Diabetic Neuropathy, Painful, Painful Diabetic Neuropathy
Conditions
Keywords
diabetic, peripheral neuropathy, shooting pain, burning pain, pins and needles pain, foot pain, ViroMed
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.
Interventions
BIOLOGICALEngensis (VM202)
gene therapy
OTHERplacebo
Sponsors
Helixmith Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| Number of Participants With Treatment-emergent Adverse Events. | Baseline to Day 270 | Number of Participants with at least one treatment-emergent adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
Participants recruited using standard methods were randomized 2:1 to Engensis or Placebo and stratified by gabapentinoid use versus non-gabapentinoid concomitant medications.
Participants by arm
| Arm | Count |
|---|---|
| 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
Engensis (VM202): gene therapy | 336 |
| 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
placebo | 164 |
| Total | 500 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 1 |
| Overall Study | Lost to Follow-up | 16 | 5 |
| Overall Study | Noncompliance | 16 | 10 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 8 |
Baseline characteristics
| Characteristic | Engensis (VM202) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.8 years STANDARD_DEVIATION 9.09 | 61.6 years STANDARD_DEVIATION 9.09 | 61.0 years STANDARD_DEVIATION 9.09 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 11 Participants | 4 Participants | 15 Participants |
| Race/Ethnicity, Customized Black or African American | 71 Participants | 29 Participants | 100 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 247 Participants | 125 Participants | 372 Participants |
| Region of Enrollment United States | 336 participants | 164 participants | 500 participants |
| Sex: Female, Male Female | 143 Participants | 45 Participants | 188 Participants |
| Sex: Female, Male Male | 193 Participants | 119 Participants | 312 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 332 | 1 / 161 |
| other Total, other adverse events | 237 / 332 | 102 / 161 |
| serious Total, serious adverse events | 32 / 332 | 16 / 161 |
Outcome results
Primary
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
Time frame: 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.
Population: Overall number of Intent-to-Treat population with available data for this assessment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Engensis (VM202) | Change in the Average 24 Hour Pain Score From Baseline to Day 90 | -1.80 units on a scale | Standard Deviation 2.05 |
| Placebo | Change in the Average 24 Hour Pain Score From Baseline to Day 90 | -1.57 units on a scale | Standard Deviation 2.07 |
Primary
Number of Participants With Treatment-emergent Adverse Events.
Number of Participants with at least one treatment-emergent adverse events.
Time frame: Baseline to Day 270
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Engensis (VM202) | Number of Participants With Treatment-emergent Adverse Events. | 241 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events. | 111 Participants |
Primary
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
Time frame: Baseline to Day 90
Population: Intent-to-Treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Engensis (VM202) | Participants With at Least at 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 90 | 69 Participants |
| Placebo | Participants With at Least at 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 90 | 28 Participants |
Secondary
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
Time frame: Baseline to Day 180
Population: Intent-to-Treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Engensis (VM202) | Change in the Average 24-hour Pain Score From Baseline to Day 180 | -2.59 units on a scale | Standard Deviation 2.38 |
| Placebo | Change in the Average 24-hour Pain Score From Baseline to Day 180 | -2.14 units on a scale | Standard Deviation 2.36 |
Secondary
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
Time frame: Baseline to Day 180
Population: Intent-to-Treat population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Engensis (VM202) | Participants With at Least a 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 180 | 113 Participants |
| Placebo | Participants With at Least a 50 Percent Reduction in Average 24-hour Pain Score From Baseline to Day 180 | 42 Participants |