<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04469270</url>
  </required_header>
  <id_info>
    <org_study_id>VMDN-003-2</org_study_id>
    <nct_id>NCT04469270</nct_id>
  </id_info>
  <brief_title>Study to Assess Safety and Efficacy of Engensis in Painful Diabetic Peripheral Neuropathy</brief_title>
  <acronym>REGAiN-1A</acronym>
  <official_title>An Adaptive, Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety and Efficacy of Engensis in Participants With Painful Diabetic Peripheral Neuropathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Helixmith Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Helixmith Co., Ltd.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the efficacy and safety of intramuscular (IM)&#xD;
      administration of Engensis on pain in participants with painful diabetic peripheral&#xD;
      neuropathy (DPN) in the feet and lower legs, as compared to Placebo, as a second Phase 3,&#xD;
      well controlled study, sufficient in supporting the efficacy and safety of Engensis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Overall Design VMDN-003-2 is an adaptive Phase 3, double-blind, randomized,&#xD;
      placebo-controlled, multicenter study designed to assess the efficacy and safety of Engensis&#xD;
      (containing the active pharmaceutical ingredient VM202) in Participants with painful DPN.&#xD;
      Following completion of the informed consent process, Screening activities (during 45 days&#xD;
      [from Day -52 to Day -7] prior to Day 0) will determine which Participants meet all-but-one&#xD;
      eligibility criteria, which are assessed by an adjudication procedure, followed by completion&#xD;
      of a 7-day eDiary prior to Day 0. Eligible participants will be enrolled and randomly&#xD;
      assigned in a double-blind fashion and in a 1:1 ratio on Day 0 to either Engensis or Placebo.&#xD;
      During Screening, medical history and familial cancer history, demographics, vital signs,&#xD;
      height, body mass index (BMI), waist size, physical examination, retinal fundoscopy (by an&#xD;
      ophthalmologist), 12-lead electrocardiogram (ECG), ultrasound of the right and left&#xD;
      gastrocnemius muscles (to guide IM Study Injections), laboratory assessments, estimated&#xD;
      glomerular filtration rate (eGFR), HBA1c levels, viral screening, a record of all concomitant&#xD;
      medications and procedures, urine drug analysis, and urine pregnancy test for females of&#xD;
      childbearing potential will be conducted. In addition, the following procedures will be&#xD;
      conducted during Screening: Hospital Anxiety and Depression Scale (HADS), Accurate Pain&#xD;
      Reporting (APR) and Placebo Response Reduction (PRR), Michigan Neuropathy Screening&#xD;
      Instrument (MNSI), and cancer screening tests.&#xD;
&#xD;
      During 7 days before Day 0 and randomization, Participants must complete the full Brief Pain&#xD;
      Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) on an eDiary for determining the&#xD;
      Average Daily Pain Scores (ADPSs) for at least 5 out of the 7 days. Adverse event (AE)&#xD;
      assessments will start upon completion of the consent process at the start of Screening.&#xD;
&#xD;
      At any time prior to dosing on Day 0, Bedside Sensory Testing (BST) should be administered.&#xD;
&#xD;
      Following randomization, and prior to the first IM injections of Engensis or Placebo on Day&#xD;
      0, the partial BPI-DPN, , and quality of life instruments will be completed. Blood will be&#xD;
      collected for testing of selected cytokines, anti-HGF antibodies, and laboratory assessments.&#xD;
&#xD;
      All Participants will receive sixteen (16) 0.5-mL IM injections of Engensis or Placebo in&#xD;
      each calf gastrocnemius muscle at each of two Visits during two Treatment Cycles: Treatment&#xD;
      Cycle 1 on Day 0 and Day 14, and Treatment Cycle 2 on Day 90 and Day 104. At 2 hours (± 1&#xD;
      hour) after completion of IM injections of Engensis or Placebo on Days 0 and 14 and Days 90&#xD;
      and 104, vital signs and blood draw for cytokine levels will be performed. Treatment-emergent&#xD;
      adverse event (TEAE) assessment, including injection site reactions, will start as of&#xD;
      randomization (Day 0) and continue throughout the study. Follow-up Study Visits will be&#xD;
      conducted on Days 28, 60, 150, and 180 or early termination (ET). Vital signs will be&#xD;
      recorded at all Study Visits. At the Day 180 Visit (end of study), the following assessments&#xD;
      will be conducted: the full BPI-DPN (performed for 7 days prior to the Day 180 Visit), MNSI,&#xD;
      BST, Patient Global Impression of Change (PGIC), and the quality of life assessments (36-item&#xD;
      Short Form Health Survey [SF-36] and EuroQol Health Utilities Index [EQ-5D]), urine drug&#xD;
      analysis, retinal fundoscopy, physical examination, concomitant medications and procedures,&#xD;
      and anti-HGF antibodies. Blood will be drawn for determination of serum chemistry, lipid&#xD;
      profile, pregnancy status, hematology, and HbA1c levels. The purpose of this study is to&#xD;
      assess the efficacy and safety of Engensis compared to Placebo as measured by changes in the&#xD;
      means of the Average Daily Pain Scores (ADPSs) of the full BPI-DPN, selected blood cytokines,&#xD;
      BST, and assessments of injection site reactions, physical examination, laboratory&#xD;
      assessments, vital signs, TEAEs, and serious adverse events (SAEs).&#xD;
&#xD;
      Study and Treatment Duration:&#xD;
&#xD;
      Screening will occur up to 52 days prior to Baseline (Day 0) and Participants will be&#xD;
      followed from Day 0, the day of first Study Injections, to Day 180/ET.&#xD;
&#xD;
      Visit Frequency:&#xD;
&#xD;
      Consented Participants will be seen and evaluated for enrollment during Screening (up to 52&#xD;
      days prior to Baseline, Day 0). There are 8 visits to the Clinical Site during the study from&#xD;
      Day 0 to Day 180 for Study Injections and follow-up.&#xD;
&#xD;
      Intervention Groups and Duration:&#xD;
&#xD;
      Two treatment groups of Participants (Engensis or Placebo) will be in the study for 180 days.&#xD;
&#xD;
      Number of Participants (N = 152 to approximately 250):&#xD;
&#xD;
      The target sample size is a minimum of 152 Participants and the maximum sample size is 250&#xD;
      Participants based on the proposed adaptive design analysis. The final sample size of&#xD;
      Participants to be enrolled and evaluated will be determined by the independent Data&#xD;
      Monitoring Committee (DMC). An interim analysis will be conducted after approximately 50% of&#xD;
      Participants in the target sample (i.e., 76 Participants) have completed the primary efficacy&#xD;
      endpoint at Day 180 or have withdrawn prematurely. The DMC will make a recommendation based&#xD;
      on an unblinded (comparative) power analysis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">October 9, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2023</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of Engensis compared to Placebo on painful DPN in the feet and lower legs comparing the Average Daily Pain Score from the Day 0 Visit to the Day 180 Visit on the Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy</measure>
    <time_frame>180 days</time_frame>
    <description>• The Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy has a minimum score of 0 and a maximum score of 10, with a higher score representing a worse outcome of more pain.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy of Engensis on the worst pain in painful DPN in the feet and lower legs by comparing the change from baseline (Day 0) in the Worst Pain score from the Brief Pain Inventory for Diabetic Peripheral Neuropathy to Day 180 compared to Placebo</measure>
    <time_frame>180 days</time_frame>
    <description>• The Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) has a minimum score of 0 and a maximum score of 10, with a higher score representing a worse outcome of more pain</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy of Engensis on reducing pain in painful DPN in the feet and lower legs by determining a ≥ 50% reduction in the Average Daily Pain Score from baseline to Day 180 using the Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy</measure>
    <time_frame>180 days</time_frame>
    <description>• The Average Daily Pain Score from the Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy has a minimum score of 0 and a maximum score of 10 with a higher score representing a worse outcome of more pain</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety of Engensis in painful DPN in the feet and lower legs by comparing the incidence of adverse and serious adverse events, the incidence of injection site reactions, and the incidence of clinically significant laboratory values to Placebo</measure>
    <time_frame>180 days</time_frame>
    <description>Incidence of adverse events (AEs) and serious adverse events (SAEs)&#xD;
Incidence of injection site reactions&#xD;
Incidence of clinically significant laboratory values</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the possibility of cellular responses to Engensis</measure>
    <time_frame>104 days</time_frame>
    <description>• Change from baseline in the TNF-alpha, IL-1b, IFNy, IL-6, IL-4, IL-10, and IL-12p70 cytokine profile post-dose at the Day 104 visit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the possibility of humoral responses to Engensis</measure>
    <time_frame>104 days</time_frame>
    <description>• Presence of hepatocyte growth factor (HGF) antibodies</description>
  </secondary_outcome>
  <other_outcome>
    <measure>To determine whether IM administration of Engensis has the potential for disease modification by measuring the improvement in Bedside Sensory Testing at Day 180 compared to Baseline</measure>
    <time_frame>180 days</time_frame>
    <description>• The Bedside Sensory Testing scale has a minimum score of 0 and a maximum score of 10 with a higher score representing a better outcome</description>
  </other_outcome>
  <other_outcome>
    <measure>To determine whether IM administration of Engensis has the potential for improving quality of life, sensation, proprioception, and deep tendon reflexes by measuring the improvement in Bedside Sensory Testing at Day 180 compared to Baseline</measure>
    <time_frame>180 days</time_frame>
    <description>• The Bedside Sensory Testing scale has a minimum score of 0 and a maximum score of 10 with a higher score representing a better outcome</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Diabetic Neuropathy, Painful</condition>
  <arm_group>
    <arm_group_label>Engensis</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>16 (ea) 0.25mg (0.5 mL) injections in each of the right and left gastrocnemius muscles on Days 0, 14, 90, and 104.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>16 0.5 mL injections in each of the right and left gastrocnemius muscles on Days 0, 14, 90, and 104.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Engensis</intervention_name>
    <description>Intramuscular injections</description>
    <arm_group_label>Engensis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Intramuscular injections</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Male or female participants age ≥ 18 years at time of completion of the informed&#xD;
             consent process&#xD;
&#xD;
          2. Type 1 or 2 diabetes mellitus (DM) and on current Standards of Medical Care in&#xD;
             Diabetes - 2020 optimal guideline-directed medical therapy in participants (including&#xD;
             vaccine recommendations if possible), AND without unstable diabetes or significant&#xD;
             medical problems, such as progressive end-organ disease, within 3 months of or during&#xD;
             Screening, in the judgment of the Investigator&#xD;
&#xD;
          3. Glycosylated hemoglobin A1c (HbA1c) of ≤ 10.0% using the first assessment collected&#xD;
             during Screening&#xD;
&#xD;
          4. Documented diagnosis of bilateral painful DPN in both lower extremities at least 6&#xD;
             months prior to Screening&#xD;
&#xD;
          5. An Average Daily Pain Score ≥ 4 (standard deviation ≥ 0.3 and ≤ 1.5) that is completed&#xD;
             during the 7 days prior to randomization (Day 0)&#xD;
&#xD;
          6. The physical examination component of the Michigan Neuropathy Screening Instrument&#xD;
             (MNSI) score of ≥ 2.5&#xD;
&#xD;
          7. If on medication for painful DPN (other than gabapentin or pregabalin), must be on a&#xD;
             stable dose defined as &lt; 50% change in total dose over 3 months prior to completion of&#xD;
             informed consent process&#xD;
&#xD;
          8. Male participants and their female partners must agree to use double-barrier&#xD;
             contraception during the study or provide proof of postmenopausal state (minimum 1&#xD;
             year) or surgical sterility&#xD;
&#xD;
          9. Male participants must not donate sperm during the study&#xD;
&#xD;
         10. Female participants must be nonpregnant, nonlactating, and either postmenopausal for&#xD;
             at least 1 year, or surgically sterile for at least 3 months, or agree to use double&#xD;
             barrier contraception from 28 days prior to randomization and/or their last confirmed&#xD;
             menstrual period prior to study randomization (whichever is longer) until the end of&#xD;
             the study&#xD;
&#xD;
         11. Capable and willing to comply with the requirements and restrictions of the protocol&#xD;
             and informed consent form&#xD;
&#xD;
         12. Able to complete all screening activities within 45 days of signing the informed&#xD;
             consent form&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Other sources of pain that would prevent accurate assessment of DPN pain (e.g.,&#xD;
             thoracic and/or lumbar root proximal neuropathy, mononeuritis multiplex)&#xD;
&#xD;
          2. Peripheral neuropathy caused by a condition other than diabetes: e.g., anatomic&#xD;
             (sciatic nerve compression), systemic (monoclonal gammopathy), metabolic (thyroid&#xD;
             disease), and toxic (alcohol use) neuropathies&#xD;
&#xD;
          3. Has taken gabapentin or pregabalin during 30 days before completion of informed&#xD;
             consent process or will take at any time during the study&#xD;
&#xD;
          4. Progressive or degenerative neurological disorder, such as amyotrophic lateral&#xD;
             sclerosis (ALS), Alzheimer's disease, Parkinson's disease, vascular dementia, multiple&#xD;
             sclerosis, or other neurological disorders determined by the Investigator to preclude&#xD;
             participation&#xD;
&#xD;
          5. Symptomatic peripheral artery disease (PAD) or PAD requiring revascularization and/or&#xD;
             that may interfere with the conduct of the study&#xD;
&#xD;
          6. Vasculitis, such as from Buerger's or other disease&#xD;
&#xD;
          7. Systolic blood pressure &gt;180 mm Hg on tolerable doses of standard antihypertensive&#xD;
             medications at Screening determined by the Investigator to preclude participation&#xD;
&#xD;
          8. Hyperlipidemia or dyslipidemia not being treated with an optimal treatment regimen&#xD;
             that follows the Standards of Care for hyperlipidemic/dyslipidemic patients with DM&#xD;
&#xD;
          9. Class 3 or 4 heart failure&#xD;
&#xD;
         10. Symptomatic bradycardia or untreated high degree atrioventricular block&#xD;
&#xD;
         11. Stroke or cerebrovascular accident or myocardial infarction within 3 months before&#xD;
             Screening&#xD;
&#xD;
         12. eGFR &lt; 30 mL/min/1.73 m2&#xD;
&#xD;
         13. Progressive renal dysfunction, defined as a decrease in eGFR to chronic kidney disease&#xD;
             (CKD) Stage 1, 2, or 3 in the past 6 months before Screening&#xD;
&#xD;
         14. Ophthalmologic conditions pertinent to signs or symptoms of proliferative diabetic&#xD;
             retinopathy (PDR) or other ocular conditions that preclude standard ophthalmologic&#xD;
             examination&#xD;
&#xD;
         15. Myopathy (e.g., Duchenne or Becker muscular dystrophy, polymyositis)&#xD;
&#xD;
         16. Any prior or planned lower extremity amputation (excluding toe amputations) due to&#xD;
             diabetic complications or prior lower leg injury (e.g., scarring, muscle atrophy) in&#xD;
             the calf area (gastrocnemius) that would significantly reduce the surface area of the&#xD;
             skin or amount of intact skeletal muscle required for the 16 treatment injections of&#xD;
             Engensis&#xD;
&#xD;
         17. Active infection requiring antimicrobial agent(s) (chronic infection or severe active&#xD;
             infection that may compromise the Participant's well-being or participation in the&#xD;
             study, in the Investigator's judgment)&#xD;
&#xD;
         18. Chronic inflammatory or autoimmune disease (e.g., Crohn's disease, rheumatoid&#xD;
             arthritis)&#xD;
&#xD;
         19. Immunosuppression due to underlying disease (e.g., rheumatoid arthritis, systemic&#xD;
             lupus erythematosus) or to currently receiving immunosuppressive drugs, (e.g.,&#xD;
             chemotherapy, corticosteroids) or to radiation therapy&#xD;
&#xD;
         20. Participants requiring chronic oral or injectable steroids and unwilling to refrain&#xD;
             from taking these drugs for the duration of the study&#xD;
&#xD;
         21. Participants with a family medical history of 2 or more first-degree relatives&#xD;
             (parent, sibling, child) diagnosed to have the same type of cancer - breast cancer,&#xD;
             cervical cancer, colon cancer, endometrial cancer, lung cancer, or prostate cancer, or&#xD;
             with a family medical history of Lynch syndrome (hereditary non-polyposis colorectal&#xD;
             cancer) in any first-degree relative; or who show positive results during cancer&#xD;
             screening&#xD;
&#xD;
         22. Positive human immunodeficiency virus (HIV) or human T-cell lymphotropic virus (HTLV)&#xD;
             I/II test at Screening&#xD;
&#xD;
         23. Participants who have not been cancer-free for ≥ 5 years with the following exceptions&#xD;
             (not excluded): Participants with in-situ basal cell or squamous cell carcinoma&#xD;
&#xD;
         24. Participants with a prior history of stem cell transplant for cancer no matter how&#xD;
             long they have been cancer-free&#xD;
&#xD;
         25. Active acute or chronic hepatitis B&#xD;
&#xD;
         26. Active hepatitis C&#xD;
&#xD;
         27. Clinically significant laboratory values or current medical conditions during&#xD;
             Screening that, in the judgment of the Investigator, should be exclusionary&#xD;
&#xD;
         28. Hospital Anxiety and Depression Scale (HADS) score of ≥ 15 on either subscale&#xD;
&#xD;
         29. History of drug abuse (the habitual taking of addictive or illegal drugs) in the past&#xD;
             3 months and positive for Drugs of Abuse, with the exception of cannabis, during&#xD;
             Screening&#xD;
&#xD;
         30. Participants unwilling to discontinue their use of the following during Screening at&#xD;
             least 7 days before starting eDiary entries and not use any of the following during&#xD;
             the study:&#xD;
&#xD;
               -  skeletal muscle relaxants&#xD;
&#xD;
               -  opioids&#xD;
&#xD;
               -  transcutaneous electrical nerve stimulation (TENS)&#xD;
&#xD;
               -  acupuncture&#xD;
&#xD;
               -  benzodiazepines (other than stable bedtime dose)&#xD;
&#xD;
               -  injectable or oral steroids&#xD;
&#xD;
         31. Participants not on a stable dose and not willing to remain on a stable dose during&#xD;
             the study for the following drugs:&#xD;
&#xD;
               -  antidepressants&#xD;
&#xD;
               -  antiepileptics&#xD;
&#xD;
               -  duloxetine&#xD;
&#xD;
         32. Participants currently using the following medications and unwilling to discontinue&#xD;
             topical use on the lower legs and feet and throughout the study:&#xD;
&#xD;
               -  capsaicin&#xD;
&#xD;
               -  anesthetic creams (except during Study Injections)&#xD;
&#xD;
               -  anesthetic patches&#xD;
&#xD;
               -  ISDN spray&#xD;
&#xD;
         33. Use of an investigational drug or treatment in past 30 days or previous participation&#xD;
             in a clinical study with Engensis&#xD;
&#xD;
         34. Body mass index (BMI) ≥ 42 kg/m2&#xD;
&#xD;
         35. Recent treatment for COVID-19 with ongoing sequelae&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Arizona Research Center</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85053</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trials - Little Rock</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>California Medical Clinic for Headache</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trials Research - Sacramento</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95821</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Innovative Research of West Florida, Inc.</name>
      <address>
        <city>Clearwater</city>
        <state>Florida</state>
        <zip>33756</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gateway Clinical Trials, LLC</name>
      <address>
        <city>O'Fallon</city>
        <state>Illinois</state>
        <zip>62269</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Foot &amp; Ankle Center of Illinois</name>
      <address>
        <city>Springfield</city>
        <state>Illinois</state>
        <zip>62704</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Research Professionals</name>
      <address>
        <city>Chesterfield</city>
        <state>Missouri</state>
        <zip>63005</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Richmond Behavioral Associates</name>
      <address>
        <city>Staten Island</city>
        <state>New York</state>
        <zip>10314</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Health Concepts</name>
      <address>
        <city>Rapid City</city>
        <state>South Dakota</state>
        <zip>57702</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nerve and Muscle Center of Texas</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Futuro Clinical Trials</name>
      <address>
        <city>McAllen</city>
        <state>Texas</state>
        <zip>78501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ClinPoint Trials LLC</name>
      <address>
        <city>Waxahachie</city>
        <state>Texas</state>
        <zip>75165</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Manassas Clinical Research Center</name>
      <address>
        <city>Manassas</city>
        <state>Virginia</state>
        <zip>20110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Eastern Virginia Medical School</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dominion Medical Associates</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <zip>23219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>June 25, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>November 3, 2022</last_update_submitted>
  <last_update_submitted_qc>November 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peripheral Nervous System Diseases</mesh_term>
    <mesh_term>Diabetic Neuropathies</mesh_term>
    <mesh_term>Pain</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04469270
org study id: VMDN-003-2
nct id: NCT04469270
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate the efficacy and safety of intramuscular (IM)
      administration of Engensis on pain in participants with painful diabetic peripheral
      neuropathy (DPN) in the feet and lower legs, as compared to Placebo, as a second Phase 3,
      well controlled study, sufficient in supporting the efficacy and safety of Engensis.
Overall Design VMDN-003-2 is an adaptive Phase 3, double-blind, randomized,
      placebo-controlled, multicenter study designed to assess the efficacy and safety of Engensis
      (containing the active pharmaceutical ingredient VM202) in Participants with painful DPN.
      Following completion of the informed consent process, Screening activities (during 45 days
      [from Day -52 to Day -7] prior to Day 0) will determine which Participants meet all-but-one
      eligibility criteria, which are assessed by an adjudication procedure, followed by completion
      of a 7-day eDiary prior to Day 0. Eligible participants will be enrolled and randomly
      assigned in a double-blind fashion and in a 1:1 ratio on Day 0 to either Engensis or Placebo.
      During Screening, medical history and familial cancer history, demographics, vital signs,
      height, body mass index (BMI), waist size, physical examination, retinal fundoscopy (by an
      ophthalmologist), 12-lead electrocardiogram (ECG), ultrasound of the right and left
      gastrocnemius muscles (to guide IM Study Injections), laboratory assessments, estimated
      glomerular filtration rate (eGFR), HBA1c levels, viral screening, a record of all concomitant
      medications and procedures, urine drug analysis, and urine pregnancy test for females of
      childbearing potential will be conducted. In addition, the following procedures will be
      conducted during Screening: Hospital Anxiety and Depression Scale (HADS), Accurate Pain
      Reporting (APR) and Placebo Response Reduction (PRR), Michigan Neuropathy Screening
      Instrument (MNSI), and cancer screening tests.

      During 7 days before Day 0 and randomization, Participants must complete the full Brief Pain
      Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) on an eDiary for determining the
      Average Daily Pain Scores (ADPSs) for at least 5 out of the 7 days. Adverse event (AE)
      assessments will start upon completion of the consent process at the start of Screening.

      At any time prior to dosing on Day 0, Bedside Sensory Testing (BST) should be administered.

      Following randomization, and prior to the first IM injections of Engensis or Placebo on Day
      0, the partial BPI-DPN, , and quality of life instruments will be completed. Blood will be
      collected for testing of selected cytokines, anti-HGF antibodies, and laboratory assessments.

      All Participants will receive sixteen (16) 0.5-mL IM injections of Engensis or Placebo in
      each calf gastrocnemius muscle at each of two Visits during two Treatment Cycles: Treatment
      Cycle 1 on Day 0 and Day 14, and Treatment Cycle 2 on Day 90 and Day 104. At 2 hours (± 1
      hour) after completion of IM injections of Engensis or Placebo on Days 0 and 14 and Days 90
      and 104, vital signs and blood draw for cytokine levels will be performed. Treatment-emergent
      adverse event (TEAE) assessment, including injection site reactions, will start as of
      randomization (Day 0) and continue throughout the study. Follow-up Study Visits will be
      conducted on Days 28, 60, 150, and 180 or early termination (ET). Vital signs will be
      recorded at all Study Visits. At the Day 180 Visit (end of study), the following assessments
      will be conducted: the full BPI-DPN (performed for 7 days prior to the Day 180 Visit), MNSI,
      BST, Patient Global Impression of Change (PGIC), and the quality of life assessments (36-item
      Short Form Health Survey [SF-36] and EuroQol Health Utilities Index [EQ-5D]), urine drug
      analysis, retinal fundoscopy, physical examination, concomitant medications and procedures,
      and anti-HGF antibodies. Blood will be drawn for determination of serum chemistry, lipid
      profile, pregnancy status, hematology, and HbA1c levels. The purpose of this study is to
      assess the efficacy and safety of Engensis compared to Placebo as measured by changes in the
      means of the Average Daily Pain Scores (ADPSs) of the full BPI-DPN, selected blood cytokines,
      BST, and assessments of injection site reactions, physical examination, laboratory
      assessments, vital signs, TEAEs, and serious adverse events (SAEs).

      Study and Treatment Duration:

      Screening will occur up to 52 days prior to Baseline (Day 0) and Participants will be
      followed from Day 0, the day of first Study Injections, to Day 180/ET.

      Visit Frequency:

      Consented Participants will be seen and evaluated for enrollment during Screening (up to 52
      days prior to Baseline, Day 0). There are 8 visits to the Clinical Site during the study from
      Day 0 to Day 180 for Study Injections and follow-up.

      Intervention Groups and Duration:

      Two treatment groups of Participants (Engensis or Placebo) will be in the study for 180 days.

      Number of Participants (N = 152 to approximately 250):

      The target sample size is a minimum of 152 Participants and the maximum sample size is 250
      Participants based on the proposed adaptive design analysis. The final sample size of
      Participants to be enrolled and evaluated will be determined by the independent Data
      Monitoring Committee (DMC). An interim analysis will be conducted after approximately 50% of
      Participants in the target sample (i.e., 76 Participants) have completed the primary efficacy
      endpoint at Day 180 or have withdrawn prematurely. The DMC will make a recommendation based
      on an unblinded (comparative) power analysis.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Efficacy of Engensis compared to Placebo on painful DPN in the feet and lower legs comparing the Average Daily Pain Score from the Day 0 Visit to the Day 180 Visit on the Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy
time frame: 180 days
description: • The Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy has a minimum score of 0 and a maximum score of 10, with a higher score representing a worse outcome of more pain.
measure: Efficacy of Engensis on the worst pain in painful DPN in the feet and lower legs by comparing the change from baseline (Day 0) in the Worst Pain score from the Brief Pain Inventory for Diabetic Peripheral Neuropathy to Day 180 compared to Placebo
time frame: 180 days
description: • The Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN) has a minimum score of 0 and a maximum score of 10, with a higher score representing a worse outcome of more pain
measure: Efficacy of Engensis on reducing pain in painful DPN in the feet and lower legs by determining a ≥ 50% reduction in the Average Daily Pain Score from baseline to Day 180 using the Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy
time frame: 180 days
description: • The Average Daily Pain Score from the Brief Pain Inventory for Participants with Diabetic Peripheral Neuropathy has a minimum score of 0 and a maximum score of 10 with a higher score representing a worse outcome of more pain
measure: Safety of Engensis in painful DPN in the feet and lower legs by comparing the incidence of adverse and serious adverse events, the incidence of injection site reactions, and the incidence of clinically significant laboratory values to Placebo
time frame: 180 days
description: Incidence of adverse events (AEs) and serious adverse events (SAEs)
Incidence of injection site reactions
Incidence of clinically significant laboratory values
measure: To evaluate the possibility of cellular responses to Engensis
time frame: 104 days
description: • Change from baseline in the TNF-alpha, IL-1b, IFNy, IL-6, IL-4, IL-10, and IL-12p70 cytokine profile post-dose at the Day 104 visit
measure: To evaluate the possibility of humoral responses to Engensis
time frame: 104 days
description: • Presence of hepatocyte growth factor (HGF) antibodies
measure: To determine whether IM administration of Engensis has the potential for disease modification by measuring the improvement in Bedside Sensory Testing at Day 180 compared to Baseline
time frame: 180 days
description: • The Bedside Sensory Testing scale has a minimum score of 0 and a maximum score of 10 with a higher score representing a better outcome
measure: To determine whether IM administration of Engensis has the potential for improving quality of life, sensation, proprioception, and deep tendon reflexes by measuring the improvement in Bedside Sensory Testing at Day 180 compared to Baseline
time frame: 180 days
description: • The Bedside Sensory Testing scale has a minimum score of 0 and a maximum score of 10 with a higher score representing a better outcome
arm group label: Engensis
arm group type: Experimental
description: 16 (ea) 0.25mg (0.5 mL) injections in each of the right and left gastrocnemius muscles on Days 0, 14, 90, and 104.
arm group label: Placebo
arm group type: Placebo Comparator
description: 16 0.5 mL injections in each of the right and left gastrocnemius muscles on Days 0, 14, 90, and 104.
intervention type: Biological
intervention name: Engensis
description: Intramuscular injections
arm group label: Engensis
intervention type: Other
intervention name: Placebo
description: Intramuscular injections
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
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country: United States
responsible party type: Sponsor
mesh term: Peripheral Nervous System Diseases
mesh term: Diabetic Neuropathies
mesh term: Pain