Safety and Efficacy Study for the Treatment of Painful Diabetic Neuropathy

A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of Engensis (VM202) in Subjects With Painful Diabetic Peripheral Neuropathy

The purpose of this study is to determine if Engensis (VM202) is safe and effective in treating painful diabetic neuropathy.

Study Overview

• Status: Completed
• Conditions: Painful Diabetic Neuropathies
• Intervention / Treatment: Other: Control- Placebo (normal saline); Biological: Low Dose: 16 mg Engensis (VM202); Biological: High Dose: 32 mg 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. There is currently no effective treatment for diabetic neuropathy, and good glycemic control is the only way to minimize the risk of occurrence. 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): 104
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Bundang-gu
    • Seongnam, Bundang-gu, Korea, Republic of, 463-707
      • Seoul National University Bundang Hospital
  • Seodaemun-gu
    • Seoul, Seodaemun-gu, Korea, Republic of, 120-752
      • Yonsei University College of Medicine Severance Hospital
  • Sosa-gu
    • Bucheon, Sosa-gu, Korea, Republic of, 422-711
      • Sejong General Hospital
  • Yeongdeungpo-gu
    • Seoul, Yeongdeungpo-gu, Korea, Republic of, 150-713
      • The Catholic University of Korea Youido St. Mary's Hospital
• United States
  • California
    • Walnut Creek, California, United States, 94598
      • Diablo Clinical Research
  • Florida
    • Orlando, Florida, United States, 32806
      • Compass Research
    • Palm Beach Gardens, Florida, United States, 33418
      • Palm Beach Neurological Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess
  • New York
    • Albany, New York, United States, 12208
      • The Neurosciences Institute Albany Medical College
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Harold Hamm Diabetes Center
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital
    • Houston, Texas, United States, 77030
      • Houston Neurocare
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Norfolk, Virginia, United States, 23510
      • East Virginia Medical School Strelitz Diabetes Center
  • Washington
    • Seattle, Washington, United States, 98057
      • Rainier Clinical Research

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age ≥ 18 years to ≤ 75 years
• 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
• Diagnosis of painful diabetic peripheral neuropathy in both lower extremities
• Lower extremity pain for at least 6 months
• Visual analog scale (VAS) score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100 mm very severe pain)
• Symptoms from the Brief Pain Neuropathy Screening (BPNS) is ≤ 5 point difference between legs at Initial Screening
• 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
• The physical examination component of the Michigan Neuropathy Screening Instrument Score (MNSI) is ≥ 3 at Screening
• Stable treatment of diabetes for at least 3 months with no anticipated changes in medication regimen, and no new symptoms associated with diabetes
• If female of childbearing potential, negative urine pregnancy test at screening and using acceptable method of birth control during the study

Exclusion Criteria:

• Peripheral neuropathy caused by condition other than diabetes
• Other pain more severe than neuropathic pain
• Progressive or degenerative neurological disorder
• Myopathy
• Inflammatory disorder of the blood vessels (inflammatory angiopathy, such as Buerger's disease)
• Active infection
• Chronic inflammatory disease (e.g., Crohn's disease, rheumatoid arthritis)
• Positive HIV or HTLV at Screening
• Active Hepatitis B or C as determined by Hepatitis B core antibody (HBcAB), antibody to Hepatitis B antigen (IgG and IgM; HbsAb), Hepatitis B surface antigen (HBsAg) and Hepatitis C antibodies (Anti-HCV) at Screening
• Subjects with known immunosuppression or currently receiving immunosuppressive drugs, chemotherapy or radiation therapy
• Stroke or myocardial infarction within last 3 months
• Ophthalmologic conditions pertinent to proliferative retinopathy or conditions that preclude standard ophthalmologic examination
• 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
• Uncontrolled hypertension as defined as sustained systolic blood pressure (SBP) > 200 mmHg or diastolic BP (DBP) > 110 mmHg at Screening
• Patients 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); patients 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
• Subjects requiring > 81 mg daily of acetylsalicylic acid; If ≥ 81 mg are taken at screening, subjects may be enrolled if willing/able to switch to another medication
• Use of any opioids; subjects may be enrolled if willing and able to discontinue use of these drugs 14 days prior to starting the 7 Day Daily Pain and Sleep Interference Diary and refrain from taking these drugs for the duration of the study
• Subjects requiring regular COX-2 inhibitor drug(s) or non-specific COX-1/COX-2 inhibiting drugs, or high dose steroids (excepting inhaled 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 duration of the study;
• Major psychiatric disorder in within last 6 months
• Body mass index (BMI) > 45 kg/m2 at Screening
• Any lower extremity amputation
• Use of an investigational drug or treatment in past 6 months
• 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: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control - Placebo (normal saline); 32 injections / calf of 0.5 mL normal saline at Day 0 and Day 14	Other: Control- Placebo (normal saline); subjects will receive thirty-two (32) 0.5 mL injections of normal saline on Day 0 and Day 14.; Other Names: Normal saline
Active Comparator: Low Dose 16mg Engensis (VM202) and Placebo; intramuscular injections in each calf for a total of 16mg Engensis (VM202): Day 0 - 32 injections / calf 16 injections of 0.5mL of VM202 / calf - (4 mg of VM202 / calf) and 16 injections of normal saline 0.5mL / calf Day 14 - 32 injections / calf and 16 injections of normal saline 0.5mL / calf 16 injections of 0.5mL of VM202 / calf - (4 mg of VM202 / calf)	Other: Control- Placebo (normal saline); subjects will receive thirty-two (32) 0.5 mL injections of normal saline on Day 0 and Day 14.; Other Names: Normal saline; Biological: Low Dose: 16 mg Engensis (VM202); Subjects in the Low Dose Group (8mg VM202 / leg) will receive the following intramuscular injections in each calf: Day 0 - 32 injections / calf: • 16 injections of 0.5mL of VM202 / calf - (4 mg of VM202 / calf) Day 14 - 32 injections / calf: • 16 injections of 0.5mL of VM202 / calf - (4 mg of VM202 / calf); Other Names: Gene Therapy
Active Comparator: High Dose 32mg Engensis (VM202); Day 0 - 32 injections of 0.5mL of VM202 / calf (8 mg of VM202 / calf) Day 14 - 32 injections of 0.5mL of VM202 / calf (8 mg of VM202 / calf) For a total of 32mg VM202	Biological: High Dose: 32 mg Engensis (VM202); Subjects in the High Dose Group (16 mg VM202 / leg) will receive the following intramuscular injections in each calf: Day 0 • 32 injections of 0.5mL of VM202 / calf (8 mg of VM202 / calf) Day 14 • 32 injections of 0.5mL of VM202 / calf (8 mg of VM202 / calf); Other Names: Gene Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Primary Study Endpoint Was the Change in Average 24-hour Pain Score From Baseline to the 6-month Follow-up.	The difference in the mean change of the 24 hour pain score was compared between the treatment groups and the placebo arm to determine treatment effect. The average pain scores were obtained from the Daily Pain and Sleep Interference Diary (recorded daily by subjects for 7 days during Screening prior to the first round of injections and again, before the 6 month follow-up). Subjects rated their 24-hor daily pain intensity according to the 11-point numerical rating scale from 0 (no pain) to 10 (worst possible pain).	seven (7) days before Day 0, Day 90, and the 6 Month and 9 Month visits

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in VAS score	The visual analog scale (VAS)scoring instrument is a 100-mm line, oriented horizontally, with the left end indicating "no pain" and the right end representing "very severe pain". The patient is asked to mark a place on the line corresponding to the current pain intensity. The distance along the scale is then converted into a numeric reading by measuring the distance of the patients mark in millimeters from the beginning of the scale (the 0 mark).	Screening, Day 0, Day 30, Day 60, Day 90, 6 months, and 9 months.
Change in mean Daily Pain and Sleep Interference Diary score from baseline to Day 90, 6 months and 9 months.	Subjects will be asked to keep a Daily Pain and Sleep Interference Diary. Subjects will be asked to rate their 24-hour average daily pain intensity score (0 = no pain, 10 = worst possible pain). The effect of pain on the subject's ability to sleep will be assessed using the sleep interference score.	Screening, Day 90, 6 months, 9 months.
Change in BPI-SF	The brief pain inventory (BPI-SF) will be self-administered during site visits on Day 0 before the treatment (injection), on Day 30, Day 60, Day 90, at 6 months and 9 months. The Questionnaire is a patient - completed numeric rating scale that assesses the severity of pain, its impact on daily functioning, and other aspects of pain (e.g. location of pain, relief from medications).	Day 0, Day 30, Day 60, Day 90, 6 months, and 9 months.
Patient's Global Impression of Change	The patient's global impression of change after treatment will be measured using the Patient's Global Impression of Change (PGIC) questionnaire. This questionnaire measures a patient's perception of how treatment has affected their level of activity, symptoms, emotions, and overall quality of life.	Day 30, Day 60, Day 90, 6 months, and 9 months.
Change in symptoms of the Brief Peripheral Neuropathy Screening (BPNS)	Subject rates the severity of symptoms of peripheral neuropathy.	Screening and 6 months.
Change in MNSI score	The Michigan Neuropathy Screening Instrument (MNSI) will be conducted at Screening in order to confirm the diagnosis of diabetic peripheral neuropathy and at 6 months and 9 months to track disease progression.The MNSI is comprised of a subject questionnaire (15 questions) and of a physical evaluation which includes a foot inspection, vibration sensation testing, muscle stretch reflexes, and monofilament testing.	Screen, 6 months and 9 months
Outcome of ≥50% reduction in average pain score	50% Reduction in average pain scores from Baseline to Day 180	Day 0 and Day 180

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics Determination of HGF serum levels	Serum HGF will be determined by ELISA and analyzed by a central laboratory.	Pre treatment Day 0, pre-treatment Day 14, Day 30, 60 and 90
Pharmacokinetics -Number of copies of VM202 in whole blood	The number of copies of VM202 in whole blood will be determined by PCR. Results will be analyzed by a central laboratory	Pre and post injection on Day 0 and Day 14, Day 21, 30, 60, and 90

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Kessler JA, Smith AG, Cha BS, Choi SH, Wymer J, Shaibani A, Ajroud-Driss S, Vinik A; VM202 DPN-II Study Group. Double-blind, placebo-controlled study of HGF gene therapy in diabetic neuropathy. Ann Clin Transl Neurol. 2015 May;2(5):465-78. doi: 10.1002/acn3.186. Epub 2015 Mar 5.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): March 12, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: November 15, 2011
• First Submitted That Met QC Criteria: November 16, 2011
• First Posted (Estimated): November 21, 2011

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: nerve pain; numbness; tingling; diabetic nerve pain; throbbing; burning; painful feet; Engensis (VM202)
• 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-002