Osteoarthritis
Conditions
Keywords
Osteo arthritis, pain control, intra- articular injections, Knee OA
Brief summary
The purpose of this study was to determine whether, in patients with mild to moderate knee osteoarthritis, canakinumab is safe and tolerable when injected intra-articularly.
Detailed description
This is a randomized, double-blind, parallel group, placebo controlled 18 weeks study, consisting of two parts: 1. Part A: an ascending single dose part in which the safety and tolerability of up to 4 different canakinumab doses are studied (starting dose 150 mg, maximum dose 600 mg). 2. Part B: a double-dummy, active-controlled, parallel design part in which the pain reduction of the canakinumab dose selected from part A is studied in comparison to Placebo and Naproxen.
Interventions
BIOLOGICALCanakinumab
Intra-articular injection
Intra-articular injection
DRUGNaproxen
Tablets for oral administration
DRUGPlacebo to Naproxen
Tablets for oral administration
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Written informed consent must be obtained before any assessment is performed. 2. Male and female patients aged 40 - 80 years (inclusive). 3. Diagnosis of knee osteoarthritis 4. Radiographic evidence of tibiofemoral compartment osteoarthritis 5. Pain in the knee during the last 24 hours.The patients should also have had pain in the affected knee on most days over the last month. 6. Patients who are willing to discontinue all non-steroidal anti-inflammatory drugs (NSAIDs) or other analgesic medication taken for any condition, including their knee pain, 7. Patients who are on stable dose of opioids for at least 1 month before screening can continue to take their opioid at this stable dose throughout the study. 8. Patients must also be willing to abstain from any intra-articular or peri-articular injections to the knee or surgery during the treatment period 9. Patients who, if they are currently taking aspirin (325 mg/day or less; as anti-coagulants), are willing to remain on a stable dose one month prior to screening and throughout the study
Exclusion criteria
1. Subjects with known hypersensitivity to any biological or investigational drugs. 2. Patients with contraindications to knee injections 3. Patients with joint effusion 4. Patients should not have rheumatoid arthritis or any connective tissue like disease 5. Secondary osteoarthritis with history and/or any evidence of the following diseases: septic arthritis, inflammatory joint disease, gout, Paget's disease of the bone, articular fracture, major dysplasias or congenital abnormality, ochronosis, acromegaly, hemochromatosis, Wilson's disease, primary osteochondromatosis, juvenile chronic arthritis with continued activity in adulthood, heritable disorders (e.g. hypermobility). Patients with secondary osteoarthritis following menisectomy or injuries of a collateral or cruciate ligament are not excluded. 6. Presence or history of underlying metabolic, endocrine, hematologic, pulmonary, cardiac, blood, renal, hepatic, infectious, psychiatric or gastrointestinal conditions 7. Evidence of tuberculosis (TB) 8. One of the risk factors for TB such as: 1. Substance abuse (e.g. injection or non-injection) 2. Health-care workers with unprotected exposure to patients who are at high risk of TB 3. Patients with TB disease before the identification and correct airborne precautions of the patient 4. close contact (i.e. share the same air space in a household or other enclosed environment for a prolonged period (days or weeks, not minutes or hours)) with a person with active pulmonary TB disease. 9. Significant medical problems, including but not limited to the following: uncontrolled hypertension,congestive heart failure, uncontrolled diabetes type I and II 10. Subjects with evidence of hepatic or blood coagulation disorders (i.e. hemophilia, etc), anemia, idiopathic thrombocytopenic purpura, or gastrointestinal disorder: severe hepatic disease, history of alcohol and drug abuse; disease of gall bladder and pancreas; active peptic ulceration, gastrointestinal bleeding or history of severe gastro-esophageal reflux disease or severe hiatus hernia; inflammatory bowel disease. 11. Use of any therapeutic protein drug (e.g. anti-tumor necrosis factor alpha (TNFα) antibody) 12. Presence of severe renal function impairment. History of renal trauma, glomerulonephritis, patients with one kidney, or renal failure requiring regular dialysis treatment. 13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive pregnancy test (serum or urine). 14. Subjects with known contra-indications to naproxen (e.g. heart or circulation problems, history of ulcer disease etc.), analgesics, antipyretics, or NSAIDs. 15. Disease of the spine or other lower extremity joints which may interfere with the assessment of the target joint. 16. Surgery on the knee within the last year. Observational arthroscopy, arthroscopic surgery or lavage of the knee within the last 6 months. 17. Use of assistive devices other than a cane (walking stick) or knee brace. 18. Subjects who have experienced, any time in the past, asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria or other allergic-type reaction after taking acetylsalicylic acid (ASA)/ aspirin or NSAIDs. 19. Any history of prior peptic ulcer disease or prior NSAID gastrointestinal complications for the past 5 years. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Intolerance Events | Baseline to Day 3 | An intolerance event is defined as an acute inflammatory reaction, characterized by a 30 mm increase in pain (on a 100 mm visual analog scale (VAS) and associated with a new or worsened synovial fluid effusion within 3 days following the intra-articular (i.a.) injection. If baseline VAS pain score is ≥ 70 mm, an intolerance event is defined as an increase in pain by 20 mm on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection. If baseline VAS pain score is ≥ 80 mm, an intolerance event is defined as an increase in pain by 10 mm on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection. If baseline pain score is ≥ 90 mm, an intolerance event is defined as the patients experiencing an unspecified increase in pain on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection. |
| Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS) | Baseline and Day 4 | After walking for 20 meters, participants were asked to assess the pain in their affected knee on a 100 mm linear visual analog scale ranging from no pain (0 mm) to unbearable pain (100 mm). A negative change from Baseline score indicates improvement. Results are from a Bayesian analysis of covariance (ANCOVA) model, fitting baseline pain VAS score as a covariate, time by treatment as fixed effects, region and subject as random effects. |
| Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale | Baseline and Week 4 | The Western Ontario and McMaster osteoarthritis Index (WOMAC) pain subscale asks patients to rate pain in the index knee joint in the last 48 hours doing different activities on a scale from none (0) to extreme pain (4). The answers are summed and the total pain subscale score ranges from 0 to 20, where higher scores indicate more pain. A negative change from Baseline score indicates improvement. Results are from a Bayesian ANCOVA model, fitting baseline WOMAC pain score as a covariate, time by treatment as fixed effects, region and patient as random effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Phase Half-life (t1/2) of Canakinumab | Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126. | The time it takes for the concentration level of canakinumab to fall to 50% of the original value. |
| Apparent Clearance of Canakinumab From Plasma (CL/F) | Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126. | — |
| Apparent Volume of Distribution During Terminal Phase (Vz/F) | Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126. | — |
| Patient's Global Assessment of Response to Treatment on Day 4 | Day 4 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Baseline and Weeks 4, 8 and 12 | After walking for 20 meters, participants were asked to assess the pain in their affected knee on a 100 mm linear visual analog scale ranging from no pain (0 mm) to unbearable pain (100 mm). Results are from a Bayesian ANCOVA model, fitting baseline pain VAS score as a covariate, time by treatment as fixed effects, region and patient as random effects. |
| Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Baseline, Day 4, Weeks 1, 2, 4, 8 and 12 | A responder is defined as a participant with a 50% or greater reduction from baseline on the VAS scale for pain assessment. After walking for 20 meters, participants were asked to assess the pain in their affected knee on a 100 mm linear visual analog scale ranging from no pain (0 mm) to unbearable pain (100 mm). |
| Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Baseline and Weeks 4, 8 and 12 | The WOMAC consists of 3 subscales: The Pain subscale asks patients to rate pain in the index knee joint in the last 48 hours during walking, using stairs, in bed, sitting or lying, and standing on a scale from none (0) to extreme pain (4). The answers are summed and the total pain subscale score ranges from 0-20. The Stiffness subscale assesses stiffness in the index knee joint during the last 48 hours doing different activities on a scale from none (0) to extreme stiffness (4). The total stiffness subscale score ranges from 0-8. The Physical Function subscale assesses difficulty performing daily physical activities during the last 48 hours on a scale from none (0) to extreme difficulty (4). The total physical function subscale score ranges from 0-68. Higher scores indicate more pain/stiffness/difficulty. Results are from a Bayesian ANCOVA model, with baseline WOMAC score as a covariate, time by treatment as fixed effects, region and patient as random effects. |
| Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Day 4, Weeks 1, 2, 4, 8 and 12 | Participants were permitted to take oral rescue medication (Acetaminophen ≤ 4 gram/day) up until 24 hours of a scheduled assessment visit during the 12-week treatment period. The estimates shown are the Kaplan-Meier estimates of the proportion of participants that took rescue medication. |
| Patient's Global Assessment of Response to Treatment at Week 2 | Week 2 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Patient's Global Assessment of Response to Treatment at Week 4 | Week 4 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Patient's Global Assessment of Response to Treatment at Week 8 | Week 8 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Patient's Global Assessment of Response to Treatment at Week 12 | Week 12 | Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Day 4 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Week 2 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Week 4 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Week 8 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Week 12 | The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor. |
| Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax) | Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126. | — |
| Maximum Observed Plasma Concentration of Canakinumab (Cmax) | Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126. | — |
| Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast) | Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126. | — |
| Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf) | Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126. | — |
Countries
Finland, France, Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Canakinumab 150 mg Participants received a single intra-articular injection of 150 mg canakinumab. | 6 |
| Part A: Canakinumab 300 mg Participants received a single intra-articular injection of 300 mg canakinumab. | 7 |
| Part A: Canakinumab 600 mg Participants received a single intra-articular injection of 600 mg canakinumab. | 6 |
| Part A: Placebo Participants received a single intra-articular injection of canakinumab-matching placebo. | 5 |
| Part B: Canakinumab Participants received a single intra-articular injection of 600 mg canakinumab on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks. | 45 |
| Part B: Placebo Participants received a single intra-articular injection of canakinumab matching placebo on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks. | 47 |
| Part B: Naproxen Participants received a single intra-articular injection of canakinumab matching placebo on Day 1 and naproxen 500mg tablets orally twice daily for 12 weeks. | 53 |
| Total | 169 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Administrative problems | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 2 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Protocol deviation | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 0 | 0 | 0 | 4 | 5 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part A: Canakinumab 150 mg | Part A: Canakinumab 300 mg | Part A: Canakinumab 600 mg | Part A: Placebo | Part B: Canakinumab | Part B: Placebo | Part B: Naproxen | Total |
|---|---|---|---|---|---|---|---|---|
| Age Continuous | 58.3 years STANDARD_DEVIATION 12.79 | 61.0 years STANDARD_DEVIATION 9.63 | 64.2 years STANDARD_DEVIATION 10.68 | 57.8 years STANDARD_DEVIATION 7.76 | NA years | NA years | NA years | 60.5 years STANDARD_DEVIATION 10.07 |
| Age, Customized | NA years | NA years | NA years | NA years | 61.4 years STANDARD_DEVIATION 8.96 | 60.3 years STANDARD_DEVIATION 9.71 | 62.2 years STANDARD_DEVIATION 8.1 | 61.3 years STANDARD_DEVIATION 8.89 |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 2 Participants | 2 Participants | 31 Participants | 31 Participants | 34 Participants | 107 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 14 Participants | 16 Participants | 19 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 4 / 7 | 3 / 6 | 3 / 5 | 17 / 45 | 25 / 47 | 26 / 53 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 | 1 / 6 | 1 / 5 | 0 / 45 | 4 / 47 | 4 / 53 |
Outcome results
Primary
Part A: Number of Participants With Intolerance Events
An intolerance event is defined as an acute inflammatory reaction, characterized by a 30 mm increase in pain (on a 100 mm visual analog scale (VAS) and associated with a new or worsened synovial fluid effusion within 3 days following the intra-articular (i.a.) injection. If baseline VAS pain score is ≥ 70 mm, an intolerance event is defined as an increase in pain by 20 mm on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection. If baseline VAS pain score is ≥ 80 mm, an intolerance event is defined as an increase in pain by 10 mm on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection. If baseline pain score is ≥ 90 mm, an intolerance event is defined as the patients experiencing an unspecified increase in pain on a 100 mm VAS associated with new or worsened synovial fluid effusion within 3 days following the i.a. injection.
Time frame: Baseline to Day 3
Population: Safety analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Canakinumab 150 mg | Part A: Number of Participants With Intolerance Events | 0 participants |
| Part A: Canakinumab 300 mg | Part A: Number of Participants With Intolerance Events | 0 participants |
| Part A: Canakinumab 600 mg | Part A: Number of Participants With Intolerance Events | 0 participants |
| Part A: Placebo | Part A: Number of Participants With Intolerance Events | 0 participants |
Primary
Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS)
After walking for 20 meters, participants were asked to assess the pain in their affected knee on a 100 mm linear visual analog scale ranging from no pain (0 mm) to unbearable pain (100 mm). A negative change from Baseline score indicates improvement. Results are from a Bayesian analysis of covariance (ANCOVA) model, fitting baseline pain VAS score as a covariate, time by treatment as fixed effects, region and subject as random effects.
Time frame: Baseline and Day 4
Population: Pharmacodynamic (PD) analysis set - Patients with any available PD data and no major protocol deviations with impact on PD data, and where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS) | -26.7 units on a scale | Standard Deviation 4.05 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS) | -26.5 units on a scale | Standard Deviation 3.97 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS) | -27.6 units on a scale | Standard Deviation 3.82 |
Primary
Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale
The Western Ontario and McMaster osteoarthritis Index (WOMAC) pain subscale asks patients to rate pain in the index knee joint in the last 48 hours doing different activities on a scale from none (0) to extreme pain (4). The answers are summed and the total pain subscale score ranges from 0 to 20, where higher scores indicate more pain. A negative change from Baseline score indicates improvement. Results are from a Bayesian ANCOVA model, fitting baseline WOMAC pain score as a covariate, time by treatment as fixed effects, region and patient as random effects.
Time frame: Baseline and Week 4
Population: Pharmacodynamic (PD) analysis set - Patients with any available PD data and no major protocol deviations with impact on PD data, and where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale | -3.5 units on a scale | Standard Deviation 0.71 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale | -4.0 units on a scale | Standard Deviation 0.68 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale | -4.5 units on a scale | Standard Deviation 0.65 |
Secondary
Apparent Clearance of Canakinumab From Plasma (CL/F)
Time frame: Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.
Population: Pharmacokinetic analysis set, where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Apparent Clearance of Canakinumab From Plasma (CL/F) | 9.58 mL/hr | Standard Deviation 3.08 |
| Part A: Canakinumab 300 mg | Apparent Clearance of Canakinumab From Plasma (CL/F) | 9.66 mL/hr | Standard Deviation 2.03 |
| Part A: Canakinumab 600 mg | Apparent Clearance of Canakinumab From Plasma (CL/F) | 13.3 mL/hr | Standard Deviation 4.27 |
| Part A: Placebo | Apparent Clearance of Canakinumab From Plasma (CL/F) | 8.65 mL/hr | Standard Deviation 3.02 |
Secondary
Apparent Volume of Distribution During Terminal Phase (Vz/F)
Time frame: Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.
Population: Pharmacokinetic analysis set, where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Apparent Volume of Distribution During Terminal Phase (Vz/F) | 7320 mL | Standard Deviation 1870 |
| Part A: Canakinumab 300 mg | Apparent Volume of Distribution During Terminal Phase (Vz/F) | 8060 mL | Standard Deviation 2830 |
| Part A: Canakinumab 600 mg | Apparent Volume of Distribution During Terminal Phase (Vz/F) | 8930 mL | Standard Deviation 3000 |
| Part A: Placebo | Apparent Volume of Distribution During Terminal Phase (Vz/F) | 8910 mL | Standard Deviation 4070 |
Secondary
Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf)
Time frame: Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.
Population: Pharmacokinetic analysis set where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf) | 16900 µg*day/mL | Standard Deviation 4780 |
| Part A: Canakinumab 300 mg | Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf) | 32400 µg*day/mL | Standard Deviation 8010 |
| Part A: Canakinumab 600 mg | Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf) | 49300 µg*day/mL | Standard Deviation 16100 |
| Part A: Placebo | Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf) | 78300 µg*day/mL | Standard Deviation 28000 |
Secondary
Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast)
Time frame: Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.
Population: Pharmacokinetic analysis set where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast) | 16900 µg*day/mL | Standard Deviation 4430 |
| Part A: Canakinumab 300 mg | Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast) | 30700 µg*day/mL | Standard Deviation 8380 |
| Part A: Canakinumab 600 mg | Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast) | 56100 µg*day/mL | Standard Deviation 23900 |
| Part A: Placebo | Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast) | 71900 µg*day/mL | Standard Deviation 23800 |
Secondary
Maximum Observed Plasma Concentration of Canakinumab (Cmax)
Time frame: Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.
Population: Pharmacokinetic analysis set where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Maximum Observed Plasma Concentration of Canakinumab (Cmax) | 23.0 µg/mL | Standard Deviation 8.54 |
| Part A: Canakinumab 300 mg | Maximum Observed Plasma Concentration of Canakinumab (Cmax) | 34.8 µg/mL | Standard Deviation 11.3 |
| Part A: Canakinumab 600 mg | Maximum Observed Plasma Concentration of Canakinumab (Cmax) | 65.5 µg/mL | Standard Deviation 14.5 |
| Part A: Placebo | Maximum Observed Plasma Concentration of Canakinumab (Cmax) | 77.8 µg/mL | Standard Deviation 22.8 |
Secondary
Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS)
After walking for 20 meters, participants were asked to assess the pain in their affected knee on a 100 mm linear visual analog scale ranging from no pain (0 mm) to unbearable pain (100 mm). Results are from a Bayesian ANCOVA model, fitting baseline pain VAS score as a covariate, time by treatment as fixed effects, region and patient as random effects.
Time frame: Baseline and Weeks 4, 8 and 12
Population: Pharmacodynamic (PD) analysis set - Patients with any available PD data and no major protocol deviations with impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 8 | -26.2 units on a scale | Standard Deviation 4.12 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 4 | -25.6 units on a scale | Standard Deviation 4.03 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 12 | -25.1 units on a scale | Standard Deviation 4.14 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 8 | -30.9 units on a scale | Standard Deviation 4.06 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 4 | -31.1 units on a scale | Standard Deviation 4.03 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 12 | -32.1 units on a scale | Standard Deviation 4.06 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 4 | -36.1 units on a scale | Standard Deviation 3.84 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 12 | -27.8 units on a scale | Standard Deviation 3.94 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) | Week 8 | -33.0 units on a scale | Standard Deviation 3.89 |
Secondary
Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales
The WOMAC consists of 3 subscales: The Pain subscale asks patients to rate pain in the index knee joint in the last 48 hours during walking, using stairs, in bed, sitting or lying, and standing on a scale from none (0) to extreme pain (4). The answers are summed and the total pain subscale score ranges from 0-20. The Stiffness subscale assesses stiffness in the index knee joint during the last 48 hours doing different activities on a scale from none (0) to extreme stiffness (4). The total stiffness subscale score ranges from 0-8. The Physical Function subscale assesses difficulty performing daily physical activities during the last 48 hours on a scale from none (0) to extreme difficulty (4). The total physical function subscale score ranges from 0-68. Higher scores indicate more pain/stiffness/difficulty. Results are from a Bayesian ANCOVA model, with baseline WOMAC score as a covariate, time by treatment as fixed effects, region and patient as random effects.
Time frame: Baseline and Weeks 4, 8 and 12
Population: Pharmacodynamic (PD) analysis set - Patients with any available PD data and no major protocol deviations with impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 12 [N= 33, 36, 39] | -13.4 units on a scale | Standard Deviation 2.01 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 8 | -1.3 units on a scale | Standard Deviation 0.37 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 8 [N=35, 36, 41] | -13.7 units on a scale | Standard Deviation 1.97 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Pain at Week 8 | -3.7 units on a scale | Standard Deviation 0.72 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 12 | -1.1 units on a scale | Standard Deviation 0.37 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 4 | -1.3 units on a scale | Standard Deviation 0.36 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Pain at Week 12 | -3.2 units on a scale | Standard Deviation 0.72 |
| Part A: Canakinumab 150 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 4 [N=38, 39, 43] | -14.1 units on a scale | Standard Deviation 1.93 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 4 | -1.5 units on a scale | Standard Deviation 0.36 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Pain at Week 12 | -4.5 units on a scale | Standard Deviation 0.69 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 8 [N=35, 36, 41] | -14.9 units on a scale | Standard Deviation 1.94 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Pain at Week 8 | -4.2 units on a scale | Standard Deviation 0.69 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 12 [N= 33, 36, 39] | -16.5 units on a scale | Standard Deviation 1.96 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 4 [N=38, 39, 43] | -15.9 units on a scale | Standard Deviation 1.93 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 8 | -1.5 units on a scale | Standard Deviation 0.36 |
| Part A: Canakinumab 300 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 12 | -1.7 units on a scale | Standard Deviation 0.37 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 12 [N= 33, 36, 39] | -14.4 units on a scale | Standard Deviation 1.8 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Pain at Week 8 | -4.6 units on a scale | Standard Deviation 0.66 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Pain at Week 12 | -4.0 units on a scale | Standard Deviation 0.66 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 8 | -2.0 units on a scale | Standard Deviation 0.35 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 12 | -1.4 units on a scale | Standard Deviation 0.35 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 4 [N=38, 39, 43] | -16.2 units on a scale | Standard Deviation 1.76 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Function at Week 8 [N=35, 36, 41] | -16.1 units on a scale | Standard Deviation 1.77 |
| Part A: Canakinumab 600 mg | Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales | Stiffness at Week 4 | -1.9 units on a scale | Standard Deviation 0.34 |
Secondary
Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS)
A responder is defined as a participant with a 50% or greater reduction from baseline on the VAS scale for pain assessment. After walking for 20 meters, participants were asked to assess the pain in their affected knee on a 100 mm linear visual analog scale ranging from no pain (0 mm) to unbearable pain (100 mm).
Time frame: Baseline, Day 4, Weeks 1, 2, 4, 8 and 12
Population: Pharmacodynamic (PD) analysis set - Patients with any available PD data and no major protocol deviations with impact on PD data. N is the number of participants with available data at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Day 4 [N=42, 44, 48] | 50.0 percentage of participants |
| Part A: Canakinumab 150 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 8 [N=36, 38, 43] | 52.8 percentage of participants |
| Part A: Canakinumab 150 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 2 [N=41, 44, 48] | 46.3 percentage of participants |
| Part A: Canakinumab 150 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 4 [N=39, 40, 46] | 51.3 percentage of participants |
| Part A: Canakinumab 150 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 12 [N=35, 37, 41] | 48.6 percentage of participants |
| Part A: Canakinumab 150 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 1 [N=42, 44, 48] | 40.5 percentage of participants |
| Part A: Canakinumab 300 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 2 [N=41, 44, 48] | 43.2 percentage of participants |
| Part A: Canakinumab 300 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 4 [N=39, 40, 46] | 55.0 percentage of participants |
| Part A: Canakinumab 300 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Day 4 [N=42, 44, 48] | 43.2 percentage of participants |
| Part A: Canakinumab 300 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 1 [N=42, 44, 48] | 45.5 percentage of participants |
| Part A: Canakinumab 300 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 8 [N=36, 38, 43] | 50.0 percentage of participants |
| Part A: Canakinumab 300 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 12 [N=35, 37, 41] | 51.4 percentage of participants |
| Part A: Canakinumab 600 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 1 [N=42, 44, 48] | 56.3 percentage of participants |
| Part A: Canakinumab 600 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 12 [N=35, 37, 41] | 53.7 percentage of participants |
| Part A: Canakinumab 600 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 8 [N=36, 38, 43] | 55.8 percentage of participants |
| Part A: Canakinumab 600 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Day 4 [N=42, 44, 48] | 47.9 percentage of participants |
| Part A: Canakinumab 600 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 2 [N=41, 44, 48] | 62.5 percentage of participants |
| Part A: Canakinumab 600 mg | Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS) | Week 4 [N=39, 40, 46] | 71.7 percentage of participants |
Secondary
Part B: Physician's Global Assessment of Response to Treatment at Day 4
The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Day 4
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Poor | 4 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Acceptable | 16 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Excellent | 8 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Good | 11 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Very poor | 3 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Acceptable | 14 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Excellent | 7 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Good | 18 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Poor | 3 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Very poor | 2 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Very poor | 1 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Poor | 7 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Excellent | 6 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Acceptable | 13 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Day 4 | Good | 21 participants |
Secondary
Part B: Physician's Global Assessment of Response to Treatment at Week 12
The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 12
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Excellent | 5 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Poor | 9 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Acceptable | 6 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Very poor | 2 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Good | 13 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Poor | 2 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Excellent | 7 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Good | 16 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Acceptable | 12 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Very poor | 0 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Good | 15 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Poor | 7 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Excellent | 10 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Very poor | 1 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 12 | Acceptable | 8 participants |
Secondary
Part B: Physician's Global Assessment of Response to Treatment at Week 2
The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 2
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Poor | 6 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Acceptable | 10 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Excellent | 7 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Good | 15 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Very poor | 2 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Acceptable | 13 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Excellent | 5 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Good | 20 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Poor | 4 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Very poor | 2 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Very poor | 0 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Poor | 4 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Excellent | 15 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Acceptable | 9 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 2 | Good | 20 participants |
Secondary
Part B: Physician's Global Assessment of Response to Treatment at Week 4
The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 4
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Poor | 5 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Very poor | 1 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Acceptable | 14 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Good | 15 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Excellent | 4 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Excellent | 5 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Acceptable | 11 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Good | 20 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Very poor | 1 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Poor | 3 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Very poor | 0 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Excellent | 9 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Good | 21 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Acceptable | 12 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 4 | Poor | 4 participants |
Secondary
Part B: Physician's Global Assessment of Response to Treatment at Week 8
The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 8
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Poor | 7 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Acceptable | 10 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Excellent | 5 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Good | 13 participants |
| Part A: Canakinumab 150 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Very poor | 1 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Acceptable | 11 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Excellent | 3 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Good | 22 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Poor | 2 participants |
| Part A: Canakinumab 300 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Very poor | 0 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Very poor | 0 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Poor | 5 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Excellent | 9 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Acceptable | 13 participants |
| Part A: Canakinumab 600 mg | Part B: Physician's Global Assessment of Response to Treatment at Week 8 | Good | 16 participants |
Secondary
Part B: Proportion of Participants Who Used Rescue Analgesic During Study
Participants were permitted to take oral rescue medication (Acetaminophen ≤ 4 gram/day) up until 24 hours of a scheduled assessment visit during the 12-week treatment period. The estimates shown are the Kaplan-Meier estimates of the proportion of participants that took rescue medication.
Time frame: Day 4, Weeks 1, 2, 4, 8 and 12
Population: Safety analysis set (all participants as assigned that received at least one dose of study drug).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Day 4 | 0.27 proportion of participants |
| Part A: Canakinumab 150 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 1 | 0.45 proportion of participants |
| Part A: Canakinumab 150 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 2 | 0.52 proportion of participants |
| Part A: Canakinumab 150 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 4 | 0.55 proportion of participants |
| Part A: Canakinumab 150 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 8 | 0.57 proportion of participants |
| Part A: Canakinumab 150 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 12 | 0.62 proportion of participants |
| Part A: Canakinumab 300 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 12 | 0.75 proportion of participants |
| Part A: Canakinumab 300 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Day 4 | 0.30 proportion of participants |
| Part A: Canakinumab 300 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 4 | 0.60 proportion of participants |
| Part A: Canakinumab 300 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 8 | 0.69 proportion of participants |
| Part A: Canakinumab 300 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 1 | 0.47 proportion of participants |
| Part A: Canakinumab 300 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 2 | 0.57 proportion of participants |
| Part A: Canakinumab 600 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 1 | 0.23 proportion of participants |
| Part A: Canakinumab 600 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 2 | 0.33 proportion of participants |
| Part A: Canakinumab 600 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 12 | 0.70 proportion of participants |
| Part A: Canakinumab 600 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 4 | 0.43 proportion of participants |
| Part A: Canakinumab 600 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Day 4 | 0.19 proportion of participants |
| Part A: Canakinumab 600 mg | Part B: Proportion of Participants Who Used Rescue Analgesic During Study | Week 8 | 0.59 proportion of participants |
Secondary
Patient's Global Assessment of Response to Treatment at Week 12
Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 12
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Poor | 11 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Acceptable | 7 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Excellent | 4 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Good | 12 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Very poor | 1 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Acceptable | 14 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Excellent | 8 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Good | 13 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Poor | 2 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Very poor | 0 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Very poor | 1 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Poor | 5 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Excellent | 7 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Acceptable | 13 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 12 | Good | 15 participants |
Secondary
Patient's Global Assessment of Response to Treatment at Week 2
Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 2
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Poor | 9 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Acceptable | 13 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Excellent | 5 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Good | 12 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Very poor | 2 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Acceptable | 14 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Excellent | 6 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Good | 16 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Poor | 5 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Very poor | 2 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Very poor | 1 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Poor | 5 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Excellent | 11 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Acceptable | 12 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 2 | Good | 19 participants |
Secondary
Patient's Global Assessment of Response to Treatment at Week 4
Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 4
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Poor | 8 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Acceptable | 10 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Excellent | 5 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Good | 15 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Very poor | 1 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Acceptable | 10 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Excellent | 6 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Good | 16 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Poor | 6 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Very poor | 2 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Very poor | 2 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Poor | 4 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Excellent | 9 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Acceptable | 13 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 4 | Good | 18 participants |
Secondary
Patient's Global Assessment of Response to Treatment at Week 8
Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Week 8
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Poor | 9 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Acceptable | 11 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Excellent | 5 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Good | 9 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Very poor | 2 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Acceptable | 8 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Excellent | 5 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Good | 19 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Poor | 5 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Very poor | 1 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Very poor | 1 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Poor | 5 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Excellent | 10 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Acceptable | 9 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment at Week 8 | Good | 18 participants |
Secondary
Patient's Global Assessment of Response to Treatment on Day 4
Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
Time frame: Day 4
Population: Pharmacodynamic analysis set, where data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Poor | 5 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Acceptable | 11 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Excellent | 6 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Good | 14 participants |
| Part A: Canakinumab 150 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Very poor | 6 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Acceptable | 13 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Excellent | 8 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Good | 16 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Poor | 5 participants |
| Part A: Canakinumab 300 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Very poor | 2 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Very poor | 2 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Poor | 6 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Excellent | 4 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Acceptable | 16 participants |
| Part A: Canakinumab 600 mg | Patient's Global Assessment of Response to Treatment on Day 4 | Good | 20 participants |
Secondary
Terminal Phase Half-life (t1/2) of Canakinumab
The time it takes for the concentration level of canakinumab to fall to 50% of the original value.
Time frame: Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.
Population: Pharmacokinetic analysis set where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Canakinumab 150 mg | Terminal Phase Half-life (t1/2) of Canakinumab | 539 hours | Standard Deviation 47.1 |
| Part A: Canakinumab 300 mg | Terminal Phase Half-life (t1/2) of Canakinumab | 578 hours | Standard Deviation 145 |
| Part A: Canakinumab 600 mg | Terminal Phase Half-life (t1/2) of Canakinumab | 474 hours | Standard Deviation 93.6 |
| Part A: Placebo | Terminal Phase Half-life (t1/2) of Canakinumab | 736 hours | Standard Deviation 243 |
Secondary
Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax)
Time frame: Day 1, pre-dose and 1, 3, 6 and 8 hours post-dose (Part A only), Day 2, 4, 8, 15, 29, 57, 85 and 126.
Population: Pharmacokinetic analysis set where data were available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Canakinumab 150 mg | Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax) | 96.2 hours |
| Part A: Canakinumab 300 mg | Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax) | 86.7 hours |
| Part A: Canakinumab 600 mg | Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax) | 144 hours |
| Part A: Placebo | Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax) | 95.9 hours |