To Determine the Safety, Tolerability, Pharmacokinetics and Effect on Pain of a Single Intra-articular Administration of Canakinumab in Patients With Osteoarthritis in the Knee

• Part A: Number of Participants With Intolerance Events [ Time Frame: Baseline to Day 3 ] [ Designated as safety issue: Yes ]
  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) [ Time Frame: Baseline and Day 4 ] [ Designated as safety issue: No ]

  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 [ Time Frame: Baseline and Week 4 ] [ Designated as safety issue: No ]

  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.

• Part B: To evaluate clinical benefit in subjects with knee OA measured by change in pain using 100 mm VAS scale and the WOMAC pain subscale of a single administration of ACZ885 (i.a.) in comparison to placebo. [ Time Frame: (VAS)Baseline to day 4, (WOMAC)Baseline to wk. 4 ] [ Designated as safety issue: Yes ]
• Part A: To determine the safety and tolerability of single ascending doses of an intra-articular administration of ACZ885 in subjects with osteoarthritis in the knee. [ Time Frame: Baseline to wk. 4 ] [ Designated as safety issue: Yes ]

• Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]

  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) [ Time Frame: Baseline, Day 4, Weeks 1, 2, 4, 8 and 12 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Baseline and Weeks 4, 8 and 12 ] [ Designated as safety issue: No ]

  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 [ Time Frame: Day 4, Weeks 1, 2, 4, 8 and 12 ] [ Designated as safety issue: Yes ]
  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 on Day 4 [ Time Frame: Day 4 ] [ Designated as safety issue: No ]
  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 2 [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Day 4 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Week 8 ] [ Designated as safety issue: No ]
  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 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
  The study physician made a global assessment of response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
• 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. ] [ Designated as safety issue: No ]
• 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. ] [ Designated as safety issue: No ]
• 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. ] [ Designated as safety issue: No ]
• 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. ] [ Designated as safety issue: No ]
• Terminal Phase Half-life (t1/2) of Canakinumab [ 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. ] [ Designated as safety issue: No ]
  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) [ 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. ] [ Designated as safety issue: No ]
• 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. ] [ Designated as safety issue: No ]

• To estimate the percentage of responders at each post baseline visit in the pain 100 mm VAS scale as achievement of > or = 50% reduction from baseline [ Time Frame: baseline to wk. 4 ] [ Designated as safety issue: Yes ]
• To characterize the amount of rescue analgesic used and time to analgesic reintroduction [ Time Frame: baseline to wk. 4 ] [ Designated as safety issue: Yes ]
• To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profiling of ACZ885 and assess the PK / PD relationships following intra-articular administration. [ Time Frame: baseline to wk. 4 ] [ Designated as safety issue: Yes ]
• To evaluate the clinical benefit in subjects with osteoarthritis in the knee, as measured by the change in the pain by using VAS score and in the WOMAC pain subscale [ Time Frame: Baseline to wk. 4 ] [ Designated as safety issue: Yes ]

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.

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.

• Biological: Canakinumab
  Intra-articular injection
  Other Name: ACZ885
• Drug: Placebo to canakinumab
  Intra-articular injection
• Drug: Naproxen
  Tablets for oral administration
• Drug: Placebo to Naproxen
  Tablets for oral administration

• Experimental: Part A: Canakinumab
  In this ascending dose part, participants received a single intra-articular injection of canakinumab. The beginning dose was 150 mg, escalating to the 300 mg dose and then to 600 mg.
  Intervention: Biological: Canakinumab
• Placebo Comparator: Part A: Placebo
  Participants received a single intra-articular injection of canakinumab-matching placebo.
  Intervention: Drug: Placebo to canakinumab
• Experimental: Part B: Canakinumab
  Participants received a single intra-articular injection of canakinumab on Day 1 and naproxen matching placebo tablets orally twice daily for 12 weeks.
  Interventions:

  • Biological: Canakinumab
  • Drug: Placebo to Naproxen
• Placebo Comparator: 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.
  Interventions:

  • Drug: Placebo to canakinumab
  • Drug: Placebo to Naproxen
• Active Comparator: 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.
  Interventions:

  • Drug: Placebo to canakinumab
  • Drug: Naproxen

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/exclusion criteria may apply.