Clinical trial NCT02427464: Phase 3 Gene Therapy for Painful Diabetic Neuropathy
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Painful Diabetic Neuropathy
Diabetic Neuropathy, Painful
Keywords: diabetic
peripheral neuropathy
shooting pain
burning pain
pins and needles pain
foot pain
ViroMed
Lead sponsor: Helixmith Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2015-04-28
Enrollment: 507
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100 mm very severe pain)
8. Symptoms from the Brief Pain Neuropathy Screening 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 is ≥ 3 at Screening
11. 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
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 Diabetic Peripheral Neuropathy
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 \> 200 mmHg or diastolic BP \> 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 intramuscular injection) and patches, isosorbide dinitrate 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 \> 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

Primary outcomes:
measure: Change in the Average 24 Hour Pain Score From Baseline to Day 90
timeFrame: 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.
measure: Participants With at Least at 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 90
timeFrame: Baseline to Day 90
measure: Number of Participants With Treatment-emergent Adverse Events.
timeFrame: Baseline to Day 270
Secondary outcomes:
measure: Change in the Average 24-hour Pain Score From Baseline to Day 180
timeFrame: Baseline to Day 180
measure: Participants With at Least a 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 180
timeFrame: Baseline to Day 180
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Research Center
state: Arizona
city: Little Rock
country: United States
facility: Clinical Trials, Inc.
state: Arkansas
city: Los Gatos
country: United States
facility: Richard S. Cherlin, MD
state: California
city: Sacramento
country: United States
facility: Northern California Research
state: California
city: San Francisco
country: United States
facility: Center for Clinical Research
state: California
city: Santa Monica
country: United States
facility: Neurological Research Institute
state: California
city: Walnut Creek
country: United States
facility: Diablo Clinical Research, Inc.
state: California
city: Fairfield
country: United States
facility: Associated Neurologists of Southern Connecticut, PC
state: Connecticut
city: Clearwater
country: United States
facility: Innovative Research of West Florida
state: Florida
city: Gainesville
country: United States
facility: University of Florida McKnight Brain Institute
state: Florida
city: Jacksonville
country: United States
facility: UF Health College of Med, Jacksonville
state: Florida
city: Orlando
country: United States
facility: Compass Research, LLC
state: Florida
city: Tampa
country: United States
facility: Clinical Research of West Florida
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute
state: Kansas
city: Boston
country: United States
facility: The Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University Medical Center Department of Neurology
state: New York
city: Raleigh
country: United States
facility: Raleigh Neurology Associates, P.A.
state: North Carolina
city: York
country: United States
facility: Martin Foot and Ankle
state: Pennsylvania
city: Houston
country: United States
facility: Nerve and Muscle Center of Texas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah -Neurology
state: Utah
city: Norfolk
country: United States
facility: EVMS (Eastern Virginia Medical School)
state: Virginia
city: Everett
country: United States
facility: Western Washington Medical Group
state: Washington
city: Renton
country: United States
facility: Rainier Clinical Research Center, Inc.
state: Washington
Study officials:
affiliation: Northwestern University
name: John A Kessler, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.