Background
Methods
Study design, participants and randomization
Inclusion criteria | Exclusion criteria |
---|---|
Provide written informed consent Males or females aged 40–65 years, inclusive Diagnosed KL grade 1, 2 or 3 knee OA in the study knee Moderate-severe pain associated with OA in the study knee as measured by a VAS pain score of between 35 and 90 mm inclusive at the screening visit BMI of 20–30 inclusive Negative results for virus antibody tests from samples taken at the screening visit: HIV 1 and 2 antibody test HCV antibody test HBV antibody test Able to read and write in English A female patient is eligible to enter the study if she meets following criteria: Not pregnant or breast feeding/lactating Females of non-childbearing potential (i.e., women who had a hysterectomy, had both ovaries surgically removed or have current documentation of tubal ligation, or are postmenopausal which is defined as 1 year without menses) Females of childbearing potential must agree to use adequate and highly effective methods of contraception throughout the study Male patients with female partners of childbearing potential must use adequate and highly effective methods of contraception such as double-barrier form for the entire duration of the study | Inability or unwillingness to comply with protocol requirements Evidence, or diagnosis, of OA in the non-study knee that is of a worse screening visit VAS score than the study knee Joint surgery in the study knee, including arthroscopy, within the last 3 years Consistently occurring major mechanical issues in the study knee including locking, catching and giving way Intra-articular injections into either knee within the last 3 months Current evidence of infection in either knee Diagnosed or symptomatic OA in other major joints (feet, hips, shoulders or spine) that is of greater clinical significance than the study knee Planned hip, knee, ankle or foot surgery including joint replacement within the expected study duration History or current evidence of other joint diseases (such as gout, rheumatoid arthritis and ankylosing spondylitis), or disease or medication affecting the bone or cartilage metabolism, including systemic corticosteroids and osteoporosis medication Unable to undergo an MRI scan for any reason including severe claustrophobia and metal implants such as hip, knee or aortic valve prosthetics Current smoker, or have been a regular (daily) smoker in the past 3 months Planned or current participation in any other interventional clinical trials Patients who require use of systemic immunosuppressants Any clinically significant condition(s) that in the opinion of the PI may compromise safety or compliance, interfere with evaluation or preclude completion of the study |
Safety and efficacy assessments
Imaging
Statistical analysis
Results
Baseline characteristics and study participants
Placebo (n = 4) | PRG 3.9M (n = 8) | PRG 6.7M (n = 8) | |
---|---|---|---|
Demographics | |||
Age (years) | 55.0 ± 10.42 | 50.8 ± 7.29 | 55.0 ± 5.15 |
Females | 3 (75%) | 2 (25%) | 3 (37.5%) |
Height (cm) | 165.0 ± 7.87 | 172.6 ± 10.99 | 174.4 ± 11.99 |
Weight (kg) | 69.8 ± 11.55 | 82.9 ± 12.44 | 81.9 ± 14.23 |
BMI (kg/m2) | 25.5 ± 2.84 | 27.7 ± 2.05 | 26.8 ± 2.98 |
OA characteristics | |||
Study knee KL OA grade 1 | 1 (25%) | 0 (0%) | 1 (12.5%) |
Study knee KL OA grade 2 | 0 (0%) | 2 (25%) | 1 (12.5%) |
Study knee KL OA grade 3 | 3 (75%) | 6 (75%) | 6 (75%) |
OA in non-study knee | 3 (75%) | 7 (87.5%) | 6 (75%) |
Patient-reported outcomes | |||
VAS pain score (0–100 mm) | 43.8 ± 7.41 | 57.0 ± 13.82 | 60.8 ± 13.01 |
WOMAC pain score (0–20) | 6.3 ± 3.86 | 6.6 ± 2.07 | 7.9 ± 3.04 |
WOMAC stiffness score (0–8) | 3.3 ± 2.06 | 3.4 ± 1.19 | 4.1 ± 1.89 |
WOMAC physical functioning score (0–68) | 16.7 ± 10.69 | 22.0 ± 9.80 | 26.8 ± 10.20 |
AQoL-4D utility score | 0.75 ± 0.213 | 0.80 ± 0.140 | 0.76 ± 0.183 |
Activity level (FitBit®; n = 18) | |||
Average daily steps | 11,071 ± 7085 | 9049 ± 2605 | 11,934 ± 12,013 |
Quantitative MRI assessments | |||
Cartilage volume (mm3) | |||
Medial tibial region | 1597.1 ± 642.95 | 2037.0 ± 665.59 | 2166.0 ± 858.29 |
Lateral tibial region | 1777.5 ± 532.24 | 2459.3 ± 836.59 | 2470.3 ± 784.52 |
Patella | 2588.3 ± 965.59 | 2895.2 ± 1204.61 | 3637.1 ± 1431.01 |
Tibial bone area (mm2) | |||
Medial region | 2045.9 ± 374.36 | 2567.4 ± 388.86 | 2727.2 ± 632.68 |
Lateral region | 1508.3 ± 364.83 | 1641.3 ± 368.14 | 1611.9 ± 582.25 |
Bone marrow lesions | |||
Medial tibiofemoral region | 1 (25%) | 4 (50%) | 8 (100%) |
Lateral tibiofemoral region | 1 (33.3%) | 4 (50%) | 2 (25%) |
Patella | 2 (50%) | 3 (37.5%) | 1 (12.5%) |
Cartilage defects | |||
Medial tibiofemoral region | 3 (75%) | 8 (100%) | 7 (100%)* |
Lateral tibiofemoral region | 4 (100%) | 8 (100%) | 7 (100%)* |
Patella | 3 (75%) | 6 (75%) | 6 (85.7%) |
Biomarkers | |||
Urine CTX-II (ng/mmol) | 336.8 ± 311.34 | 149.9 ± 44.45 | 230.9 ± 136.69 |
Urine C2C (ng/mmol) | 1591.6 ± 715.73 | 2388.9 ± 1616.07 | 1049.0 ± 1026.84 |
Serum HA (ng/mL) | 32.6 ± 6.32 | 49.7 ± 19.95 | 47.0 ± 24.05 |
Serum MIF (ng/mL) | 12.9 ± 3.32 | 13.2 ± 5.34 | 15.5 ± 2.86 |
Serum CTX-I (ng/mL) | 0.3 ± 0.08 | 0.3 ± 0.15 | 0.4 ± 0.10 |
Adverse events
Placebo (n = 4) | PRG 3.9M (n = 8) | PRG 6.7M (n = 8) | |
---|---|---|---|
Patient summary | |||
TEAEs | 4 (100.0) | 8 (100.0) | 8 (100.0) |
Most common TEAEsa | |||
Arthralgia | 4 (100.0) | 6 (75.0) | 8 (100.0) |
Joint effusion | 3 (75.0) | 6 (75.0) | 3 (37.5) |
Upper respiratory tract infection | 1 (25.0) | 2 (25.0) | 3 (37.5) |
Joint stiffness | 3 (75.0) | 2 (25.0) | 1 (12.5) |
Joint lock | 1 (25.0) | 2 (25.0) | 1 (12.5) |
IP-related TEAEs | 3 (75.0) | 7 (87.5) | 6 (75.0) |
Arthralgia | 3 (75.0) | 4 (50.0) | 5 (62.5) |
Joint effusion | 1 (25.0) | 3 (37.5) | 2 (25.0) |
Joint stiffness | 1 (25.0) | 2 (25.0) | 1 (12.5) |
Bursitis | – | 1 (12.5) | 1 (12.5) |
Joint swelling | – | 1 (12.5) | 1 (12.5) |
Injection site pain | – | – | 1 (12.5) |
Joint lock | – | 1 (12.5) | – |
Joint warmth | – | 1 (12.5) | – |
Malaise | – | 1 (12.5) | – |
Paraesthesia | – | 1 (12.5) | – |
Event summary | |||
TEAEs | 43 | 55 | 71 |
Mild | 35 (81.4) | 45 (81.8) | 63 (88.7) |
Moderate | 8 (18.6) | 9 (16.4) | 8 (11.3) |
Severe | 0 (0.0) | 1 (1.8) | 0 (0.0) |
SAEs | 0 (0.0) | 0 (0.0) | 0 (0.0) |
IP-related TEAEs | 5 (11.6) | 16 (29.1) | 13 (18.3) |
Other safety assessments
Group | Parameter | Visit | Value | Laboratory reference range (low, high) | Status |
---|---|---|---|---|---|
Placebo | Neutrophils | Month 12 | 1.6 109/L | (2, 7.5) | L |
WBC | Month 12 | 3.6 109/L | (4, 11) | L | |
PRG 6.7M | ALT | Month 12 | 69 U/L | (5, 40) | H |
AST | Month 12 | 96 U/L | (10, 40) | H | |
PRG 6.7M | Potassium | Month 6 | 5.6 mmol/L | (3.5, 5.5) | H |
Concomitant medications
Effect of PRG on knee pain and function
Effect of PRG on knee structure
Placebo (n = 4) | PRG 3.9M (n = 8) | PRG 6.7M (n = 8) | Placebo – PRG 3.9M | Placebo – PRG 6.7M | |
---|---|---|---|---|---|
Lateral tibial cartilage volume, mm3 | − 95.4 (− 172.6, − 18.2) p = 0.019 | 11.1 (− 37.1, 59.3) p = 0.628 | − 78.0 (− 125.9, − 30.1) p = 0.004 | 106.5 (13.6, 199.4) p = 0.028 | 17.4 (− 74.6, 109.4) p = 0.690 |
Lateral tibial cartilage volume, % change | − 5.0 (− 8.8, − 1.3) p = 0.012 | 0.4 (− 2.0, 2.7) p = 0.730 | − 3.5 (− 5.8, − 1.2) p = 0.006 | 5.4 (0.9, 9.9) p = 0.022 | 1.5 (− 2.9, 6.0) p = 0.475 |
Medial tibial cartilage volume, mm3 | − 15.4 (− 166.8, − 136.0) p = 0.830 | − 30.3 (− 141.2, 80.5) p = 0.567 | − 73.8 (− 186.1, 38.6) p = 0.181 | − 14.9 (− 203.2, 173.4) p = 0.868 | − 58.3 (− 250.6, 133.9) p = 0.526 |
Medial tibial cartilage volume, % change | − 1.7 (− 8.8, 5.3) p = 0.607 | − 1.5 (− 6.7, 3.6) p = 0.532 | − 3.5 (− 8.7, 1.8) p = 0.178 | 0.2 (− 8.6, 9.0) p = 0.964 | − 1.7 (− 10.7, 7.2) p = 0.685 |
Lateral tibial bone area, mm2 | − 10.0 (− 70.9, 50.9) p = 0.730 | − 8.5 (− 54.4, 37.4) p = 0.698 | 25.6 (− 71.6, 20.4) p = 0.253 | 1.5 (− 74.7, 77.7) p = 0.967 | − 15.6 (− 92.1, 60.9) p = 0.669 |
Lateral tibial bone area, % change | − 0.2 (− 4.0, 3.6) p = 0.906 | − 0.2 (− 3.1, 2.7) p = 0.888 | − 2.0 (− 4.9, 0.9) p = 0.158 | 0.0 (− 4.8, 4.8) p = 0.993 | − 1.8 (− 6.6, 3.0) p = 0.436 |
Medial tibial bone area, mm2 | 30.4 (− 41.6, 102.4) p = 0.381 | 50.3 (1.1, 99.6) p = 0.046 | − 17.0 (− 68.1, 34.1) p = 0.487 | 20.0 (− 68.6, 108.5) p = 0.636 | − 47.4 (− 140.4, 45.6) p = 0.293 |
Medial tibial bone area, % change | 1.4 (− 1.6, 4.3) p = 0.336 | 2.0 (− 0.0, 4.0) p = 0.051 | − 1.0 (− 3.1, 1.1) p = 0.326 | 0.6 (− 3.0, 4.3) p = 0.712 | − 2.4 (− 6.2, 1.4) p = 0.205 |