Safety and Efficacy Study for the Treatment of Painful Diabetic Neuropathy

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.

• Low Dose: 16 mg Engensis (VM202) (Biological), also known as Gene Therapy: 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)
• High Dose: 32 mg Engensis (VM202) (Biological), also known as Gene Therapy: 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)
• Control- Placebo (normal saline) (Other), also known as Normal saline: subjects will receive thirty-two (32) 0.5 mL injections of normal saline on Day 0 and Day 14.

Primary outcomes

• The Primary Study Endpoint Was the Change in Average 24-hour Pain Score From Baseline to the 6-month Follow-up. [seven (7) days before 9 Month visit]: 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).

Sex: All, ages: 18 Years to 75 Years

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

Participant flow

Outcome results

• The Primary Study Endpoint Was the Change in Average 24-hour Pain Score From Baseline to the 6-month Follow-up. (Primary), Mean, units on a scale: High Dose 32mg Engensis (VM202) -1.94 +/- 1.96; Low Dose 16mg Engensis (VM202) and Placebo -2.78 +/- 2.23; Control - Placebo (Normal Saline) -1.59 +/- 1.89

Adverse events

Time frame: Baseline (Day 0) to Day 270

Serious adverse events by term

Other adverse events by term

• Results publication: 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. PMID 26000320

• Study Protocol (PDF, 2012-08-01)
• Statistical Analysis Plan (PDF, 2014-04-09)

• Jack Kessler, MD, Principal investigator, Northwestern University