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Safety and Efficacy of Intravenous ACZ885 and Oral Methotrexate Therapy in Patients With Early Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT00487825
First received: June 18, 2007
Last updated: July 24, 2012
Last verified: July 2012
  Purpose

This study was intended to evaluate the safety and efficacy of intravenous (IV) ACZ885 and oral methotrexate (MTX) therapy in patients with early rheumatoid arthritis (RA)


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Canakinumab (investigational)
Drug: Placebo
Drug: Methotrexate (MTX)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A 26-week, Phase II, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Assess the Response to Treatment (ACR50) and to Determine a Biomarker Profile in Responders to ACZ885 (Anti-interleukin-1beta Monoclonal Antibody) Plus MTX as Compared to MTX Alone in Early Rheumatoid Arthritis Patients

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Response to Intravenous Canakinumab and Oral Methotrexate (MTX) Compared to MTX Alone as Determined by 50% Improvement in Symptoms According to the American College of Rheumatology Criteria (ACR50) [ Time Frame: 6, 14, and 26 weeks of treatment ] [ Designated as safety issue: No ]

    A patient was considered as improved according to the ACR50 criteria if she/he had at least a 50 % improvement in both the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures:

    • Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm)
    • Patient's global assessment of disease activity (VAS 100 mm)
    • Physician's global assessment of disease activity (VAS 100 mm)
    • Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score)
    • Acute phase reactant (high sensitivity C-reactive Protein (hsCRP))


Secondary Outcome Measures:
  • Response to Intravenous (IV) Canakinumab and Oral Methotrexate (MTX) Therapy (ACR20, 70, 90) Compared to MTX Alone [ Time Frame: At 6 weeks, 14 weeks, and 26 weeks ] [ Designated as safety issue: No ]

    A patient was considered as improved according to the criteria of ACR 20 equaling at least 20%, ACR70 = 70%, and ACR90 = 90% improvement in the tender and the swollen 28-joint count, and in at least 3 of the following 5 measures:

    • Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm)
    • Patient's global assessment of disease activity (VAS 100 mm)
    • Physician's global assessment of disease activity (VAS 100 mm)
    • Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score)
    • Acute phase reactant (high sensitivity C-reactive Protein (hsCRP))

  • Percentage of Participants Achieving a Good European League Against Rheumatism (EULAR) Response (Based on the Disease Activity Score (DAS28)) at 26 Weeks [ Time Frame: At 26 weeks ] [ Designated as safety issue: No ]
    At each visit (including baseline) the DAS28 is derived as: DAS28 = 0.56*√ (tender28) + 0.28 * √ (swollen28) + 0.36 * loge(CRP+1) + 0.014*PGDA+ 0.96; where tender28 is the tender 28-joint count, swollen28 is the swollen 28-joint count, PGDA is the patient's global assessment of disease activity. Patients can be scored on a range of 0 to 10. When current DAS < 3.2, good response is defined as >1.2 improvement in DAS from baseline and non-response is improvement of ≤0.6. When current DAS >5.1, non-response is improvement of >0.6 but ≤1.2 . All others are moderate responses.

  • The Number of Participants in Clinical Remission Based on Disease Activity Score (DAS)28 and Simplified Disease Activity Index (SDAI) [ Time Frame: At 6 weeks, 14 weeks and 24 weeks ] [ Designated as safety issue: No ]

    At each visit (including baseline) the DAS28 and SDAI variables were derived using the following formulas:

    DAS28 = 0.56*√ (tender28) + 0.28 * √ (swollen28) + 0.36 * loge(CRP+1) + 0.014*PGDA+ 0.96; SDAI = tender28 + swollen28 + CRP + (PGDA / 10) + (EGDA / 10) where tender28 is the tender 28-joint count, swollen28 is the swollen 28-joint count, CRP is C-reactive protein, PGDA is the patient's global assessment of disease activity and EGDA is the physician's global assessment of disease activity.

    The Number of Participants in clinical remission is defined as the DAS28 ≤ 2.6 or SDAI ≤ 3.3.



Enrollment: 78
Study Start Date: March 2007
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Canakinumab + Methotrexate
Canakinumab, human anti-interleukin-1beta monoclonal antibody plus Methotrexate (MTX). Intravenous (IV) Infusion of 600mg canakinumab on Day 1, 15 continuing every 4 weeks up to week 26. MTX was given as variable dosing regimen of 7.5 mg-15 mg weekly.
Drug: Canakinumab (investigational)
Canakinumab was supplied in 6 mL colorless glass vials each containing nominally 150 mg canakinumab (with 20% overfill). The vials were kept at 2-8°C. At the investigator's site, solutions for infusion were prepared depending on the volume and dose administered.
Other Name: ACZ885
Drug: Methotrexate (MTX)
Methotrexate (MTX) was supplied in tablet form, each of 2.5 mg strength.
Active Comparator: Methotrexate + placebo
Methotrexate (MTX) was given as variable dosing regimen of 7.5 mg-15 mg weekly. Intravenous (IV) Placebo Solution, given in the same mode of administration as the canakinumab solution.
Drug: Placebo
Matching placebo was supplied in form of a lyophilized cake (Powder for Solution for Infusion). At the investigator's site, solutions for infusion were prepared depending on the volume and dose administered.
Drug: Methotrexate (MTX)
Methotrexate (MTX) was supplied in tablet form, each of 2.5 mg strength.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and female patients of 18 to 75 years of age (inclusive)
  • Recent definite diagnosis of rheumatoid arthritis (RA) (<3 years since diagnosis), classified by American Rheumatism Association 1987 revised criteria.
  • Candidate for methotrexate (MTX) or biologic due to erosive arthritis, with no contraindications to such therapy, including:
  • Negative tuberculin skin test reaction
  • Normal chest X-ray (within the last year) prior to possibility of receiving MTX (r/o lung fibrosis).
  • Active disease: at least 6 swollen and 6 painful tender joints of 28 joint count,
  • Vital signs should be within the following ranges:
  • 18-59 years of age: oral temperature between 35.0-37.5 °C systolic blood pressure, 90-140 mm Hg diastolic blood pressure, 50-90 mm Hg pulse rate, 40 - 90 beats per minute
  • 60-75 years of age: oral temperature between 35.0-37.5 °C systolic blood pressure, 100-160 mm Hg diastolic blood pressure, 50-100 mm Hg pulse rate, 50 - 100 beats per minute
  • Women of child-bearing potential willing to practice double-barrier contraception during the study for at least 3 months following last study drug administration. Postmenopausal women must have no regular menstrual bleeding for at least 1 year prior to inclusion. Surgically sterilized women at least 6 months prior to screening.

Male patients must be using a double-barrier local contraception and refrain from fathering a child in the 3 months following last study drug administration.

  • Weight: at least 45 kg; body mass index (BMI) within the range of 18 to 34.
  • Oral corticosteroids are permitted as long as patients are on a stable dose (up to 10 mg) for at least 4 weeks before study start.

Exclusion Criteria:

  • Unable to have Magnetic Resonance Imaging (MRI) of wrist.
  • Patients with magnetizable metal parts/devices on and in the body that could interfere with the MRI
  • Patients with an unstable active medical condition that could impair evaluation of study results.
  • Previous treatment with biological therapy or MTX.
  • Limited kidney function (creatinine clearance under 60 ml/min)
  • Previous treatment with other disease-modifying anti-rheumatic drugs such as sulfasalazine, hydroxychloroquine within 4 weeks of screening.
  • Corticosteroids injections into joints within 4 weeks prior to screening.
  • Participation in any clinical investigation within 4 weeks prior to study start or longer if required by local regulations, and for any other limitation of participation based on local regulations.
  • Blood donation or loss of > 400 mL within 8 weeks before study start, or longer if required by local regulation.
  • Significant illness within 2 weeks of study start.
  • Past personal or family medical history of clinically significant ECG abnormalities or cardiac issues.
  • History of:

    • fainting, orthostatic hypotension, sinus arrhythmia asthma and chronic obstructive pulmonary disease, clinically significant drug allergy or urticaria, eczematous dermatitis, and/or known hypersensitivity to the study drug or drugs similar to the study drug.
    • disease of the blood building system, serious or active infections, gastric ulcers.
    • surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the patient in case of participation in the study.
    • immunodeficiency diseases, including a positive Human Immunodeficiency Virus (HIV) (ELISA and Western blot) test result.
    • positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result.
    • drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00487825

  Show 22 Study Locations
Sponsors and Collaborators
Novartis
Investigators
Principal Investigator: Novartis Investigative site
  More Information

No publications provided

Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT00487825     History of Changes
Other Study ID Numbers: CACZ885A2204
Study First Received: June 18, 2007
Results First Received: January 24, 2011
Last Updated: July 24, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
ACR20, ACR50, ACZ885 (anti-interleukin-1beta monoclonal antibody), rheumatoid arthritis, methotrexate

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Antibodies, Monoclonal
Methotrexate
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014