Phase 3 Gene Therapy for Painful Diabetic Neuropathy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Painful Diabetic Neuropathy, Diabetic Neuropathy, Painful

Intervention / Treatment
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* Biological: Engensis (VM202)
* Other: placebo


Participation Criteria
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Eligibility Criteria
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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 (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 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 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 DPN 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 (SBP) > 200 mmHg or diastolic BP (DBP) > 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 IM injection) and patches, isosorbide dinitrate (ISDN) 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 (BMI) > 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Engensis (VM202)<br>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)<br>* gene therapy<br>|
| Placebo Comparator: Placebo<br>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<br> <br> |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetic, peripheral neuropathy, shooting pain, burning pain, pins and needles pain, foot pain, ViroMed