Osteoarthritis, Knee
Conditions
Brief summary
The purpose of this study is to evaluate the safety, efficacy and pharmacokinetics (PK) of EP-104IAR in patients with osteoarthritis (OA) of the knee
Detailed description
This is a randomized, double-blind, placebo-controlled, single injection, 24-week study to evaluate the safety, efficacy and PK of EP-104IAR in subjects with osteoarthritis knee pain Following screening and baseline assessments to determine eligibility, each participant will receive a single IA injection of either EP-104IAR or placebo (vehicle). Participants will be followed up for 24 weeks following the injection for safety, PK and efficacy assessments.
Interventions
DRUGEP-104IAR 25 mg
Single 5 mL intra-articular injection
DRUGVehicle
Single 5 mL intra-articular injection
Sponsors
NBCD A/S
Eupraxia Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Subjects will be randomized to received either EP-104IAR or placebo (vehicle) in a parallel group fashion.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Males or females, aged ≥40 years * Body Mass Index (BMI) ≤ 40.0 kg/m2 * Diagnosis of primary OA of the Index knee, with symptoms present for at least 6 months * OA severity Grade 2 or 3 (based on Kellgren Lawrence Grading Scale) * Unsatisfactory pain relief from at least 2 prior standard OA treatments * Qualifying pain in the Index knee during the baseline period * Ambulatory (without the need for a cane/other walking aide) * Female subjects willing to use highly effective birth control methods to prevent pregnancy * Willing and able to comply with study procedures and restrictions, including abstaining from use of restricted medications. Key
Exclusion criteria
* OA of the Index knee due to acute injury or trauma, or unstable joint * X-ray evidence of chondrocalcinosis * Diagnosed or suspected ipsilateral hip OA * Knee pain that is not attributable to OA of the knee * Any other disorders that impact mobility, strength or sensation, or are a co-existent source of pain or inflammation that interfere with assessment of knee pain and function * History of infection in the Index knee * Skin breakdown on the Index knee where the injection will take place * Total Knee Replacement, or any other surgery (including arthroscopy) for the Index knee within prior 12 months, or planned surgery during the study * Total Knee Replacement Surgery of the non-Index knee within prior 6 months, or planned surgery (any location) during the study that would require a restricted medication * IA injection of corticosteroids in any joint within prior 3 months or IA injection of extended-release corticosteroids in any joint within prior 6 months * IA injection in the Index knee of platelet rich plasma, or other prolotherapy within prior 3 months, or hyaluronic acid within prior 6 months * Recent, current or planned use of corticosteroids for any indication (except for permitted uses) * Recent, current or planned use of prohibited medications (including analgesics, marijuana, investigational drugs and devices, immunosuppressive therapy), or unwilling or unable to stop using prohibited medications during the study. * Conditions including: sarcoidosis, amyloidosis, osteomyelitis, Cushing's Syndrome, hepatic or renal disease, Psychotic disorder, bipolar disorder, symptomatic depressive or anxiety disorders. * Current malignancy of any type, or history of a malignancy within prior 12 months * Active or quiescent systemic fungal, bacterial (including tuberculosis) viral (including HIV, Hepatitis B or C) or parasitic infections, or ocular herpes simplex, or any recent infection requiring IV or oral antibiotics * Laboratory results indicative of adrenal insufficiency, diabetes or renal or hepatic disease. * Positive urine drug screen for a substance of abuse * Females who are pregnant, lactating * Known or suspected hypersensitivity or contraindication to ingredients in the study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale | 12 weeks | Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (scores scaled 0-10, with 10 being the worst). Least squares mean from a mixed model for repeated measures (MMRM) for change from baseline with fixed effects for site, treatment, week, treatment-by-week interaction; random effect for subject; and covariate baseline WOMAC pain score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Function Subscale | 12 weeks | Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function subscale (scores scaled 0-10, with 10 being the worst). Function subscale includes questions related to the physical functioning of osteoarthritis e.g. stair use, standing, walking etc. From a mixed model for repeated measures (MMRM) for change from baseline with fixed effects for site, treatment, week, treatment-by-week interaction; random effect for subject; and covariate baseline WOMAC function score. |
| Difference Between EP-104IAR and Vehicle in the Area Under the Curve (AUC) of WOMAC Pain Subscale | 12 weeks | Area under the curve in change from baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (scores scaled 0-10, with 10 being the worst) from Week 0 to Week 12 was calculated on a per-individual basis using the linear trapezoidal rule. AUC was normalized to account for subjects whose actual days and nominal days at Week 12 differed. Treatments were compared using an ANCOVA model containing site; individual baseline WOMAC Pain; and treatment group as covariates. |
| Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale | 24 weeks | Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (scores scaled 0-10, with 10 being the worst). Least squares mean from a mixed model for repeated measures (MMRM) for change from baseline with fixed effects for site, treatment, week, treatment-by-week interaction; random effect for subject; and covariate baseline WOMAC pain score. |
| Difference Between EP-104IAR and Vehicle in OMERACT-OARSI Strict Responders | 12 weeks | Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) strict responders are defined as at least 50% improvement (decrease from baseline) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain or function subscales (scores scaled 0-10, with 10 being the worst) and an absolute change of at least 2 in the respective score. Patients who discontinued prior to Week 12 were considered non-responders. |
Countries
Czechia, Denmark, Poland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EP-104IAR 25 mg A single use intra-articular injection containing 25 mg of EP-104IAR
EP-104IAR 25 mg: Single 5 mL intra-articular injection | 163 |
| Placebo (Vehicle) A single use intra-articular injection containing no active ingredients
Vehicle: Single 5 mL intra-articular injection | 155 |
| Total | 318 |
Baseline characteristics
| Characteristic | EP-104IAR 25 mg | Placebo (Vehicle) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 72 Participants | 66 Participants | 138 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants | 89 Participants | 180 Participants |
| Age, Continuous | 64.0 years STANDARD_DEVIATION 9.31 | 63.2 years STANDARD_DEVIATION 9.37 | 63.6 years STANDARD_DEVIATION 9.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 161 Participants | 152 Participants | 313 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 162 Participants | 153 Participants | 315 Participants |
| Region of Enrollment Czechia | 40 participants | 35 participants | 75 participants |
| Region of Enrollment Denmark | 85 participants | 84 participants | 169 participants |
| Region of Enrollment Poland | 38 participants | 36 participants | 74 participants |
| Sex: Female, Male Female | 94 Participants | 89 Participants | 183 Participants |
| Sex: Female, Male Male | 69 Participants | 66 Participants | 135 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 163 | 0 / 155 |
| other Total, other adverse events | 76 / 163 | 68 / 155 |
| serious Total, serious adverse events | 4 / 163 | 1 / 155 |
Outcome results
Primary
Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (scores scaled 0-10, with 10 being the worst). Least squares mean from a mixed model for repeated measures (MMRM) for change from baseline with fixed effects for site, treatment, week, treatment-by-week interaction; random effect for subject; and covariate baseline WOMAC pain score.
Time frame: 12 weeks
Population: The intention-to-treat (ITT) population consists of all subjects who were both randomized to and received treatment. Analysis was conducted allocating subjects to the treatment to which they were randomized, irrespective of what was actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EP-104IAR 25 mg | Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale | -2.89 score on a scale | Standard Error 0.166 |
| Placebo (Vehicle) | Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale | -2.23 score on a scale | Standard Error 0.171 |
p-value: 0.004ANCOVA
Secondary
Difference Between EP-104IAR and Vehicle in OMERACT-OARSI Strict Responders
Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) strict responders are defined as at least 50% improvement (decrease from baseline) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain or function subscales (scores scaled 0-10, with 10 being the worst) and an absolute change of at least 2 in the respective score. Patients who discontinued prior to Week 12 were considered non-responders.
Time frame: 12 weeks
Population: The intention-to-treat (ITT) population consists of all subjects who were both randomized to and received treatment. Analysis was conducted allocating subjects to the treatment to which they were randomized, irrespective of what was actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| EP-104IAR 25 mg | Difference Between EP-104IAR and Vehicle in OMERACT-OARSI Strict Responders | 87 Participants |
| Placebo (Vehicle) | Difference Between EP-104IAR and Vehicle in OMERACT-OARSI Strict Responders | 61 Participants |
p-value: 0.028Fisher Exact
Secondary
Difference Between EP-104IAR and Vehicle in the Area Under the Curve (AUC) of WOMAC Pain Subscale
Area under the curve in change from baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (scores scaled 0-10, with 10 being the worst) from Week 0 to Week 12 was calculated on a per-individual basis using the linear trapezoidal rule. AUC was normalized to account for subjects whose actual days and nominal days at Week 12 differed. Treatments were compared using an ANCOVA model containing site; individual baseline WOMAC Pain; and treatment group as covariates.
Time frame: 12 weeks
Population: The intention-to-treat (ITT) population consists of all subjects who were both randomized to and received treatment. Analysis was conducted allocating subjects to the treatment to which they were randomized, irrespective of what was actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EP-104IAR 25 mg | Difference Between EP-104IAR and Vehicle in the Area Under the Curve (AUC) of WOMAC Pain Subscale | -235.67 score on a scale multiplied by days | Standard Error 11.769 |
| Placebo (Vehicle) | Difference Between EP-104IAR and Vehicle in the Area Under the Curve (AUC) of WOMAC Pain Subscale | -166.78 score on a scale multiplied by days | Standard Error 12.169 |
p-value: <0.001ANCOVA
Secondary
Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Function Subscale
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function subscale (scores scaled 0-10, with 10 being the worst). Function subscale includes questions related to the physical functioning of osteoarthritis e.g. stair use, standing, walking etc. From a mixed model for repeated measures (MMRM) for change from baseline with fixed effects for site, treatment, week, treatment-by-week interaction; random effect for subject; and covariate baseline WOMAC function score.
Time frame: 12 weeks
Population: The intention-to-treat (ITT) population consists of all subjects who were both randomized to and received treatment. Analysis was conducted allocating subjects to the treatment to which they were randomized, irrespective of what was actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EP-104IAR 25 mg | Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Function Subscale | -2.59 score on a scale | Standard Error 0.161 |
| Placebo (Vehicle) | Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Function Subscale | -2.04 score on a scale | Standard Error 0.166 |
p-value: 0.014ANCOVA
Secondary
Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (scores scaled 0-10, with 10 being the worst). Least squares mean from a mixed model for repeated measures (MMRM) for change from baseline with fixed effects for site, treatment, week, treatment-by-week interaction; random effect for subject; and covariate baseline WOMAC pain score.
Time frame: 24 weeks
Population: The intention-to-treat (ITT) population consists of all subjects who were both randomized to and received treatment. Analysis was conducted allocating subjects to the treatment to which they were randomized, irrespective of what was actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| EP-104IAR 25 mg | Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale | -2.26 score on a scale | Standard Error 0.171 |
| Placebo (Vehicle) | Difference in Change From Baseline Between EP-104IAR and Vehicle in WOMAC Pain Subscale | -2.11 score on a scale | Standard Error 0.175 |
p-value: 0.518ANCOVA