Clinical Trial to Evaluate the Efficacy and Safety of LEVI-04 in Patients With Osteoarthritis of the Knee

This is a phase 2, randomized, double-blind, placebo-controlled trial of multiple doses and multiple administrations of LEVI-04 for the treatment of pain due to osteoarthritis of the knee.

The study consists of a Screening Period (including a Diary Run- In/analgesic wash-out Period), Randomization, Post-Randomization Period, and a Follow-up Period. Up to 624 participants will be enrolled and randomized to one of four Treatment Arms at the ratio 1:1:1:1

The overall objective of this study is to evaluate the efficacy and safety of LEVI-04 compared to placebo in patients with knee OA.

Eligibility Criteria:
Inclusion Criteria:

1. Signed Informed Consent form (ICF).
2. Male or female participants between ≥40 and ≤80 years of age.
3. BMI ≤40 kg/m2.
4. The ability to utilize the eDiary device provided by study sites.
5. History of knee pain on most days for at least 3 months prior to Screening
6. Confirmation of OA of the knee

   1. Radiographs of both knees with a Posterior-Anterior, Fixed-flexion view taken during the Screening Period.
   2. American College of Rheumatology (ACR) clinical and radiographic diagnostic criteria.
7. Evidence of knee OA with a KL grade ≥2, determined through central reading.
8. Target Knee must have a score of ≥20 out of 50 on the WOMAC pain subscale during Screening and at Randomization
9. The Baseline (NRS) Pain score will be derived from the last seven days of the Diary Run-In Period and must meet following criteria:

   1. Completion of Average Daily (NRS) Pain score on at least 6 of the 7 days.
   2. Mean Average Daily (NRS) Pain score must be ≥4.0 and ≤9.0
   3. Mean Average Daily (NRS) Pain variability must be ≤1.5
10. If female, not of childbearing potential defined as post-menopausal for at least 1 year, or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or practicing an agreed upon highly effective method of birth control throughout the study period.
11. If male and sexually active with partner of childbearing potential, willing to agree to practice a highly effective method of contraception from Visit 2 and at least 3 months after Visit 11 (week 20).
12. Willing to withdraw from any medication for Osteoarthritis including, but not limited to, Opioids, Non-Steroidal Anti-inflammatories (NSAIDs), COX-2 inhibitors, Topical medication, and Duloxetine.
13. Participant agrees to take only the allowed Rescue Medications from the start of the Diary Run-In Period through study completion (maximum 4000 mg paracetamol per day).

Exclusion Criteria:

1. Presence of OA of other major joints (including but not limited to nontarget knee) that could interfere with assessment of pain due to OA of the target knee, in the opinion of the investigator.
2. Current comorbid condition, other than OA, known to be significantly associated with arthritis or joint pathology, including but not necessarily limited to autoimmune disease with significant joint involvement (e.g., Rheumatoid Arthritis or Paget's disease; Seronegative Spondyloarthropathies (e.g. Ankylosing Spondylitis, Psoriasis arthritis, Reactive arthritis); or other systemic disease involving the target knee (including endocrinopathies).
3. The following conditions should be excluded: Known presence of rapidly Progressive Osteoarthritis (RPOA), primary osteonecrosis (including spontaneous osteonecrosis of the knee), subchondral insufficiency fractures (SIF), avascular necrosis, osteoporotic fractures, atrophic OA, excessive malalignment of the knee (anatomical axis angle greater than 10 degrees), pathological fractures, or stress fracture or reaction, vertical tear of the posterior meniscal root, or large or extensive subchondral cysts, or target knee anserine or patellar bursitis of clinical relevance
4. Hip dislocation and congenital hip dysplasia with degenerative joint disease should be excluded.
5. History of gout with recent (\< 6 months) pain flares and uncontrolled uric acid levels. Participants with a history or diagnosis of pseudogout (calcium pyrophosphate dihydrate crystal deposition disease) can enroll if there has not been a flare within 6 months prior to screening and use of NSAIDs is not required for management of this condition.
6. Presence of neuropathic pain deemed likely to interfere with trial endpoints, complex regional pain syndrome, or chronic widespread pain syndromes e.g., fibromyalgia.
7. History of significant trauma (e.g., intra-articular fracture) or surgery (excluding injection therapies and arthroscopy) to a knee, hip, or shoulder within the previous 1 year
8. Planned major surgery or other major invasive procedures while participating in the study.
9. Surgery or stent placement for coronary artery disease in the six months prior to screening .
10. Nondiagnostic arthroscopy performed on the target knee joint within 180 days prior to Screening; or diagnostic arthroscopy performed on the target knee joint within 90 days prior to Screening.
11. Intraarticular injection therapies to the target knee joint within 12 weeks prior to Screening, or to any non-target joint within 6 weeks prior to Screening.
12. Participants likely to be deemed unfit for joint replacement surgery due to concomitant illness, in the investigator opinion.
13. Opioid use, including Tramadol, of 4 or more instances per week over the month prior to Screening.
14. Known history of hypersensitivity to monoclonal antibodies.
15. Presence of any medical condition or unstable health status that, in the judgment of the investigator, might adversely impact the safety of the participant.
16. Signs and symptoms of significant cardiac disease, including but not limited to established ischemic heart disease, peripheral arterial disease and /or cerebrovascular disease (unstable angina, myocardial infarction, cardiovascular thrombotic events, transient ischemic attacks, and stroke in the six months prior to screening)
17. Active malignancy or history of malignancy within the past 5 years, with exception of resected and cured basal cell carcinoma and squamous cell carcinoma of the skin.
18. Clinically significant abnormal laboratory parameter(s) and/or ECG parameter(s) during Screening, that, in the judgment of the Investigator, would preclude the participant from participation in this study.
19. Participation in other studies involving investigational drug(s) within 30 days (or 90 days for biologics) prior to screening.
20. History of Carpal Tunnel Syndrome with symptoms within one year of Screening or a Boston Carpal Tunnel Questionnaire (Symptom Severity Scale) mean score ≥3.
21. A total Symptom Impact score on the Survey of Autonomic Symptoms ≥3.
22. Pregnant or breast feeding.
23. Previously received any form of anti-NGF
24. Requires walker or wheelchair for mobility (walking stick permitted).
25. Active or historic substance abuse within one year of Screening in the opinion of the Investigator.
26. Medical history within 5 years of Screening that involves suicidal ideation, suicide attempt, or increased risk of suicide as assessed by the Investigator.
27. Presence of any contraindication to MRI