not using duloxetine (Cymbalta), any antidepressants (e.g. amitriptyline and venlafaxine), any other antiepileptics (e.g., valproic acid, carbamazepine, vigabatrin), subjects must agree not to start these drugs for the first 6 months of the study.

    Subjects on these medications at study entry must maintain a stable dose for the first 6 months of the study;

19. Subjects requiring > 81 mg daily of acetylsalicylic acid; subjects may be enrolled if willing/able to switch to ≤ 81 mg daily of acetylsalicylic acid or to another medication;
20. Subjects requiring regular COX-2 inhibitor drug(s) or non-specific COX-1/COX-2 inhibiting drugs, or high dose steroids (except inhaled steroids or ocular steroids); subjects may be enrolled if willing/able to undergo medication wash-out prior to the first dosing and to refrain from taking these drugs for the first 6 months of the study;
21. Major psychiatric disorder within last 6 months that would interfere with study participation;
22. Body mass index (BMI) > 45 kg/m2 at Screening;
23. Any lower extremity amputation due to diabetic complications;
24. Use of an investigational drug or treatment in past 6 months, or prior participation in any study of VM202; and
25. Unable or unwilling to give informed consent.

Contacts and Locations

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Contacts

Contact: Sheila Yi		sheila@viromed.co.kr

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Sponsors and Collaborators

ViroMed Co., Ltd.

MedTech Consultants Inc.

Investigators

Principal Investigator:	John A Kessler, MD	Northwestern University

More Information

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Responsible Party:	ViroMed Co., Ltd.
ClinicalTrials.gov Identifier:	NCT02427464 History of Changes
Other Study ID Numbers:	VMDN-003
First Posted:	April 28, 2015
Last Update Posted:	October 23, 2017
Last Verified:	July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by ViroMed Co., Ltd.:

diabetic; neuropathy; shooting pain; burning pain	pins and needles pain; foot pain; ViroMed

Additional relevant MeSH terms:

Peripheral Nervous System Diseases; Pain; Diabetic Neuropathies; Neuromuscular Diseases; Nervous System Diseases	Neurologic Manifestations; Signs and Symptoms; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases