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Safety, Tolerability & Pharmacokinetics of LEVI-04 in Healthy Volunteers and Patients With Osteoarthritis Knee Pain

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ClinicalTrials.gov Identifier: NCT03227796
Recruitment Status : Recruiting
First Posted : July 24, 2017
Last Update Posted : September 27, 2018
Sponsor:
Collaborator:
Hammersmith Medicines Research
Information provided by (Responsible Party):
Levicept

Brief Summary:
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)

Condition or disease Intervention/treatment Phase
Healthy Volunteers Osteoarthritis Drug: LEVI-04 Drug: Placebo Phase 1

Detailed Description:

There will be 8 cohorts of 7 subjects each. Cohorts 1-3 will be composed of healthy volunteers. Cohorts 4-8 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: First-in-human, phase 1, single centre, placebo-controlled, double-blind, single ascending dose study in heathy volunteers and osteoarthritis patients
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Double-blind
Primary Purpose: Other
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
Actual Study Start Date : July 28, 2017
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis

Arm Intervention/treatment
Experimental: Cohort 1 Healthy Volunteers Active
LEVI-04 0.003 mg/kg single intravenous dose Healthy Volunteers
Drug: LEVI-04
LEVI-04 intravenous infusion

Experimental: Cohort 2 Healthy Volunteers Active
LEVI-04 Dose Level 2 (planned 0.01 mg/kg) single intravenous dose Healthy Volunteers
Drug: LEVI-04
LEVI-04 intravenous infusion

Experimental: Cohort 3 Healthy Volunteers Active
LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Healthy Volunteers
Drug: LEVI-04
LEVI-04 intravenous infusion

Experimental: Cohort 4 Osteoarthritis Patients Active
LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Osteoarthritis Patients
Drug: LEVI-04
LEVI-04 intravenous infusion

Experimental: Cohort 5 Osteoarthritis Patients Active
LEVI-04 Dose Level 4 (planned 0.1 mg/kg) single intravenous dose Osteoarthritis Patients
Drug: LEVI-04
LEVI-04 intravenous infusion

Experimental: Cohort 6 Osteoarthritis Patients Active
LEVI-04 Dose Level 5 (planned 0.3 mg/kg) single intravenous dose Osteoarthritis Patients
Drug: LEVI-04
LEVI-04 intravenous infusion

Experimental: Cohort 7 Osteoarthritis Patients Active
LEVI-04 Dose Level 6 (planned 1.0 mg/kg) single intravenous dose Osteoarthritis Patients
Drug: LEVI-04
LEVI-04 intravenous infusion

Experimental: Cohort 8 Osteoarthritis Patients Active
LEVI-04 Dose Level 7 (planned 3.0 mg/kg) single intravenous dose Osteoarthritis Patients
Drug: LEVI-04
LEVI-04 intravenous infusion

Placebo Comparator: Cohort 1 Healthy Volunteers Placebo
Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
Drug: Placebo
Placebo intravenous infusion

Placebo Comparator: Cohort 2 Healthy Volunteers Placebo
Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
Drug: Placebo
Placebo intravenous infusion

Placebo Comparator: Cohort 3 Healthy Volunteers Placebo
Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
Drug: Placebo
Placebo intravenous infusion

Placebo Comparator: Cohort 4 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Drug: Placebo
Placebo intravenous infusion

Placebo Comparator: Cohort 5 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Drug: Placebo
Placebo intravenous infusion

Placebo Comparator: Cohort 6 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Drug: Placebo
Placebo intravenous infusion

Placebo Comparator: Cohort 7 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Drug: Placebo
Placebo intravenous infusion

Placebo Comparator: Cohort 8 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Drug: Placebo
Placebo intravenous infusion




Primary Outcome Measures :
  1. 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 ]
    adverse events; laboratory tests; electrocardiograms and injection site reaction assessments

  2. 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 ]
    Neurological assessment (Survey of Autonomic Symptoms (SAS) Questionnaire)

  3. 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 ]
    Neurological assessment (Boston Carpal Tunnel Questionnaire (BCTQ)

  4. 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 ]
    Neurological assessment (the carpal tunnel syndrome (CTS) 4th finger neurological test)


Secondary Outcome Measures :
  1. 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 ]
    Maximum serum concentration

  2. 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 ]
    Time to reach maximum serum concentration

  3. 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 ]
    Area under the serum concentration-time curve from time zero to time of last measurable concentration

  4. 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 ]
    Terminal elimination half-life

  5. 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 ]
    Apparent total body clearance after intravenous administration

  6. 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 ]
    Terminal elimination rate constant

  7. 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 ]
    Apparent volume of distribution during the terminal elimination phase

  8. 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 ]
    Presence / concentration of any anti-drug antibodies to LEVI-04


Other Outcome Measures:
  1. Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (rescue medication) [ Time Frame: Up to Day 105 for osteoarthritis patients ]
    Use of rescue medication, by treatment and time point

  2. Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (NRS-11) [ Time Frame: Up to Day 105 for osteoarthritis patients ]
    Assessment of pain using the Numerical Rating Scale-11 (NRS-11) questionnaire by treatment and time point

  3. Pharmacodynamics of LEVI-04 in osteoarthritis patients - pain relief (WOMAC) [ Time Frame: Up to Day 105 for osteoarthritis patients ]
    Assessment of pain using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire by treatment and time point

  4. 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 ]
    Measurement of total, free and LEVI-04 bound Nerve Growth Factor (NGF)

  5. 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 ]
    Measurement of Neurotropin-3 (NT-3)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Body mass index 18.0-35.0 kg/m2
  • Willing and able to give written fully informed consent
  • Men with female partners of childbearing potential must agree to follow the requirements for effective contraception throughout the study and for 112 days post-dose
  • Women of non childbearing potential
  • Healthy volunteers (aged 18 to 65 years) willing to give written consent to have data entered into the Over-volunteering Prevention System
  • Osteoarthritis patients (aged 30-80 years) with diagnosis of mild to moderate osteoarthritis of the knee, with X-ray confirmation as diagnosed by a trained radiology reviewer
  • Osteoarthritis patients willing to discontinue all pain medication, except rescue medication (paracetamol), from the run-in visit until the end of the study
  • Osteoarthritis patients with a Numerical Rating Scale-11 pain score of between 5 and <9, inclusive, in the index knee at screening. If taking regular pain medication, should show an increase of at least 1 point following washout of analgesia. The average pain score of between 5 and <9, inclusive, based on four of the seven daily readings during the seven day initial pain assessment period

Exclusion Criteria:

  • Women of childbearing potential, or who are pregnant or lactating
  • Clinically relevant abnormal history, physical findings, electrocardiograph, or laboratory values at screening that could interfere with the objectives of the trial or the safety of the subject
  • Presence of acute or chronic illness or history of chronic illness (other than osteoarthritis, controlled diabetes, asthma or hypertension for osteoarthritis patients), sufficient to invalidate participation in the trial or make it unnecessarily hazardous
  • Impaired endocrine, thyroid, hepatic, respiratory (other than asthma that has been controlled by the use of acceptable medication for at least 3 months prior to screening) or renal function; or history of any psychotic mental illness or clinically significant psychiatric disorder
  • History of carpal tunnel syndrome with signs or symptoms within one year before screening or a Boston Carpal Tunnel Questionnaire score >3
  • Moderate or severe carpal tunnel syndrome based on the 4th finger neurological test
  • History of cancer within 5 years before screening, except for appropriately treated cutaneous basal cell or squamous cell cancers
  • History, diagnosis, or signs of neurological disease including but not limited to stroke, peripheral or autonomic neuropathy, diabetic neuropathy, multiple sclerosis, epilepsy or seizure disorder with history of seizure within last 2 years, myopathy, Alzheimer's disease or other types of dementia and head trauma within last 2 years
  • Survey of Autonomic Symptoms score of at least 3
  • Uncontrolled type 1 diabetes or type 2 diabetes with HbA1c <7.5% (type 1 diabetics and type 2 diabetics that have been controlled by acceptable medication for at least three months prior to screening are permitted if HbA1c < 7.5%).
  • History or signs and symptoms of coronary heart disease or stroke
  • QTcF interval <330 msec or ≥430 msec for males, and ≥450 msec for females at the screening examination, unless judged not clinically significant by an investigator
  • Presence of Chronic Obstructive Pulmonary Disease
  • Moderate / severe depression indicated by a score of ≥10 out of 24 in the Personal Health Questionnaire Depression Scale
  • History or presence of severe adverse reaction to any drug or a history of sensitivity to mannitol or histidine
  • Use of prescription medicine (other than the permitted medicines) during 28 days before the dose of trial medication (14 days for pain medication for osteoarthritis patients)
  • Use of an over-the-counter medicine, except paracetamol, during the 7 days before the first dose of trial medication
  • Dosed in another clinical trial of a new chemical entity or prescription medicine within last 3 months
  • Previous use of any Tropomyosin-receptor kinase (TrkA) inhibitor, Nerve Growth Factor-targeted therapy (eg tanezumab), or experimental biological treatment in last 6 months. More than 6 doses of anti- nerve growth factor (NGF) antibody during participation in a trial is not permitted.
  • History / presence of drug / alcohol abuse in last year, or intake of >21 units of alcohol weekly (men) or >14 units of alcohol weekly (women) or >10 cigarettes daily
  • Evidence of drug abuse
  • Uncontrolled hypertension (supine) at screening outside 90-140 mm Hg systolic, 40-90 mm Hg diastolic; heart rate in supine position at screening outside 40-100 beats/min. (Diagnosed hypertension that has been controlled within the above limits using acceptable medication for at least 3 months prior to screening is permitted.)
  • Possibility that will not cooperate with requirements of the trial
  • Positive test for hepatitis B, hepatitis C or Human Immunodeficiency Virus
  • Loss of more than 400mL blood during last 3 months, eg as a blood donor
  • Objection by General Practitioner to trial entry

Also for osteoarthritis patients:

  • History of inflammatory arthritis, including rheumatoid arthritis, seronegative spondyloarthropathy (eg ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease related arthropathy), gout, pseudogout in index knee (appropriate crystals on aspiration or C-reactive protein elevation during attacks), metabolic joint disease, endocrinopathy, lupus erythematosus, joint infection, connective tissue disease or septic arthritis
  • Radiographic evidence of:

    • excessive malalignment of the knee
    • severe chondrocalcinosis or other arthropathies (eg rheumatoid arthritis)
    • systemic metabolic bone disease (eg pseudogout, Paget's disease, metastatic calcifications)
    • large cystic lesions, primary or metastatic tumour lesions
    • stress or traumatic fracture
    • Rapidly Progressive Osteoarthritis, or any condition which would indicate an increased risk for developing it
    • atrophic or hypotrophic osteoarthritis
    • subchondral insufficiency fractures
    • spontaneous osteonecrosis of the knee
    • osteonecrosis
    • pathologic fracture
  • History of osteonecrosis / osteoporotic fracture (including minimally traumatic or atraumatic fracture)
  • History of significant trauma (including sports injury) or surgery to a knee, hip or shoulder within last year
  • Planned surgery to a knee, hip or shoulder during the study
  • Fibromyalgia, regional pain caused by lumbar / cervical compression with radiculopathy, or other moderate/severe pain that may confound assessment of knee pain
  • Intra-articular injection of corticosteroid in the index knee within 3 months, or to any other joint within 1 month of the initial pain assessment
  • Intra-articular injection of any hyaluronan product in the index knee within 6 months before the initial pain assessment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03227796


Contacts
Contact: Recruitment Team 08007838792 recruit@hmrlondon.com

Locations
United Kingdom
Hammersmith Medicines Research Recruiting
London, United Kingdom, NW10 7EW
Sponsors and Collaborators
Levicept
Hammersmith Medicines Research
Investigators
Principal Investigator: Malcolm Boyce, MD FRCP FFPM Hammersmith Medicines Research

Responsible Party: Levicept
ClinicalTrials.gov Identifier: NCT03227796     History of Changes
Other Study ID Numbers: LEVI-04_17_01
First Posted: July 24, 2017    Key Record Dates
Last Update Posted: September 27, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Levicept:
osteoarthritis
knee
healthy
volunteer
LEVI-04

Additional relevant MeSH terms:
Osteoarthritis
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases