Introduction
Materials and methods
Investigational products
Study design
Procedures common to both protocols | Screening (Visit 1) | Study period | ||
---|---|---|---|---|
Day 1 (Baseline Visit 2) | Days 7, 30, 60, 90, 120, 150 (Visits 3, 4, 5, 6, 7, 8) | Day 180 (Visit 9) | ||
Signed Informed Consent | X | |||
Inclusion/Exclusion Reviewed | X | X | X | |
Medical/Surgical/Medication History | X | |||
Physical Examination | X | |||
Vital Signs | X | X | X | X |
Heighta, Weight, BMI | X | X | ||
Clinical Assessment for Knee Pain & Swelling | X | X | X | X |
Knee Flexion Range of Motion | X | X | X | |
X-ray examination | X | |||
WOMAC Score | X | X | X | X |
VAS Scale | X | X | X | X |
LFI Score | X | X | X | X |
Clinical Laboratory Tests (hematology, chemistry, urinalysis) | X | X | ||
Urine Pregnancy Test (if applicable) | X | X | X | |
Serum biomarker analysis-COMP | X | X | ||
Randomization Number Assigned | X | |||
Investigational Product Administration | X | |||
Dispense Subject Diary | X | X | ||
Collect/Review Subject Diary | X | X | ||
Provide Directions for Concomitant Medication and Rescue Medication Use | X | X | X | |
Dispense New Investigational Product | X | X | ||
Review Product Accountability | X | X | ||
Assess use of Concomitant Medications | X | X | X | |
Adverse Events Assessed | X | X | X | |
Procedures Confined to Protocol 003348 | ||||
Synovial fluid biomarker—MMP-3 and IL-6 | X | X | ||
Serum biomarker analysis—CRP | X | X |
Clinical endpoints
Study subjects
Inclusion |
• Ambulatory, 40–75 years of age, with a BMI of 18 to 30 kg/m2
|
• Females of childbearing age must agree to use a medically approved form of birth control and have a negative urine pregnancy test result throughout the study |
• Female subjects of limited to no childbearing potential must be amenorrheic for at least 1 year or have had a hysterectomy, a bilateral oophorectomy, or both |
• Unilateral or bilateral OA of the knee for greater than 3 months plus a Kellgren and Lawrence radiographic grade of 2 or 3 |
• VAS score during knee movement between 40–70 mm after 7 day withdrawal of excluded medications |
• LFI score between 6–10 points after 7 day withdrawal of excluded medications |
• Clinical laboratory results that are within normal range or considered not clinically significant by the Principal Investigator |
• Be willing to participate in all scheduled visits, tests, and other trial procedures according to the clinical protocol |
• Be willing to refrain from taking ibuprofen, aspirin or other NSAIDS, or any other pain reliever (OTC or prescription) during the entire trial other than acetaminophen (paracetamol) as rescue medication |
• Provide a signed and dated informed consent indicating that the subject has been informed of all pertinent aspects and possible risks associated with participation in the trial |
Exclusion |
• History of hypersensitivity to the rescue medication or any of the products used in the study |
• History of hypersensitivity to eggs, chicken or fowl, or shellfish |
• History of inflammatory arthropathy, severe RA, OA (VAS score greater than 70), or Systemic Lupus Erythematosus |
• Hyperuricemia (>440 μmol/L), past history of gout, or both |
• Anticipation of surgery within the next 4 months |
• Recent injury in the target knee (past 4 months) |
• History of use for corticosteroid, indomethacin, glucosamine & chondroitin within 3 months of Visit 2; intra-articular treatments, including injections of corticosteroid or hyaluronic acid; consumption of Omega 3 fatty acids dietary supplements within 6 months preceding the treatment period (a 2-week washout period is allowed for subjects taking omega 3 fatty acid supplements) |
• History of congestive heart failure |
• Anticipated problems with product consumption |
• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurologic diseases, or malignancies within the last 5 years |
• High alcohol intake (>2 standard drinks per day) or use of recreational drugs (e.g., cocaine, methamphetamine, marijuana, etc.) |
• Females who are pregnant or lactating or planning to become pregnant |
• History of any mental illness that might impair the ability of subjects to provide a written informed consent |
• Consumed acetaminophen (paracetamol), ibuprofen, aspirin or other NSAIDS, or any other pain reliever (OTC or prescription), or any natural health product, (excluding vitamins) within 7 days of first visit |
• Participation in any clinical trials within 30 days prior to first visit |
Ethics, consent and permissions
Randomization & blinding
Dosing regimen
Prior and concomitant therapies
Rescue medications
Compliance and safety
Study evaluations
Synovial fluid biomarkers
Serum biomarkers
Statistics
Results
Demographics and baseline characteristics
Characteristics | Placebo (n = 58) | GC (n = 65) | UC-II (n = 63) |
---|---|---|---|
Sex ((n) male + (n) female) | 28M + 30F | 28M + 37F | 33M + 30F |
Age (years) | 53.1 ± 1.02 | 52.6 ± 1.02 | 53.5 ± 0.99 |
Height (cm) | 162 ± 1.00 | 161 ± 1.12 | 161 ± 0.89 |
Body weight (kg) | 64.5 ± 1.20 | 66.0 ± 1.13 | 65.5 ± 1.12 |
Body mass index (kg/m2) | 24.7 ± 0.40 | 25.5 ± 0.40 | 25.2 ± 0.37 |
Kellgren Lawrence radiographic score | |||
Grade 2 (n) | 39 | 45 | 42 |
Grade 3 (n) | 19 | 20 | 21 |
Lequesne's Functional Index | 7.74 ± 0.12 | 8.02 ± 0.12 | 7.90 ± 0.13 |
Visual analog score (mm) | 58.2 ± 0.97 | 59.1 ± 0.97 | 58.4 ± 0.99 |
Total WOMAC score | 1382 ± 34.8 | 1396 ± 31.8 | 1398 ± 27.9 |
Mean WOMAC pain | 56.9 ± 1.36 | 57.5 ± 1.33 | 58.1 ± 1.03 |
Mean WOMAC physical function | 57.9 ± 1.51 | 58.5 ± 1.37 | 58.3 ± 1.24 |
Mean WOMAC stiffness | 56.3 ± 1.63 | 57.3 ± 1.52 | 58.1 ± 1.32 |
Knee flexion ROM (°) | 114 ± 1.62 | 114 ± 1.36 | 114 ± 1.57 |
Serum CRP (mg/L)a
| 5.29 ± 1.47 | 8.15 ± 1.79 | 3.35 ± 0.58 |
Serum COMP (ng/mL)b
| 325.2 ± 30.5 | 381.2 ± 44.1 | 334.6 ± 36.5 |
Synovial IL-6 (ng/mL)c
| 13.3 ± 4.73 | 13.9 ± 5.57 | 15.3 ± 6.04 |
Synovial MMP-3 (μg/mL)d
| 4.03 ± 1.20 | 2.54 ± 0.78 | 4.86 ± 1.74 |
Subject dropouts
Study product compliance
Total WOMAC score
Analytical method | Type of analysis | Time point (Days) | Placebo (n = 53) | GC (n = 57) | UC-II (n = 54) |
p value (95 % CI) | |||
---|---|---|---|---|---|---|---|---|---|
Overalla
| GC vs PBO | UC-II vs PBOb
| UC-II vs GC | ||||||
ANCOVA | mITT | 180 | −414 ± 28.5 | −454 ± 27.5 | −551 ± 28.2 | 0.002 | 0.56 (−134 to 53) | 0.002 (−232 to −42) | 0.04c (−190 to −3) |
MMRM | mITT | 180 | −397 ± 28.6 | −452 ± 27.6 | −514 ± 28.3 | 0.014 | 0.33 (−148 to 37) | 0.0097 (−210 to −24) | 0.25 (−153 to 30) |
(n = 58) | (n = 65) | (n = 63) | |||||||
iAUC | ITT | 1 to 180 | −1479 ± 137 | −1751 ± 130 | −2042 ± 132 | 0.014 | 0.33 (−718 to 174) | 0.0098 (−1012 to −113) | 0.26 (−727 to 146) |
Total WOMAC score based on baseline COMP levels
COMP (ng/mL) | Analytical method | Type of analysis | Time point (Days) | Placebo (n = 27) | GC (n = 28) | UC-II (n = 27) |
p value (95 % CI) | |||
---|---|---|---|---|---|---|---|---|---|---|
Overalla
| GC vs PBO | UC-II vs PBO | UC-II vs GC | |||||||
≥285 | ANCOVA | mITT | 180 | −368 ± 41.7 | −396 ± 40.9 | −574 ± 41.6 | 0.002 | 0.88 (−168 to 112) | 0.002b (−347 to −65) | 0.009c (−317 to −38) |
MMRM | mITT | 180 | −351 ± 44.1 | −398 ± 41.1 | −540 ± 44.2 | 0.006 | 0.71 (−188 to 94) | 0.006b (−330 to −48) | 0.048c (−282 to −1) | |
iAUCd
| ITT | 1 to 180 | −1351 ± 212 | −1582 ± 204 | −2384 ± 207 | 0.003 | 0.72 (−934 to 473) | 0.002b (−1741 to −325) | 0.02c (−1498 to −107) | |
(n = 26) | (n = 29) | (n = 26) | ||||||||
<285 | ANCOVA | mITT | 180 | −463 ± 38.8 | −508 ± 36.6 | −526 ± 38.7 | 0.48 | 0.67 (−173 to 82) | 0.49 (−195 to 68) | 0.94 (−145 to 109) |
MMRM | mITT | 180 | −442 ± 38.2 | −493 ± 37.3 | −521 ± 38.1 | 0.34 | 0.60 (−178 to 76) | 0.32 (−208 to 50) | 0.86 (−155 to 100) | |
iAUCe
| ITT | 1 to 180 | −1626 ± 185 | −1908 ± 178 | −1902 ± 185 | 0.49 | 0.52 (−896 to 333) | 0.55 (−902 to 350) | 0.99 (−607 to 618) |
WOMAC mean subscores—pain, stiffness and physical function
Parameter reduction | Day | Placebo (n = 53) | GC (n = 57) | UC-II (n = 54) |
p value | |||
---|---|---|---|---|---|---|---|---|
Overalla
| GC vs PBO | UC-II vs PBOb
| UC-II vs GCc
| |||||
WOMAC pain | 7 | 3.21 ± 0.58 | 4.57 ± 0.54 | 3.88 ± 0.55 | - | - | - | - |
30 | 6.61 ± 1.04 | 7.89 ± 1.00 | 9.18 ± 1.01 | - | - | - | - | |
60 | 8.17 ± 1.10 | 10.1 ± 1.07 | 12.7 ± 1.09 | 0.0149 | - | 0.011 | - | |
90 | 11.2 ± 1.17 | 12.7 ± 1.14 | 16.4 ± 1.16 | 0.0063 | - | 0.0059 | - | |
120 | 12.9 ± 1.28 | 15.6 ± 1.22 | 19.9 ± 1.26 | 0.0005 | - | 0.0004 | 0.040 | |
150 | 15.0 ± 1.21 | 17.5 ± 1.16 | 21.5 ± 1.20 | 0.0007 | - | 0.0006 | 0.047 | |
180 | 17.0 ± 1.25 | 19.2 ± 1.20 | 24.0 ± 1.23 | 0.0003 | - | 0.0003 | 0.016 | |
WOMAC stiffness | 7 | 3.47 ± 0.64 | 4.22 ± 0.61 | 4.24 ± 0.62 | - | - | - | - |
30 | 6.81 ± 1.10 | 8.76 ± 1.05 | 9.28 ± 1.07 | - | - | - | - | |
60 | 9.36 ± 1.28 | 11.5 ± 1.25 | 13.1 ± 1.27 | - | - | - | - | |
90 | 11.3 ± 1.36 | 13.8 ± 1.32 | 17.0 ± 1.35 | 0.0158 | - | 0.010 | - | |
120 | 13.6 ± 1.40 | 15.0 ± 1.34 | 20.0 ± 1.39 | 0.0035 | - | 0.0039 | 0.029 | |
150 | 15.5 ± 1.32 | 17.7 ± 1.26 | 21.3 ± 1.31 | 0.0079 | - | 0.0058 | - | |
180 | 17.8 ± 1.31 | 19.4 ± 1.27 | 23.8 ± 1.30 | 0.0043 | - | 0.004 | 0.044 | |
WOMAC physical function | 7 | 3.17 ± 0.56 | 4.14 ± 0.53 | 3.91 ± 0.53 | - | - | - | - |
30 | 6.30 ± 1.00 | 7.80 ± 0.96 | 9.26 ± 0.98 | - | - | - | - | |
60 | 7.75 ± 1.08 | 9.50 ± 1.05 | 11.9 ± 1.07 | 0.0278 | - | 0.020 | - | |
90 | 10.4 ± 1.17 | 12.1 ± 1.14 | 15.1 ± 1.16 | 0.0182 | - | 0.0136 | - | |
120 | 12.7 ± 1.20 | 14.5 ± 1.15 | 17.9 ± 1.19 | 0.0083 | - | 0.0064 | - | |
150 | 14.8 ± 1.19 | 16.9 ± 1.14 | 20.0 ± 1.18 | 0.0078 | - | 0.006 | - | |
180 | 17.3 ± 1.21 | 18.8 ± 1.16 | 22.5 ± 1.20 | 0.0068 | - | 0.007 | - |
Mean VAS score
LFI score
Knee flexion
Serum biomarkers
Matrix | Parameter reduction | Day | Placebo (n) | GC (n) | UC-II (n) |
---|---|---|---|---|---|
Serum | COMP (ng/mL) | 180 | −51.2 ± 31.3 (53) | −56.5 ± 36.0 (56) | −69.6 ± 40.8 (53) |
CRP (mg/L) | 180 | 15.1 ± 6.33 (26) | 9.09 ± 5.36 (28) | 13.0 ± 4.64 (28) | |
Synovial | IL-6 (ng/mL) | 180 | −9.54 ± 4.83 (23) | −9.72 ± 5.28 (24) | −11.8 ± 5.37 (21) |
MMP-3 (μg/mL) | 180 | −2.24 ± 1.26 (25) | −0.93 ± 0.79 (27) | −2.67 ± 1.85 (23) |
Synovial fluid biomarkers
Rescue medication usage
Day | Placebo | GC | UC-II |
---|---|---|---|
7 | 11/58 | 12/65 | 3/63 |
30 | 18/58 | 7/63 | 4/61 |
60 | 12/58 | 9/61 | 6/59 |
90 | 12/56 | 8/59 | 3/57 |
120 | 13/54 | 13/59 | 7/55 |
150 | 10/54 | 12/59 | 3/55 |
180 | 11/53 | 7/57 | 4/54 |
Entire study period | 28/58 | 21/65 | 11/63a
|
Safety assessments
Parameter (Units) | Baseline | Day 180 | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Normal range | Placebo (n = 58) | GC (n = 65) | UC-II (n = 63) |
p value GC vs PBO |
p value UC-II vs PBO |
p value UC-II vs GC | Placebo (n = 53) | GC (n = 56) | UC-II (n = 53) |
p value GC vs PBO |
p value UC-II vs PBO |
p value UC-II vs GC | |
Hematology | |||||||||||||
Hemoglobin (gm/dL) | 12.1–17.2 | 12.1 ± 0.22 | 11.9 ± 0.21 | 12.1 ± 0.20 | 0.7613 | 0.9948 | 0.8095 | 12.7 ± 0.24 | 12.4 ± 0.20 | 12.7 ± 0.18 | 0.4454 | 0.9727 | 0.5851 |
ESR (mm/h) | 0–29 | 21.1 ± 1.77 | 23.9 ± 2.18 | 17.5 ± 1.56 | 0.7629 | 0.1034 | 0.0144 | 15.1 ± 1.24 | 17.0 ± 1.91 | 13.6 ± 1.28 | 0.9424 | 0.5364 | 0.3387 |
RBC (million/mm3) | 4.7–6.1 | 4.29 ± 0.08 | 4.21 ± 0.08 | 4.33 ± 0.09 | 0.7747 | 0.9388 | 0.5498 | 4.32 ± 0.08 | 4.25 ± 0.08 | 4.37 ± 0.08 | 0.7935 | 0.8946 | 0.5129 |
WBC (/mm3) | 4500-10,000 | 7979 ± 234 | 8248 ± 222 | 7795 ± 249 | 0.7020 | 0.8483 | 0.3523 | 7984 ± 204 | 7981 ± 209 | 7769 ± 204 | 1.0000 | 0.7706 | 0.7639 |
Platelet count (x100000/mm3) | 1.5-4.5 | 2.77 ± 0.08 | 2.84 ± 0.08 | 2.78 ± 0.08 | 0.7837 | 0.9946 | 0.8319 | 2.77 ± 0.07 | 2.84 ± 0.07 | 2.77 ± 0.09 | 0.8304 | 0.9993 | 0.8113 |
Liver Function | |||||||||||||
Albumin (gm/dL) | 3.5–5.5 | 3.98 ± 0.06 | 4.02 ± 0.06 | 3.94 ± 0.06 | 0.8957 | 0.9089 | 0.6503 | 4.00 ± 0.05 | 4.03 ± 0.05 | 3.96 ± 0.04 | 0.8931 | 0.8902 | 0.6292 |
ALP (IU/L) | 44–147 | 117 ± 5.74 | 118 ± 5.84 | 115 ± 5.57 | 0.9871 | 0.9838 | 0.9404 | 123 ± 5.72 | 116 ± 5.49 | 115 ± 5.59 | 0.5622 | 0.4847 | 0.9890 |
SGOT (U/L) | 10–34 | 25.2 ± 0.93 | 24.0 ± 0.97 | 24.4 ± 0.60 | 0.5778 | 0.7796 | 0.9421 | 24.6 ± 0.73 | 23.9 ± 0.81 | 23.9 ± 0.65 | 0.7711 | 0.7930 | 0.9995 |
SGPT (U/L) | 5–35 | 25.9 ± 1.23 | 25.0 ± 1.40 | 24.1 ± 0.95 | 0.5977 | 0.6004 | 1.0000 | 24.5 ± 0.94 | 24.3 ± 1.00 | 23.3 ± 0.99 | 0.9688 | 0.7119 | 0.8427 |
Total bilirubin (mg/dL) | 0.3–1.9 | 0.78 ± 0.08 | 0.69 ± 0.03 | 0.72 ± 0.03 | 0.5376 | 0.9424 | 0.7343 | 0.72 ± 0.03 | 0.67 ± 0.03 | 0.78 ± 0.04 | 0.4243 | 0.6098 | 0.0718 |
Cardiac Function | |||||||||||||
Systolic BP (mm Hg) | <120 | 125 ± 1.28 | 127 ± 1.35 | 127 ± 1.21 | 0.5980 | 0.7320 | 0.9752 | 127 ± 1.18 | 125 ± 1.33 | 128 ± 1.22 | 0.7263 | 0.8949 | 0.4409 |
Diastolic BP (mm Hg) | < 80 | 81.2 ± 1.19 | 80.2 ± 0.83 | 81.7 ± 1.02 | 0.7544 | 0.9283 | 0.5094 | 80.2 ± 1.03 | 80.5 ± 1.07 | 78.9 ± 0.96 | 0.9877 | 0.6233 | 0.5180 |
Pulse rate (beats/min) | 60–100 | 80.0 ± 0.92 | 79.6 ± 0.98 | 80.3 ± 0.99 | 0.9149 | 0.9719 | 0.7956 | 80.0 ± 0.89 | 78.2 ± 0.82 | 79.2 ± 1.03 | 0.3201 | 0.8018 | 0.6989 |
Renal Function | |||||||||||||
Creatinine (mg/dL) | 0.6–1.3 | 1.00 ± 0.03 | 1.01 ± 0.04 | 0.96 ± 0.03 | 0.9995 | 0.5767 | 0.5778 | 0.96 ± 0.03 | 0.95 ± 0.02 | 0.96 ± 0.02 | 0.9904 | 0.9846 | 0.9508 |
BUN (mg/dL) | 6–24 | 18.1 ± 1.08 | 18.0 ± 1.11 | 18.0 ± 1.15 | 0.9929 | 0.9878 | 0.9992 | 18.6 ± 1.11 | 17.8 ± 1.09 | 17.9 ± 1.02 | 0.7602 | 0.7953 | 0.9985 |
Study group | |||
---|---|---|---|
Placebo (n = 58) | GC (n = 65) | UCII (n = 63) | |
Severity | |||
Mild | 7 | 21 | 5 |
Moderate | 2 | 7 | 3 |
Severe | 0 | 0 | 0 |
Relationship to Test Article | |||
Not related | 8 | 14 | 8 |
Possible | 1 | 13 | 0 |
Definite | 0 | 1 | 0 |
Body System and AEs | |||
Gastrointestinal | |||
Acidity | 2 | 3 | 2 |
Acute peptic disorder | 1 | 0 | 1 |
Diarrhea | 1 | 1 | 0 |
Epigastric burning | 0 | 1 | 0 |
Febrile Enteritis | 0 | 1 | 0 |
Heart burn | 0 | 1 | 0 |
Vomiting | 0 | 1 | 0 |
Nausea | 0 | 1 | 0 |
Pain | |||
Arthralgia | 0 | 1 | 0 |
Body pain | 0 | 1 | 0 |
Low back pain | 1 | 1 | 0 |
Neck Pain | 0 | 1 | 1 |
Headache | 2 | 4 | 0 |
Myalgia | 0 | 1 | 0 |
Dermatology | |||
Itching | 0 | 2 | 0 |
Xerotic skin | 0 | 0 | 1 |
Pulmonary/Upper Respiratory | |||
Lower respiratory tract infection | 0 | 0 | 2 |
Upper respiratory tract infection | 0 | 1 | 0 |
Cough | 0 | 2 | 0 |
Genitourinary | |||
Burning micturition | 1 | 0 | 0 |
Burning sensation | 0 | 0 | 1 |
Cardiovascular | |||
Palpitation | 0 | 2 | 0 |
Constitutional Symptoms | |||
Fever | 1 | 2 | 0 |
Insomnia | 0 | 1 | 0 |
Total Number of Adverse Events Experienced During Study | 9 | 28 | 8 |
Total Number of Subjects Experiencing Adverse Events: n (%) | 7/58 (12 %) | 20/65 (31 %) | 8/63 (13 %) |