Phase 3 Gene Therapy for Painful Diabetic Neuropathy

A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of VM202 in Participants With Painful Diabetic Peripheral Neuropathy

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 peripheral neuropathy.

A total of 507 of 477 planned participants were randomized in a 2:1 ratio to one of two treatment groups. Note that 500 participants received IP treatment, whereas 7 participants did not receive IP treatment.

Treatments - Engensis (VM202) - 336 Engensis of 318 planned participants

Control - Placebo (VM202 vehicle) - 164 Placebo of 159 planned participants

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

Study Overview

• Status: Completed
• Conditions: Diabetic Neuropathy, Painful; Painful Diabetic Neuropathy
• Intervention / Treatment: Other: placebo; Biological: Engensis (VM202)

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. Current treatments of diabetic peripheral neuropathy (DPN) are 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.

• Study Type: Interventional
• Enrollment (Actual): 507
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85023
      • Arizona Research Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Clinical Trials, Inc.
  • California
    • Los Gatos, California, United States, 95032
      • Richard S. Cherlin, MD
    • Sacramento, California, United States, 95821
      • Northern California Research
    • San Francisco, California, United States, 94115
      • Center for Clinical Research
    • Santa Monica, California, United States, 90404
      • Neurological Research Institute
    • Walnut Creek, California, United States, 94598
      • Diablo Clinical Research, Inc.
  • Connecticut
    • Fairfield, Connecticut, United States, 06824
      • Associated Neurologists of Southern Connecticut, PC
  • Florida
    • Clearwater, Florida, United States, 33756
      • Innovative Research of West Florida
    • Gainesville, Florida, United States, 32611
      • University of Florida McKnight Brain Institute
    • Jacksonville, Florida, United States, 32207
      • UF Health College of Med, Jacksonville
    • Orlando, Florida, United States, 32806
      • Compass Research, LLC
    • Tampa, Florida, United States, 33603
      • Clinical Research of West Florida
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • The Brigham and Women's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center Department of Neurology
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Raleigh Neurology Associates, P.A.
  • Pennsylvania
    • York, Pennsylvania, United States, 17402
      • Martin Foot and Ankle
  • Texas
    • Houston, Texas, United States, 77030
      • Nerve and Muscle Center of Texas
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah -Neurology
  • Virginia
    • Norfolk, Virginia, United States, 23510
      • EVMS (Eastern Virginia Medical School)
  • Washington
    • Everett, Washington, United States, 98208
      • Western Washington Medical Group
    • Renton, Washington, United States, 98057
      • Rainier Clinical Research Center, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years to ≤ 75 years
2. Documented history of type I or II diabetes with current treatment control (HbA1c of ≤ 10.0% at Screening) and currently on medication for diabetes (oral, injectable, 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 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
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 (except for lidocaine cream prior to IM injection) 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 180 days of the study. Subjects on these medications at study entry must maintain a stable dose until Day 180 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 until Day 180 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 until Day 180 of the study
21. Major psychiatric disorder within the last 180 days 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 Engensis (VM202)
25. Unable or unwilling to give informed consent

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
Experimental: Engensis (VM202); Subjects randomized to the Engensis (VM202) treatment arm received 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	Biological: Engensis (VM202); gene therapy
Placebo Comparator: Placebo; Subjects in the placebo control group received 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	Other: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Average 24 Hour Pain Score From Baseline to Day 90	Participants rated their 24-hour average daily pain intensity score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in a Daily Pain and Sleep Interference Diary	The Pain and Sleep Interference diary was completed by participants for at least 5 assessments during a 7-day period at Screening (the mean 24-hour score was the reference/baseline score) and within 14 days prior to Day 90 visit.
Participants With at Least at 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 90	Number of participants with at least a 50 percent reduction in average 24-hour pain score, using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary	Baseline to Day 90
Number of Participants With Treatment-emergent Adverse Events.	Number of Participants with at least one treatment-emergent adverse events.	Baseline to Day 270

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Average 24-hour Pain Score From Baseline to Day 180	Participants rated their 24-hour average daily pain intensity score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary	Baseline to Day 180
Participants With at Least a 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 180	The number of participants with at least a 50% reduction in average 24-hour pain score using an 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain) in the Daily Pain and Sleep Interference Diary	Baseline to Day 180

Collaborators and Investigators

• Sponsor: Helixmith Co., Ltd.
• Investigators: Principal Investigator: John A Kessler, MD, Northwestern University

Publications and helpful links

General Publications

• Kessler JA, Shaibani A, Sang CN, Christiansen M, Kudrow D, Vinik A, Shin N; VM202 study group. Gene therapy for diabetic peripheral neuropathy: A randomized, placebo-controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor. Clin Transl Sci. 2021 May;14(3):1176-1184. doi: 10.1111/cts.12977. Epub 2021 Feb 2.

Helpful Links

• Clin Transl Sci. 2021;00:1-9

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: April 22, 2015
• First Submitted That Met QC Criteria: April 27, 2015
• First Posted (Estimate): April 28, 2015

Study Record Updates

• Last Update Posted (Actual): August 22, 2022
• Last Update Submitted That Met QC Criteria: July 26, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: peripheral neuropathy; foot pain; diabetic; shooting pain; burning pain; pins and needles pain; ViroMed
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Pain; Diabetic Neuropathies
• Other Study ID Numbers: VMDN-003

Plan for Individual participant data (IPD)

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