Phase 3 Gene Therapy for Painful Diabetic Neuropathy
Condition: Painful Diabetic Neuropathy; Diabetic Neuropathy, Painful
MeSH terms: Peripheral Nervous System Diseases; Diabetic Neuropathies; Pain
Intervention: Engensis (VM202); placebo
Intervention description: gene therapy
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 507.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: diabetic; peripheral neuropathy; shooting pain; burning pain; pins and needles pain; foot pain; ViroMed

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 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.
    

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 (VAS) score of ≥ 40 mm at Initial Screening (0 mm = no pain - 100
             mm very severe pain)

          8. Symptoms from the Brief Pain Neuropathy Screening (BPNS) 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 (MNSI) is ≥ 3 at Screening

         11. 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

         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 DPN

          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 (SBP) > 200
             mmHg or diastolic BP (DBP) > 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 IM
                  injection) and patches, isosorbide dinitrate (ISDN) 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 (BMI) > 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