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
Overview
- Phase
- Phase 1
- Intervention
- LEVI-04
- Conditions
- Healthy Volunteers
- Sponsor
- Levicept
- Enrollment
- 56
- Locations
- 2
- Primary Endpoint
- Incidence of treatment emergent adverse events [Safety and tolerability]
- Status
- Completed
- Last Updated
- 5 years ago
Overview
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)
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Body mass index 18.0-\<32.0 kg/m2 (healthy volunteers) and 18.0-\<40.0 kg/m2 (osteoarthritis patients)
- •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 or Total Neuropathy Score nurse
- •History of cancer within 5 years before screening, except for appropriately treated cutaneous basal cell or squamous cell cancers; cervical cancer; and low grade stable prostate cancer
- •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; head trauma within last 2 years; and episodic lower limb radiculopathy, nerve compression, or sciatica (provided diagnosed as due to nerve root compression and not as a manifestation of systemic neuropathy or radiculopathy)
- •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%).
Arms & Interventions
Cohort 1 Healthy Volunteers Active
LEVI-04 0.003 mg/kg single intravenous dose Healthy Volunteers
Intervention: LEVI-04
Cohort 2 Healthy Volunteers Active
LEVI-04 Dose Level 2 (planned 0.01 mg/kg) single intravenous dose Healthy Volunteers
Intervention: LEVI-04
Cohort 3 Healthy Volunteers Active
LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Healthy Volunteers
Intervention: LEVI-04
Cohort 1 Healthy Volunteers Placebo
Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
Intervention: Placebo
Cohort 4 Osteoarthritis Patients Active
LEVI-04 Dose Level 3 (planned 0.03 mg/kg) single intravenous dose Osteoarthritis Patients
Intervention: LEVI-04
Cohort 5 Osteoarthritis Patients Active
LEVI-04 Dose Level 4 (planned 0.1 mg/kg) single intravenous dose Osteoarthritis Patients
Intervention: LEVI-04
Cohort 6 Osteoarthritis Patients Active
LEVI-04 Dose Level 5 (planned 0.3 mg/kg) single intravenous dose Osteoarthritis Patients
Intervention: LEVI-04
Cohort 7 Osteoarthritis Patients Active
LEVI-04 Dose Level 6 (planned 1.0 mg/kg) single intravenous dose Osteoarthritis Patients
Intervention: LEVI-04
Cohort 8 Healthy Volunteers Active
LEVI-04 Dose Level 7 (planned 3.0 mg/kg) single intravenous dose Healthy Volunteers
Intervention: LEVI-04
Cohort 2 Healthy Volunteers Placebo
Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
Intervention: Placebo
Cohort 3 Healthy Volunteers Placebo
Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
Intervention: Placebo
Cohort 4 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Intervention: Placebo
Cohort 5 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Intervention: Placebo
Cohort 6 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Intervention: Placebo
Cohort 7 Osteoarthritis Patients Placebo
Placebo to match LEVI-04 single intravenous dose Osteoarthritis Patients
Intervention: Placebo
Cohort 8 Healthy Volunteers Placebo
Placebo to match LEVI-04 single intravenous dose Healthy Volunteers
Intervention: Placebo
Outcomes
Primary Outcomes
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
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)
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 or Total Neuropathy Score nurse)
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)
Secondary Outcomes
- Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - maximum concentration(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)
- Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - clearance(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)
- Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - time to maximum concentration(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)
- Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - half-life(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)
- Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - volume of distribution(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)
- Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - Area Under the Curve(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)
- Pharmacokinetics of single ascending intravenous doses of LEVI-04 in healthy volunteers and osteoarthritis patients - elimination rate(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)
- To assess the formation of anti-drug antibodies (ADA) to LEVI-04 in healthy volunteers and osteoarthritis patients(Up to Day 56 post-dose for healthy volunteers and up to Day 105 post-dose for osteoarthritis patients)