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

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

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)

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Canakinumab (investigational); Drug: Methotrexate (MTX); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Novartis Investigative Site
• Germany
  • Nuernberg, Germany
    • Novartis Investigative Site
• Italy
  • Milan, Italy
    • Novartis Investigative Site
• Netherlands
  • Arnhem, Netherlands
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain
    • Novartis Investigative Site
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Rheumatology Associates of Northern Alabama (Dr. William Shergy)
    • Tuscaloosa, Alabama, United States, 35406
      • Clinic for Rheumatic Diseases (Dr. Richard Jones, III)
  • Arizona
    • Paradise Valley, Arizona, United States, 85253
      • Arizona Arthritis and Rheumatology Research (Dr. Paul Caldron)
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research (Dr. Steven Mathews)
    • South Miami, Florida, United States, 33143
      • Center for Arthritis and Rheumatic Diseases (Dr. Michael Weitz)
    • Tamarac, Florida, United States, 33321
      • West Broward Rheumatology Associates, Incorporated (Dr. Elias Halpert)
  • Illinois
    • Rockford, Illinois, United States, 61107
      • Rockford Orthopedic Associates (Dr. Richard Olson)
  • Iowa
    • Urbandale, Iowa, United States, 50322
      • Mercy Arthritis and Osteoporosis Center (Dr. Alan Braun)
  • Missouri
    • Richmond Heights, Missouri, United States, 63117
      • Clayton Medical Research (Dr. Iri Don)
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Westroads Medical Group (Dr. William Palmer)
  • Nevada
    • Reno, Nevada, United States, 89502
      • Arthritis Center of Reno (Dr. Malin Prupas)
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Oklahoma Center for Arthritis therapy and Research (Dr. James McKay)
  • Texas
    • Austin, Texas, United States, 78704
      • MetaClin Research, Incorporated (Dr. Paul Pickrell)
    • Carlton, Texas, United States, 75007
      • John M. Joseph, MD (Dr. John Joseph)
    • Mesquite, Texas, United States, 75150
      • Southwest Rheumatology, P.A. (Dr. Atul Singhal)
  • Virginia
    • Arlington, Virginia, United States, 22205
      • Arthritis Clinic of Northern Virginia (Dr. Philip Kempf)
  • Washington
    • Spokane, Washington, United States, 99204
      • Arthritis Northwest Rheumatology, PLLC (Dr. Jeffrey Butler)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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: Methotrexate (MTX); Methotrexate (MTX) was supplied in tablet form, each of 2.5 mg strength.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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))	6, 14, and 26 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response to Intravenous (IV) Canakinumab and Oral Methotrexate (MTX) Therapy (ACR20, 70, 90) Compared to MTX Alone	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))	At 6 weeks, 14 weeks, and 26 weeks
Percentage of Participants Achieving a Good European League Against Rheumatism (EULAR) Response (Based on the Disease Activity Score (DAS28)) at 26 Weeks	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.	At 26 weeks
The Number of Participants in Clinical Remission Based on Disease Activity Score (DAS)28 and Simplified Disease Activity Index (SDAI)	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.	At 6 weeks, 14 weeks and 24 weeks

Collaborators and Investigators

• Sponsor: Novartis

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: June 18, 2007
• First Submitted That Met QC Criteria: June 18, 2007
• First Posted (Estimate): June 19, 2007

Study Record Updates

• Last Update Posted (Estimate): August 1, 2012
• Last Update Submitted That Met QC Criteria: July 24, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: ACR20, ACR50, ACZ885 (anti-interleukin-1beta monoclonal antibody), rheumatoid arthritis, methotrexate
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: CACZ885A2204