Phase 3 Gene Therapy for Painful Diabetic Neuropathy

Phase 3

Completed

Conditions: Painful Diabetic Neuropathy
Diabetic Neuropathy, Painful

Interventions: Other: placebo
Biological: Engensis (VM202)

Registration Number: NCT02427464

Lead Sponsor: Helixmith Co., Ltd.

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 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 Investigational product treatment, whereas 7 participants did not receive Investigational product 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.

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 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 507

Inclusion Criteria

Age ≥ 18 years to ≤ 75 years
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)
No significant changes anticipated in diabetes medication regimen
No new symptoms associated with diabetes within the last 3 months prior to study entry
Diagnosis of painful diabetic peripheral neuropathy in both lower extremities
Lower extremity pain for at least 6 months
Visual analog scale score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100 mm very severe pain)
Symptoms from the Brief Pain Neuropathy Screening 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 is ≥ 3 at Screening
Subjects on gabapentin (Neurontin), pregabalin (Lyrica), duloxetine (Cymbalta) for painful Diabetic Peripheral Neuropathy at study entry must be on stable regimen of these treatments for at least 3 months prior to study entry
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 that would prevent assessment of Diabetic Peripheral Neuropathy
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 surface 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
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
Ophthalmologic conditions pertinent to proliferative retinopathy or conditions that preclude standard ophthalmologic examination
Uncontrolled hypertension defined as sustained systolic blood pressure > 200 mmHg or diastolic BP > 110 mmHg at Screening
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
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 intramuscular injection) and patches, isosorbide dinitrate spray,
- transcutaneous electrical nerve stimulation (TENS), acupuncture
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;
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
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
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
Major psychiatric disorder within the last 180 days that would interfere with study participation
Body mass index > 45 kg/m2 at Screening
Any lower extremity amputation due to diabetic complications
Use of an investigational drug or treatment in past 6 months, or prior participation in any study of Engensis (VM202)
Unable or unwilling to give informed consent

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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
Engensis (VM202)	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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Adverse Events.	Baseline to Day 270	Number of Participants with at least one treatment-emergent adverse events.
Participants With at Least at 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 90	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
Change in the Average 24 Hour Pain Score From Baseline to Day 90	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 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

Secondary Outcome Measures

Name	Time	Method
Change in the Average 24-hour Pain Score From Baseline to Day 180	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
Participants With at Least a 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 180	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

Trial Locations

Locations (25): Martin Foot and Ankle
🇺🇸
York, Pennsylvania, United States
University of Florida McKnight Brain Institute
🇺🇸
Gainesville, Florida, United States
Raleigh Neurology Associates, P.A.
🇺🇸
Raleigh, North Carolina, United States
Richard S. Cherlin, MD
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Los Gatos, California, United States
EVMS (Eastern Virginia Medical School)
🇺🇸
Norfolk, Virginia, United States
UF Health College of Med, Jacksonville
🇺🇸
Jacksonville, Florida, United States
Western Washington Medical Group
🇺🇸
Everett, Washington, United States
Columbia University Medical Center Department of Neurology
🇺🇸
New York, New York, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
The Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States
Nerve and Muscle Center of Texas
🇺🇸
Houston, Texas, United States
University of Kansas Medical Center Research Institute
🇺🇸
Kansas City, Kansas, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
University of Utah -Neurology
🇺🇸
Salt Lake City, Utah, United States
Arizona Research Center
🇺🇸
Phoenix, Arizona, United States
Clinical Trials, Inc.
🇺🇸
Little Rock, Arkansas, United States
Diablo Clinical Research, Inc.
🇺🇸
Walnut Creek, California, United States
Center for Clinical Research
🇺🇸
San Francisco, California, United States
Associated Neurologists of Southern Connecticut, PC
🇺🇸
Fairfield, Connecticut, United States
Neurological Research Institute
🇺🇸
Santa Monica, California, United States
Innovative Research of West Florida
🇺🇸
Clearwater, Florida, United States
Northern California Research
🇺🇸
Sacramento, California, United States
Clinical Research of West Florida
🇺🇸
Tampa, Florida, United States
Compass Research, LLC
🇺🇸
Orlando, Florida, United States
Rainier Clinical Research Center, Inc.
🇺🇸
Renton, Washington, United States