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

Study Overview
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Brief Summary
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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)

Official Title
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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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Canakinumab (investigational)
* Drug: Placebo
* Drug: Methotrexate (MTX)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canakinumab + Methotrexate<br>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)<br>* 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.<br>* Other names: ACZ885;Drug: Methotrexate (MTX)<br>* Methotrexate (MTX) was supplied in tablet form, each of 2.5 mg strength.<br>|
| Active Comparator: Methotrexate + placebo<br>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<br>* 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.<br>Drug: Methotrexate (MTX)<br>* Methotrexate (MTX) was supplied in tablet form, each of 2.5 mg strength.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACR20, ACR50, ACZ885 (anti-interleukin-1beta monoclonal antibody), rheumatoid arthritis, methotrexate