Clinical trial NCT01160822: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Osteoarthritis
Keywords: Osteo arthritis
pain control
intra- articular injections
Knee OA
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-07-12
Enrollment: 169
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Part A: Number of Participants With Intolerance Events
timeFrame: Baseline to Day 3
measure: Part B: Change From Baseline to Day 4 in Pain Using 100 mm Visual Analog Scale (VAS)
timeFrame: Baseline and Day 4
measure: Part B: Change From Baseline to Week 4 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) Pain Subscale
timeFrame: Baseline and Week 4
Secondary outcomes:
measure: Part B: Change From Baseline in Pain Using 100 mm Visual Analog Scale (VAS)
timeFrame: Baseline and Weeks 4, 8 and 12
measure: Part B: Percentage of Responders in the Pain 100 mm Visual Analog Scale (VAS)
timeFrame: Baseline, Day 4, Weeks 1, 2, 4, 8 and 12
measure: Part B: Change From Baseline in WOMAC Pain, Stiffness and Physical Function Subscales
timeFrame: Baseline and Weeks 4, 8 and 12
measure: Part B: Proportion of Participants Who Used Rescue Analgesic During Study
timeFrame: Day 4, Weeks 1, 2, 4, 8 and 12
measure: Patient's Global Assessment of Response to Treatment on Day 4
timeFrame: Day 4
measure: Patient's Global Assessment of Response to Treatment at Week 2
timeFrame: Week 2
measure: Patient's Global Assessment of Response to Treatment at Week 4
timeFrame: Week 4
measure: Patient's Global Assessment of Response to Treatment at Week 8
timeFrame: Week 8
measure: Patient's Global Assessment of Response to Treatment at Week 12
timeFrame: Week 12
measure: Part B: Physician's Global Assessment of Response to Treatment at Day 4
timeFrame: Day 4
measure: Part B: Physician's Global Assessment of Response to Treatment at Week 2
timeFrame: Week 2
measure: Part B: Physician's Global Assessment of Response to Treatment at Week 4
timeFrame: Week 4
measure: Part B: Physician's Global Assessment of Response to Treatment at Week 8
timeFrame: Week 8
measure: Part B: Physician's Global Assessment of Response to Treatment at Week 12
timeFrame: Week 12
measure: Maximum Observed Plasma Concentration of Canakinumab (Cmax)
timeFrame: 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.
measure: Time to Reach the Maximum Observed Plasma Concentration of Canakinumab (Tmax)
timeFrame: 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.
measure: Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUClast)
timeFrame: 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.
measure: Area Under the Concentration Time Curve From Time Zero to Infinity AUC(0-inf)
timeFrame: 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.
measure: Terminal Phase Half-life (t1/2) of Canakinumab
timeFrame: 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.
measure: Apparent Clearance of Canakinumab From Plasma (CL/F)
timeFrame: 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.
measure: Apparent Volume of Distribution During Terminal Phase (Vz/F)
timeFrame: 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.
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group, LLC
state: Alabama
city: Mesa
country: United States
facility: Arizona Arthritis & Rheumatology Research, PLLC
state: Arizona
city: San Diego
country: United States
facility: San Diego Arthritis & Osteoporosis Medical Clinic
state: California
city: Westlake Village
country: United States
facility: Westlake Medical Research
state: California
city: Chicago
country: United States
facility: Rush-Presbyterian St. Lukes Medical Center
state: Illinois
city: Topeka
country: United States
facility: Cotton O'Neil Clinical Research Institute
state: Kansas
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Knoxville
country: United States
facility: Volunteer Research Group
state: Tennessee
city: Helsinki
country: Finland
facility: Novartis Investigative site
city: Kuopio
country: Finland
facility: Novartis Investigative site
city: Creteil
country: France
facility: Novartis Investigative site
city: Berlin
country: Germany
facility: Novartis Investigative site
city: Erlangen
country: Germany
facility: Novartis Investigative site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: