<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/NCT03227796</url>
  </required_header>
  <id_info>
    <org_study_id>LEVI-04_17_01</org_study_id>
    <nct_id>NCT03227796</nct_id>
  </id_info>
  <brief_title>Safety, Tolerability &amp; Pharmacokinetics of LEVI-04 in Healthy Volunteers and Patients With Osteoarthritis Knee Pain</brief_title>
  <official_title>A Randomised, Double-blind, Placebo-controlled, Single Ascending Dose, Phase 1 Study to Evaluate the Safety, Tolerability and Pharmacokinetics of LEVI-04 in Healthy Volunteers and Patients With Pain Attributed to Osteoarthritis of the Knee</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Levicept</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hammersmith Medicines Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>MAC Clinical Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Levicept</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a first-in-human, phase 1, single centre, placebo-controlled, double-blind, single&#xD;
      ascending dose study of LEVI-04 in heathy volunteers and osteoarthritis patients (with pain&#xD;
      attributed to osteoarthritis of the knee)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There will be 8 cohorts of 7 subjects each. Cohorts 1-3 and 8 will be composed of healthy&#xD;
      volunteers. Cohorts 4-7 will be composed of osteoarthritis patients. Cohort 4 will be a&#xD;
      bridging cohort; osteoarthritis patients in Cohort 4 will receive the same dose as the&#xD;
      healthy volunteers in Cohort 3, if deemed safe.&#xD;
&#xD;
      Each subject will be assigned to receive a single dose of LEVI-04 or matching placebo. Each&#xD;
      dose will be administered as an intravenous infusion over 30 minutes. Planned doses will&#xD;
      start at 0.003 mg/kg in Cohort 1, and may be increased to 3.0 mg/kg in Cohort 8. The planned&#xD;
      doses may be changed, depending on the safety, tolerability and pharmacokinetic results after&#xD;
      previous doses. The dose selected for each cohort will be determined by the Safety Review&#xD;
      Team, following review of all available pharmacokinetic and safety data. For each escalating&#xD;
      dose, there will be at least 2 weeks between the start of each cohort (at least 14 days&#xD;
      between Day 0 for the last subject in the previous cohort and Day 0 for the first subject in&#xD;
      the subsequent cohort), to allow for review of safety, tolerability and pharmacokinetic data.&#xD;
      In each cohort, 5 subjects will receive LEVI-04 and 2 subjects will receive matching placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 28, 2017</start_date>
  <completion_date type="Actual">March 31, 2021</completion_date>
  <primary_completion_date type="Actual">March 31, 2021</primary_completion_date>
  <phase>Phase 1</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>
    <intervention_model_description>First-in-human, phase 1, placebo-controlled, double-blind, single ascending dose study in heathy volunteers and osteoarthritis patients</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of treatment emergent adverse events [Safety and tolerability]</measure>
    <time_frame>Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>adverse events; laboratory tests; electrocardiograms and injection site reaction assessments</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Baseline in neurological assessments [Safety and tolerability] - SAS</measure>
    <time_frame>Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Neurological assessment (Survey of Autonomic Symptoms (SAS) Questionnaire)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Baseline in neurological assessments [Safety and tolerability] - BCTQ</measure>
    <time_frame>Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Neurological assessment (Boston Carpal Tunnel Questionnaire (BCTQ)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Baseline in neurological assessments [Safety and tolerability] - 4th finger test</measure>
    <time_frame>Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Neurological assessment (the carpal tunnel syndrome (CTS) 4th finger neurological test or Total Neuropathy Score nurse)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - maximum concentration</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Maximum serum concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - time to maximum concentration</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Time to reach maximum serum concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - Area Under the Curve</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Area under the serum concentration-time curve from time zero to time of last measurable concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - half-life</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Terminal elimination half-life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - clearance</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Apparent total body clearance after intravenous administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - elimination rate</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Terminal elimination rate constant</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - volume of distribution</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Apparent volume of distribution during the terminal elimination phase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess the formation of anti-drug antibodies (ADA) to LEVI-04 in healthy volunteers and osteoarthritis patients</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients</time_frame>
    <description>Presence / concentration of any anti-drug antibodies to LEVI-04</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (rescue medication)</measure>
    <time_frame>Up to Day 105 for osteoarthritis patients</time_frame>
    <description>Use of rescue medication, by treatment and time point</description>
  </other_outcome>
  <other_outcome>
    <measure>Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (NRS-11)</measure>
    <time_frame>Up to Day 105 for osteoarthritis patients</time_frame>
    <description>Assessment of pain using the Numerical Rating Scale-11 (NRS-11) questionnaire by treatment and time point</description>
  </other_outcome>
  <other_outcome>
    <measure>Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (WOMAC)</measure>
    <time_frame>Up to Day 105 for osteoarthritis patients</time_frame>
    <description>Assessment of pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire by treatment and time point</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory analyses of pharmacological biomarkers relevant to the actions of LEVI-04 in healthy volunteers and osteoarthritis patients (NGF)</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 for osteoarthritis patients</time_frame>
    <description>Measurement of total, free and LEVI-04 bound Nerve Growth Factor (NGF)</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory analyses of pharmacological biomarkers relevant to the actions of LEVI-04 in healthy volunteers and osteoarthritis patients (NT-3)</measure>
    <time_frame>Up to Day 56 post-dose for healthy volunteers and up to Day 105 for osteoarthritis patients</time_frame>
    <description>Measurement of Neurotropin-3 (NT-3)</description>
  </other_outcome>
  <number_of_arms>16</number_of_arms>
  <enrollment type="Actual">56</enrollment>
  <condition>Healthy Volunteers</condition>
  <condition>Osteoarthritis</condition>
  <arm_group>
    <arm_group_label>Cohort 1 Healthy Volunteers Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 0.003 mg/kg single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 Healthy Volunteers Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 Dose Level 2 (planned 0.01 mg/kg) single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3 Healthy Volunteers Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 Dose Level 4 (planned 0.1 mg/kg) single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 6 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 Dose Level 5 (planned 0.3 mg/kg) single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 7 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 Dose Level 6 (planned 1.0 mg/kg) single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 8 Healthy Volunteers Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>LEVI-04 Dose Level 7 (planned 3.0 mg/kg) single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 1 Healthy Volunteers Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 Healthy Volunteers Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3 Healthy Volunteers Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 6 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 7 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 8 Healthy Volunteers Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match LEVI-04 single intravenous dose Healthy Volunteers</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LEVI-04</intervention_name>
    <description>LEVI-04 intravenous infusion</description>
    <arm_group_label>Cohort 1 Healthy Volunteers Active</arm_group_label>
    <arm_group_label>Cohort 2 Healthy Volunteers Active</arm_group_label>
    <arm_group_label>Cohort 3 Healthy Volunteers Active</arm_group_label>
    <arm_group_label>Cohort 4 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_label>Cohort 5 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_label>Cohort 6 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_label>Cohort 7 Osteoarthritis Patients Active</arm_group_label>
    <arm_group_label>Cohort 8 Healthy Volunteers Active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo intravenous infusion</description>
    <arm_group_label>Cohort 1 Healthy Volunteers Placebo</arm_group_label>
    <arm_group_label>Cohort 2 Healthy Volunteers Placebo</arm_group_label>
    <arm_group_label>Cohort 3 Healthy Volunteers Placebo</arm_group_label>
    <arm_group_label>Cohort 4 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_label>Cohort 5 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_label>Cohort 6 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_label>Cohort 7 Osteoarthritis Patients Placebo</arm_group_label>
    <arm_group_label>Cohort 8 Healthy Volunteers Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Body mass index 18.0-&lt;32.0 kg/m2 (healthy volunteers) and 18.0-&lt;40.0 kg/m2&#xD;
             (osteoarthritis patients)&#xD;
&#xD;
          -  Willing and able to give written fully informed consent&#xD;
&#xD;
          -  Men with female partners of childbearing potential must agree to follow the&#xD;
             requirements for effective contraception throughout the study and for 112 days&#xD;
             post-dose&#xD;
&#xD;
          -  Women of non childbearing potential&#xD;
&#xD;
          -  Healthy volunteers (aged 18 to 65 years) willing to give written consent to have data&#xD;
             entered into the Over-volunteering Prevention System&#xD;
&#xD;
          -  Osteoarthritis patients (aged 30-80 years) with diagnosis of mild to moderate&#xD;
             osteoarthritis of the knee, with X-ray confirmation as diagnosed by a trained&#xD;
             radiology reviewer&#xD;
&#xD;
          -  Osteoarthritis patients willing to discontinue all pain medication, except rescue&#xD;
             medication (paracetamol), from the run-in visit until the end of the study&#xD;
&#xD;
          -  Osteoarthritis patients with a Numerical Rating Scale-11 pain score of between 5 and&#xD;
             &lt;9, inclusive, in the index knee at screening. If taking regular pain medication,&#xD;
             should show an increase of at least 1 point following washout of analgesia. The&#xD;
             average pain score of between 5 and &lt;9, inclusive, based on four of the seven daily&#xD;
             readings during the seven day initial pain assessment period&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Women of childbearing potential, or who are pregnant or lactating&#xD;
&#xD;
          -  Clinically relevant abnormal history, physical findings, electrocardiograph, or&#xD;
             laboratory values at screening that could interfere with the objectives of the trial&#xD;
             or the safety of the subject&#xD;
&#xD;
          -  Presence of acute or chronic illness or history of chronic illness (other than&#xD;
             osteoarthritis, controlled diabetes, asthma or hypertension for osteoarthritis&#xD;
             patients), sufficient to invalidate participation in the trial or make it&#xD;
             unnecessarily hazardous&#xD;
&#xD;
          -  Impaired endocrine, thyroid, hepatic, respiratory (other than asthma that has been&#xD;
             controlled by the use of acceptable medication for at least 3 months prior to&#xD;
             screening) or renal function; or history of any psychotic mental illness or clinically&#xD;
             significant psychiatric disorder&#xD;
&#xD;
          -  History of carpal tunnel syndrome with signs or symptoms within one year before&#xD;
             screening or a Boston Carpal Tunnel Questionnaire score &gt;3&#xD;
&#xD;
          -  Moderate or severe carpal tunnel syndrome based on the 4th finger neurological test or&#xD;
             Total Neuropathy Score nurse&#xD;
&#xD;
          -  History of cancer within 5 years before screening, except for appropriately treated&#xD;
             cutaneous basal cell or squamous cell cancers; cervical cancer; and low grade stable&#xD;
             prostate cancer&#xD;
&#xD;
          -  History, diagnosis, or signs of neurological disease including but not limited to:&#xD;
             stroke; peripheral or autonomic neuropathy; diabetic neuropathy; multiple sclerosis;&#xD;
             epilepsy or seizure disorder with history of seizure within last 2 years; myopathy;&#xD;
             Alzheimer's disease or other types of dementia; head trauma within last 2 years; and&#xD;
             episodic lower limb radiculopathy, nerve compression, or sciatica (provided diagnosed&#xD;
             as due to nerve root compression and not as a manifestation of systemic neuropathy or&#xD;
             radiculopathy)&#xD;
&#xD;
          -  Survey of Autonomic Symptoms score of at least 3&#xD;
&#xD;
          -  Uncontrolled type 1 diabetes or type 2 diabetes with HbA1c &lt;7.5% (type 1 diabetics and&#xD;
             type 2 diabetics that have been controlled by acceptable medication for at least three&#xD;
             months prior to screening are permitted if HbA1c &lt; 7.5%).&#xD;
&#xD;
          -  History or signs and symptoms of coronary heart disease or stroke&#xD;
&#xD;
          -  QTcF interval &lt;330 msec or ≥430 msec for males, and ≥450 msec for females at the&#xD;
             screening examination, unless judged not clinically significant by an investigator&#xD;
&#xD;
          -  Presence of Chronic Obstructive Pulmonary Disease&#xD;
&#xD;
          -  Moderate / severe depression indicated by a score of ≥10 out of 24 in the Personal&#xD;
             Health Questionnaire Depression Scale&#xD;
&#xD;
          -  History or presence of severe adverse reaction to any drug or a history of sensitivity&#xD;
             to mannitol or histidine&#xD;
&#xD;
          -  Use of prescription medicine (other than the permitted medicines) during 28 days&#xD;
             before the dose of trial medication (14 days for pain medication for osteoarthritis&#xD;
             patients)&#xD;
&#xD;
          -  Use of an over-the-counter medicine, except paracetamol, during the 7 days before the&#xD;
             first dose of trial medication&#xD;
&#xD;
          -  Dosed in another clinical trial of a new chemical entity or prescription medicine&#xD;
             within last 3 months&#xD;
&#xD;
          -  Previous use of any Tropomyosin-receptor kinase (TrkA) inhibitor, Nerve Growth&#xD;
             Factor-targeted therapy (eg tanezumab), or experimental biological treatment in last 6&#xD;
             months. More than 6 doses of anti- nerve growth factor (NGF) antibody during&#xD;
             participation in a trial is not permitted.&#xD;
&#xD;
          -  History / presence of drug / alcohol abuse in year before screening, or intake of &gt;28&#xD;
             units of alcohol weekly or currently smoking &gt;10 cigarettes daily&#xD;
&#xD;
          -  Evidence of drug abuse&#xD;
&#xD;
          -  Uncontrolled hypertension (supine) at screening outside 90-140 mm Hg systolic, 40-90&#xD;
             mm Hg diastolic; heart rate in supine position at screening outside 40-100 beats/min.&#xD;
             (Diagnosed hypertension that has been controlled within the above limits using&#xD;
             acceptable medication for at least 3 months prior to screening is permitted.)&#xD;
&#xD;
          -  Possibility that will not cooperate with requirements of the trial&#xD;
&#xD;
          -  Positive test for hepatitis B, hepatitis C or Human Immunodeficiency Virus&#xD;
&#xD;
          -  Loss of more than 400mL blood during last 3 months, eg as a blood donor&#xD;
&#xD;
          -  Objection by General Practitioner to trial entry&#xD;
&#xD;
          -  Poor venous access&#xD;
&#xD;
        Also for osteoarthritis patients:&#xD;
&#xD;
          -  History of inflammatory arthritis, including rheumatoid arthritis, seronegative&#xD;
             spondyloarthropathy (eg ankylosing spondylitis, psoriatic arthritis, inflammatory&#xD;
             bowel disease related arthropathy), gout, pseudogout in index knee (as diagnosed by&#xD;
             appropriate crystals on aspiration or C-reactive protein elevation during attacks&#xD;
             (subjects with gout or pseudogout in a joint other than the index knee must have&#xD;
             disease that is controlled by medication, with a serum uric acid within the target&#xD;
             range; should their index knee flare up during the study, gout must be excluded),&#xD;
             metabolic joint disease, endocrinopathy, lupus erythematosus, joint infection,&#xD;
             connective tissue disease, septic arthritis&#xD;
&#xD;
          -  Radiographic evidence of:&#xD;
&#xD;
               -  excessive malalignment of the knee&#xD;
&#xD;
               -  severe chondrocalcinosis or other arthropathies (eg rheumatoid arthritis)&#xD;
&#xD;
               -  systemic metabolic bone disease (eg pseudogout, Paget's disease, metastatic&#xD;
                  calcifications)&#xD;
&#xD;
               -  large cystic lesions, primary or metastatic tumour lesions&#xD;
&#xD;
               -  acute or healing stress or traumatic fracture (subjects with established united/&#xD;
                  malunited intra or extra-articular fractures of the knee from historic injuries&#xD;
                  [&gt;12 months prior to screening] who have developed features of post-traumatic&#xD;
                  osteoarthritis can be included in the trial, provided that clinically and&#xD;
                  radiologically there is no excessive malalignment of the knee)&#xD;
&#xD;
               -  Rapidly Progressive Osteoarthritis, or any condition which would indicate an&#xD;
                  increased risk for developing it&#xD;
&#xD;
               -  atrophic or hypotrophic osteoarthritis&#xD;
&#xD;
               -  subchondral insufficiency fractures&#xD;
&#xD;
               -  spontaneous osteonecrosis of the knee&#xD;
&#xD;
               -  osteonecrosis&#xD;
&#xD;
               -  pathologic fracture&#xD;
&#xD;
          -  History of osteonecrosis / osteoporotic fracture (including minimally traumatic or&#xD;
             atraumatic fracture)&#xD;
&#xD;
          -  History of significant trauma (including sports injury) or surgery to a knee, hip or&#xD;
             shoulder within last year&#xD;
&#xD;
          -  Planned surgery to a knee, hip or shoulder during the study&#xD;
&#xD;
          -  Fibromyalgia, regional pain caused by lumbar / cervical compression with&#xD;
             radiculopathy, or other moderate/severe pain that may confound assessment of knee pain&#xD;
&#xD;
          -  Intra-articular injection of corticosteroid in the index knee within 3 months, or to&#xD;
             any other joint within 1 month of the initial pain assessment&#xD;
&#xD;
          -  Intra-articular injection of any hyaluronan product in the index knee within 6 months&#xD;
             before the initial pain assessment&#xD;
&#xD;
          -  Any other medical or psychiatric condition, or laboratory abnormality, that may&#xD;
             increase the risk associated with study participation or may interfere with the&#xD;
             interpretation of study results and, in the judgment of the investigator would make&#xD;
             the subject inappropriate for entry into this study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>79 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Denisa Wilkes, MUDr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hammersmith Medicines Research</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>MAC Clinical Research - Early Phase Unit</name>
      <address>
        <city>Manchester</city>
        <state>Greater Manchester</state>
        <zip>M13 9NQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hammersmith Medicines Research</name>
      <address>
        <city>London</city>
        <zip>NW10 7EW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>May 31, 2017</study_first_submitted>
  <study_first_submitted_qc>July 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2017</study_first_posted>
  <last_update_submitted>April 6, 2021</last_update_submitted>
  <last_update_submitted_qc>April 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>osteoarthritis</keyword>
  <keyword>knee</keyword>
  <keyword>healthy</keyword>
  <keyword>volunteer</keyword>
  <keyword>LEVI-04</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>May 24, 2022</submitted>
    <returned>February 24, 2023</returned>
  </pending_results>
  <!-- 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/NCT03227796
org study id: LEVI-04_17_01
nct id: NCT03227796
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is a first-in-human, phase 1, single centre, placebo-controlled, double-blind, single
      ascending dose study of LEVI-04 in heathy volunteers and osteoarthritis patients (with pain
      attributed to osteoarthritis of the knee)
There will be 8 cohorts of 7 subjects each. Cohorts 1-3 and 8 will be composed of healthy
      volunteers. Cohorts 4-7 will be composed of osteoarthritis patients. Cohort 4 will be a
      bridging cohort; osteoarthritis patients in Cohort 4 will receive the same dose as the
      healthy volunteers in Cohort 3, if deemed safe.

      Each subject will be assigned to receive a single dose of LEVI-04 or matching placebo. Each
      dose will be administered as an intravenous infusion over 30 minutes. Planned doses will
      start at 0.003 mg/kg in Cohort 1, and may be increased to 3.0 mg/kg in Cohort 8. The planned
      doses may be changed, depending on the safety, tolerability and pharmacokinetic results after
      previous doses. The dose selected for each cohort will be determined by the Safety Review
      Team, following review of all available pharmacokinetic and safety data. For each escalating
      dose, there will be at least 2 weeks between the start of each cohort (at least 14 days
      between Day 0 for the last subject in the previous cohort and Day 0 for the first subject in
      the subsequent cohort), to allow for review of safety, tolerability and pharmacokinetic data.
      In each cohort, 5 subjects will receive LEVI-04 and 2 subjects will receive matching placebo.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: First-in-human, phase 1, placebo-controlled, double-blind, single ascending dose study in heathy volunteers and osteoarthritis patients
primary purpose: Other
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Double-blind
measure: Incidence of treatment emergent adverse events [Safety and tolerability]
time frame: Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients
description: adverse events; laboratory tests; electrocardiograms and injection site reaction assessments
measure: Change from Baseline in neurological assessments [Safety and tolerability] - SAS
time frame: Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients
description: Neurological assessment (Survey of Autonomic Symptoms (SAS) Questionnaire)
measure: Change from Baseline in neurological assessments [Safety and tolerability] - BCTQ
time frame: Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients
description: Neurological assessment (Boston Carpal Tunnel Questionnaire (BCTQ)
measure: Change from Baseline in neurological assessments [Safety and tolerability] - 4th finger test
time frame: Change from Baseline at Day 56 post-dose for healthy volunteers and change from Baseline at Day 105 post-dose for osteoarthritis patients
description: Neurological assessment (the carpal tunnel syndrome (CTS) 4th finger neurological test or Total Neuropathy Score nurse)
measure: Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - maximum concentration
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Maximum serum concentration
measure: Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - time to maximum concentration
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Time to reach maximum serum concentration
measure: Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - Area Under the Curve
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Area under the serum concentration-time curve from time zero to time of last measurable concentration
measure: Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - half-life
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Terminal elimination half-life
measure: Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - clearance
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Apparent total body clearance after intravenous administration
measure: Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - elimination rate
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Terminal elimination rate constant
measure: Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - volume of distribution
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Apparent volume of distribution during the terminal elimination phase
measure: To assess the formation of anti-drug antibodies (ADA) to LEVI-04 in healthy volunteers and osteoarthritis patients
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients
description: Presence / concentration of any anti-drug antibodies to LEVI-04
measure: Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (rescue medication)
time frame: Up to Day 105 for osteoarthritis patients
description: Use of rescue medication, by treatment and time point
measure: Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (NRS-11)
time frame: Up to Day 105 for osteoarthritis patients
description: Assessment of pain using the Numerical Rating Scale-11 (NRS-11) questionnaire by treatment and time point
measure: Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (WOMAC)
time frame: Up to Day 105 for osteoarthritis patients
description: Assessment of pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire by treatment and time point
measure: Exploratory analyses of pharmacological biomarkers relevant to the actions of LEVI-04 in healthy volunteers and osteoarthritis patients (NGF)
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 for osteoarthritis patients
description: Measurement of total, free and LEVI-04 bound Nerve Growth Factor (NGF)
measure: Exploratory analyses of pharmacological biomarkers relevant to the actions of LEVI-04 in healthy volunteers and osteoarthritis patients (NT-3)
time frame: Up to Day 56 post-dose for healthy volunteers and up to Day 105 for osteoarthritis patients
description: Measurement of Neurotropin-3 (NT-3)
arm group label: Cohort 1 Healthy Volunteers Active
arm group type: Experimental
description: LEVI-04 0.003 mg/kg single intravenous dose Healthy Volunteers
arm group label: Cohort 2 Healthy Volunteers Active
arm group type: Experimental
description: LEVI-04 Dose Level 2 (planned 0.01 mg/kg) single intravenous dose Healthy Volunteers
arm group label: Cohort 3 Healthy Volunteers Active
arm group type: Experimental
description: LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Healthy Volunteers
arm group label: Cohort 4 Osteoarthritis Patients Active
arm group type: Experimental
description: LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Osteoarthritis Patients
arm group label: Cohort 5 Osteoarthritis Patients Active
arm group type: Experimental
description: LEVI-04 Dose Level 4 (planned 0.1 mg/kg) single intravenous dose Osteoarthritis Patients
arm group label: Cohort 6 Osteoarthritis Patients Active
arm group type: Experimental
description: LEVI-04 Dose Level 5 (planned 0.3 mg/kg) single intravenous dose Osteoarthritis Patients
arm group label: Cohort 7 Osteoarthritis Patients Active
arm group type: Experimental
description: LEVI-04 Dose Level 6 (planned 1.0 mg/kg) single intravenous dose Osteoarthritis Patients
arm group label: Cohort 8 Healthy Volunteers Active
arm group type: Experimental
description: LEVI-04 Dose Level 7 (planned 3.0 mg/kg) single intravenous dose Healthy Volunteers
arm group label: Cohort 1 Healthy Volunteers Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
arm group label: Cohort 2 Healthy Volunteers Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
arm group label: Cohort 3 Healthy Volunteers Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
arm group label: Cohort 4 Osteoarthritis Patients Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
arm group label: Cohort 5 Osteoarthritis Patients Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
arm group label: Cohort 6 Osteoarthritis Patients Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
arm group label: Cohort 7 Osteoarthritis Patients Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
arm group label: Cohort 8 Healthy Volunteers Placebo
arm group type: Placebo Comparator
description: Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
intervention type: Drug
intervention name: LEVI-04
description: LEVI-04 intravenous infusion
arm group label: Cohort 1 Healthy Volunteers Active
arm group label: Cohort 2 Healthy Volunteers Active
arm group label: Cohort 3 Healthy Volunteers Active
arm group label: Cohort 4 Osteoarthritis Patients Active
arm group label: Cohort 5 Osteoarthritis Patients Active
arm group label: Cohort 6 Osteoarthritis Patients Active
arm group label: Cohort 7 Osteoarthritis Patients Active
arm group label: Cohort 8 Healthy Volunteers Active
intervention type: Drug
intervention name: Placebo
description: Placebo intravenous infusion
arm group label: Cohort 1 Healthy Volunteers Placebo
arm group label: Cohort 2 Healthy Volunteers Placebo
arm group label: Cohort 3 Healthy Volunteers Placebo
arm group label: Cohort 4 Osteoarthritis Patients Placebo
arm group label: Cohort 5 Osteoarthritis Patients Placebo
arm group label: Cohort 6 Osteoarthritis Patients Placebo
arm group label: Cohort 7 Osteoarthritis Patients Placebo
arm group label: Cohort 8 Healthy Volunteers Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 79 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Denisa Wilkes, MUDr
role: Principal Investigator
affiliation: Hammersmith Medicines Research
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Osteoarthritis
sharing ipd: No
submitted: May 24, 2022
returned: February 24, 2023