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

• ClinicalTrials.gov Identifier: NCT01160822
• Recruitment Status: Completed
• First Posted: July 12, 2010
• Results First Posted: August 30, 2012
• Last Update Posted: October 30, 2012
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Osteoarthritis	Biological: Canakinumab; Drug: Placebo to canakinumab; Drug: Naproxen; Drug: Placebo to Naproxen	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 169 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double Blind, Placebo and Naproxen Controlled, Multi-center, Study 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
• Study Start Date: April 2010
• Actual Primary Completion Date: July 2011
• Actual Study Completion Date: July 2011

Arms and Interventions

Arm	Intervention/treatment
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.	Biological: Canakinumab; Intra-articular injection; Other Name: ACZ885
Placebo Comparator: Part A: Placebo; Participants received a single intra-articular injection of canakinumab-matching placebo.	Drug: Placebo to canakinumab; Intra-articular injection
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.	Biological: Canakinumab; Intra-articular injection; Other Name: ACZ885; Drug: Placebo to Naproxen; Tablets for oral administration
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.	Drug: Placebo to canakinumab; Intra-articular injection; Drug: Placebo to Naproxen; Tablets for oral administration
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.	Drug: Placebo to canakinumab; Intra-articular injection; Drug: Naproxen; Tablets for oral administration

Outcome Measures

Primary Outcome Measures :

1. Part A: Number of Participants With Intolerance Events [ Time Frame: 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.
2. Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS) [ Time Frame: 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.

3. Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale [ Time Frame: 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 Outcome Measures :

1. Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS) [ Time Frame: 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.

2. 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 ]
   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).
3. Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales [ Time Frame: 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.

4. Part B: Proportion of Participants Who Used Rescue Analgesic During Study [ Time Frame: 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.
5. Patient's Global Assessment of Response to Treatment on Day 4 [ Time Frame: Day 4 ]
   Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
6. Patient's Global Assessment of Response to Treatment at Week 2 [ Time Frame: Week 2 ]
   Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
7. Patient's Global Assessment of Response to Treatment at Week 4 [ Time Frame: Week 4 ]
   Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
8. Patient's Global Assessment of Response to Treatment at Week 8 [ Time Frame: Week 8 ]
   Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
9. Patient's Global Assessment of Response to Treatment at Week 12 [ Time Frame: Week 12 ]
   Participants made a global assessment of their response to treatment using a 5-point Likert scale: Excellent, Good, Acceptable, Poor, Very Poor.
10. Part B: Physician's Global Assessment of Response to Treatment at Day 4 [ Time Frame: 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.
11. Part B: Physician's Global Assessment of Response to Treatment at Week 2 [ Time Frame: 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.
12. Part B: Physician's Global Assessment of Response to Treatment at Week 4 [ Time Frame: 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.
13. Part B: Physician's Global Assessment of Response to Treatment at Week 8 [ Time Frame: 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.
14. Part B: Physician's Global Assessment of Response to Treatment at Week 12 [ Time Frame: 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.
15. 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. ]
16. 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. ]
17. 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. ]
18. 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. ]
19. 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. ]
    The time it takes for the concentration level of canakinumab to fall to 50% of the original value.
20. 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. ]
21. 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. ]

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

Pinnacle Research Group, LLC

Anniston, Alabama, United States, 36207

United States, Arizona

Arizona Arthritis & Rheumatology Research, PLLC

Mesa, Arizona, United States, 85202

United States, California

San Diego Arthritis & Osteoporosis Medical Clinic

San Diego, California, United States, 92108

Westlake Medical Research

Westlake Village, California, United States, 91361

United States, Illinois

Rush-Presbyterian St. Lukes Medical Center

Chicago, Illinois, United States, 60612

United States, Kansas

Cotton O'Neil Clinical Research Institute

Topeka, Kansas, United States, 66606

United States, Pennsylvania

Altoona Center for Clinical Research

Duncansville, Pennsylvania, United States, 16635

United States, Tennessee

Volunteer Research Group

Knoxville, Tennessee, United States, 37920

Finland

Novartis Investigative site

Helsinki, Finland

Novartis Investigative site

Kuopio, Finland

France

Novartis Investigative site

Creteil, France

Germany

Novartis Investigative site

Berlin, Germany

Novartis Investigative site

Erlangen, Germany

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01160822
• Other Study ID Numbers: CACZ885C2201; 2009-015017-48 ( EudraCT Number )
• First Posted: July 12, 2010
• Results First Posted: August 30, 2012
• Last Update Posted: October 30, 2012
• Last Verified: September 2012

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Osteo arthritis; pain control; intra- articular injections; Knee OA

Additional relevant MeSH terms:

Osteoarthritis; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Naproxen; Antibodies, Monoclonal; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Gout Suppressants; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunologic Factors