Arthritis, Joint Diseases, Knee Osteoarthritis, Musculoskeletal Diseases, Osteo Arthritis Knee, Pain, Rheumatic Diseases
Conditions
Keywords
Osteoarthritis, Knee, Levi-04
Brief summary
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.
Detailed description
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.
Interventions
DRUGLEVI-04
LEVI-04, a fully human chimeric fusion protein that combines the Fc fragment of human immunoglobulin G1 with the p75 neurotrophin receptor (p75 NTR), for the treatment of chronic pain.
OTHERPlacebo
Saline vehicle
Sponsors
Nordic Bioscience Clinical Development (NBCD)
Levicept
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double- Blind
Intervention model description
This is a 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.
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Least Squares Mean Change From Baseline in WOMAC Pain | Week 17 Change from Baseline | The primary efficacy endpoint is the change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score, measured on a 0-10 point scale (0=no pain; 10=worse pain; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Least Squares Mean Change From Baseline in Post-Staircase Evoked Pain Procedure (StEPP) Pain Intensity | Week 17 Change from Baseline | Change from baseline in pain intensity measured following the Staircase Evoked Pain Procedure (StEPP), using a numeric rating scale ranging from 0 to 10 (0=no pain; 10=worse pain; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome) |
| Least Squares Mean Change From Baseline in WOMAC Physical Function | Week 17 Change from Baseline | Change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function subscale, measured on a 0 to 10 point scale (0=no impact on physical function; 10=worse impact on physical function; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome) |
| Least Squares Mean Change From Baseline in WOMAC Joint Stiffness Subscale | Week 17 Change from Baseline | Change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Joint Stiffness Subscale, scored on a 0 to 10 point scale (0=no stiffness; 10=worst stiffness; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome) |
| Least Squares Mean Change From Baseline in Patient Global Assessment | Week 17 Change from Baseline | Change from baseline in the Patient Global Assessment, measured on a 0 to 10 numeric rating scale where 0 indicates Very good and 10 indicates Very bad. The result reported is the mean change from baseline; therefore, the greater the reduction in units, the better the outcome. |
Countries
Czechia, Denmark, Hong Kong, Moldova, Poland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 0.3 mg/kg LEVI-04 Intravenous infusion of 0.3 mg/kg LEVI-04 | 130 |
| 1.0 mg/kg LEVI-04 Intravenous infusion of 1.0 mg/kg LEVI-04 | 130 |
| 2.0 mg/kg LEVI-04 Intravenous infusion of 2.0 mg/kg LEVI-04 | 129 |
| Placebo Intravenous infusion of saline vehicle as placebo | 129 |
| Total | 518 |
Baseline characteristics
| Characteristic | 0.3 mg/kg LEVI-04 | 1.0 mg/kg LEVI-04 | 2.0 mg/kg LEVI-04 | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 62 Participants | 75 Participants | 62 Participants | 83 Participants | 282 Participants |
| Age, Categorical Between 18 and 65 years | 68 Participants | 55 Participants | 67 Participants | 46 Participants | 236 Participants |
| Age, Continuous | 63.2 years STANDARD_DEVIATION 7.68 | 64.5 years STANDARD_DEVIATION 8.37 | 63.1 years STANDARD_DEVIATION 7.8 | 65.4 years STANDARD_DEVIATION 7.8 | 64.0 years STANDARD_DEVIATION 8.07 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 15 Participants | 17 Participants | 22 Participants | 66 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 117 Participants | 115 Participants | 112 Participants | 107 Participants | 451 Participants |
| Region of Enrollment Czechia | 40 participants | 39 participants | 30 participants | 34 participants | 143 participants |
| Region of Enrollment Denmark | 51 participants | 50 participants | 60 participants | 50 participants | 211 participants |
| Region of Enrollment Hong Kong | 12 participants | 15 participants | 17 participants | 22 participants | 66 participants |
| Region of Enrollment Moldova | 6 participants | 2 participants | 6 participants | 3 participants | 17 participants |
| Region of Enrollment Poland | 21 participants | 24 participants | 16 participants | 20 participants | 81 participants |
| Sex: Female, Male Female | 67 Participants | 80 Participants | 69 Participants | 76 Participants | 292 Participants |
| Sex: Female, Male Male | 63 Participants | 50 Participants | 60 Participants | 53 Participants | 226 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 129 | 0 / 130 | 0 / 129 | 0 / 129 |
| other Total, other adverse events | 36 / 129 | 44 / 130 | 58 / 129 | 62 / 129 |
| serious Total, serious adverse events | 0 / 129 | 1 / 130 | 3 / 129 | 3 / 129 |
Outcome results
Primary
Least Squares Mean Change From Baseline in WOMAC Pain
The primary efficacy endpoint is the change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale score, measured on a 0-10 point scale (0=no pain; 10=worse pain; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome)
Time frame: Week 17 Change from Baseline
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Pain | -2.77 units on 0-10 point scale | Standard Error 0.16 |
| 1.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Pain | -2.87 units on 0-10 point scale | Standard Error 0.17 |
| 2.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Pain | -3.05 units on 0-10 point scale | Standard Error 0.17 |
| Placebo | Least Squares Mean Change From Baseline in WOMAC Pain | -2.26 units on 0-10 point scale | Standard Error 0.17 |
Secondary
Least Squares Mean Change From Baseline in Patient Global Assessment
Change from baseline in the Patient Global Assessment, measured on a 0 to 10 numeric rating scale where 0 indicates Very good and 10 indicates Very bad. The result reported is the mean change from baseline; therefore, the greater the reduction in units, the better the outcome.
Time frame: Week 17 Change from Baseline
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in Patient Global Assessment | -2.3 units on 0-10 point scale | Standard Error 0.18 |
| 1.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in Patient Global Assessment | -2.6 units on 0-10 point scale | Standard Error 0.18 |
| 2.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in Patient Global Assessment | -2.8 units on 0-10 point scale | Standard Error 0.19 |
| Placebo | Least Squares Mean Change From Baseline in Patient Global Assessment | -1.7 units on 0-10 point scale | Standard Error 0.19 |
Secondary
Least Squares Mean Change From Baseline in Post-Staircase Evoked Pain Procedure (StEPP) Pain Intensity
Change from baseline in pain intensity measured following the Staircase Evoked Pain Procedure (StEPP), using a numeric rating scale ranging from 0 to 10 (0=no pain; 10=worse pain; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome)
Time frame: Week 17 Change from Baseline
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in Post-Staircase Evoked Pain Procedure (StEPP) Pain Intensity | -2.5 units on 0-10 pain scale | Standard Error 0.2 |
| 1.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in Post-Staircase Evoked Pain Procedure (StEPP) Pain Intensity | -2.6 units on 0-10 pain scale | Standard Error 0.19 |
| 2.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in Post-Staircase Evoked Pain Procedure (StEPP) Pain Intensity | -3.0 units on 0-10 pain scale | Standard Error 0.2 |
| Placebo | Least Squares Mean Change From Baseline in Post-Staircase Evoked Pain Procedure (StEPP) Pain Intensity | -1.8 units on 0-10 pain scale | Standard Error 0.2 |
Secondary
Least Squares Mean Change From Baseline in WOMAC Joint Stiffness Subscale
Change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Joint Stiffness Subscale, scored on a 0 to 10 point scale (0=no stiffness; 10=worst stiffness; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome)
Time frame: Week 17 Change from Baseline
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Joint Stiffness Subscale | -2.60 units on 0-10 point scale | Standard Error 0.179 |
| 1.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Joint Stiffness Subscale | -2.82 units on 0-10 point scale | Standard Error 0.179 |
| 2.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Joint Stiffness Subscale | -3.20 units on 0-10 point scale | Standard Error 0.182 |
| Placebo | Least Squares Mean Change From Baseline in WOMAC Joint Stiffness Subscale | -1.75 units on 0-10 point scale | Standard Error 0.185 |
Secondary
Least Squares Mean Change From Baseline in WOMAC Physical Function
Change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Physical Function subscale, measured on a 0 to 10 point scale (0=no impact on physical function; 10=worse impact on physical function; the result reported is mean change from baseline, therefore the greater the reduction in units the better the outcome)
Time frame: Week 17 Change from Baseline
Population: ITT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Physical Function | -2.40 units on 0-10 point scale | Standard Error 0.159 |
| 1.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Physical Function | -2.49 units on 0-10 point scale | Standard Error 0.159 |
| 2.0 mg/kg LEVI-04 | Least Squares Mean Change From Baseline in WOMAC Physical Function | -2.75 units on 0-10 point scale | Standard Error 0.162 |
| Placebo | Least Squares Mean Change From Baseline in WOMAC Physical Function | -1.84 units on 0-10 point scale | Standard Error 0.164 |