Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis
Brief summary
This study was intended to assess the safety, efficacy, and response to treatment using the American College of Rheumatology (ACR) criteria of 20% improvement in symptoms (ACR20) and to investigate a potential biomarker profile in adult patients with established rheumatoid arthritis
Interventions
DRUGACZ885 (investigational)
The ACZ885 was supplied in 6 mL colorless glass vials each containing nominally 150 mg ACZ885 (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.
DRUGPlacebo
Matching placebo of ACZ885 was supplied in the 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.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
RA patients: * Male and female patients aged 18 - 75 years (inclusive). * Body weight between 50 and 100 kg (inclusive). * Post menopausal or surgically sterile female patients are allowed. Female patients of child-bearing potential may participate if they are already on a stable dose of methotrexate. Additional birth control details to be provided at screening. Male patients must use an effective contraception method during the study and at least for 2 months following the completion/discontinuation of the study. * Diagnosis of RA, classified by American Rheumatism Association 1987 revised criteria. Disease duration of at least 6 months is essential. * Functional status class I, II or III classified according to the American College of Rheumatology 1991 revised criteria. * Active disease evaluation (≥ 6 tender and ≥ 6 swollen joints) * Prior treatment with 1-3 disease-modifying anti-rheumatic drugs (DMARDs) - Patients should have failed at least 1 DMARD but should not be deemed refractory to all therapies. It is expected that patients are on a current treatment with methotrexate ≤ 25 mg/week and with the current dose stable for at least 3 months, however patients who did not tolerate MTX may also be considered. All patients will take folic acid 1 mg daily, or 5 mg weekly post MTX dose, to minimize toxicity, according to local guidelines. In addition to methotrexate, patients may be on either a stable dose of non-steroidal anti-inflammatory drugs (NSAIDs) and/or a stable dose of oral corticosteroids (prednisone or equivalent ≤ 10 mg daily) for at least 4 weeks prior to randomization. Patients who failed any DMARDs will be allowed. * Negative purified protein derivative (PPD) tuberculin skin test reaction (PPD 5 tuberculin units or as according to local standard practice).
Exclusion criteria
RA patients: * Previous treatment with anti-Tumor Necrosis Factor (TNF)-α or anti IL-1 therapy (or other biological therapy), immunosuppressive agents such as cyclosporine, mycophenolate or tacrolimus. The following washout period will be required for such patients to be eligible to participate in the trial. 1. 2 months washout prior to screening for etanercept or adalimumab 2. 3 months washout prior to screening for infliximab 3. 3 months washout prior to screening for rituximab 4. 1 month washout prior to screening for cyclosporine, mycophenolate and tacrolimus. * If patient has been discontinued from other DMARDs (disease modifying antirheumatic drugs) for lack of efficacy or toxicity, the patient should be at least 1 month off the agent. * Patients with congestive heart failure, QT prolongation syndrome or poorly controlled diabetes mellitus. Patients with a history of QTc prolongation will be excluded. * Patients who have received intra-articular or systemic corticosteroid injections having been required for treatment of acute RA flare (not being part of a regular therapeutic regimen) within 4 weeks prior to randomization. *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response to Treatment (ACR20) in Adult Patients With Established Rheumatoid Arthritis (RA) | 6 weeks and 12 weeks | At each post-dose visit, an ACR20 responder was defined as someone who achieved at least 20% improvement in the tender and the swollen 28-joint count, and 20% improvement 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
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of ACZ885 by Assessing the Response to Treatment Using the Simple Disease Index (SDAI) | 6 weeks and 12 weeks | SDAI is derived by the number of swollen joints and tender joints using the 28-joint count (tender28 and swollen28). SDAI measures the high sensitivity C-reactive protein (hsCRP) level, patient's global disease activity (PGDA) and evaluator's global disease activity (EGDA). PGDA and EGDA are measured on a 100 mm Visual Analogue Scale (VAS), ranging from no arthritis activity to maximal arthritis activity. SDAI = tender28 + swollen28 + CRP + (PGDA/10) + (EGDA/10). Lower scores indicate less disease activity. |
| Efficacy of ACZ885 (Canakinumab) by Assessing the Response to Treatment Using the Disease Activity Score (DAS28) | 6 weeks and 12 weeks | DAS28 is derived by the number of swollen joints and tender joints using the 28-joint count (tender28 and swollen28). DAS28 measures the C-reactive protein (CRP) (in mg/L) and the patient's general health (GH). GH is measured on a 100 mm Visual Analogue Scale (VAS), ranging from no arthritis activity to maximal arthritis activity. DAS28 = 0.56\*√(tender28) + 0.28\*√(swollen28) + 0.36\*log\_e(CRP+1) + 0.014\*PGDA + 0.96. Lower scores indicate less disease activity. |
Countries
Russia, Spain, Switzerland, Turkey (Türkiye)
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ACZ885 (Canakinumab) : RA Patients Patients with Rheumatoid Arthritis RA taking 600 mg of ACZ885 (Canakinumab) Intravenous (IV) on Day 1, Day 15, and Day 43. | 50 |
| ACZ885 (Canakinumab) : Healthy Volunteers Healthy Volunteers taking 600 mg of ACZ885 (Canakinumab) Intravenous (IV) on Day 1 | 10 |
| Placebo Comparator: RA Patients Rheumatoid Arthritis patients who received placebo Intravenous (IV) on Day 1, Day 15 and Day 43. | 10 |
| Placebo Comparator: Healthy Volunteers Healthy Volunteers who received placebo Intravenous (IV) at Day 1. | 10 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | ACZ885 (Canakinumab) : RA Patients | ACZ885 (Canakinumab) : Healthy Volunteers | Placebo Comparator: RA Patients | Placebo Comparator: Healthy Volunteers | Total |
|---|---|---|---|---|---|
| Age Continuous | 54.4 Years STANDARD_DEVIATION 13.42 | 28.8 Years STANDARD_DEVIATION 7.42 | 46.2 Years STANDARD_DEVIATION 12.83 | 28.0 Years STANDARD_DEVIATION 5.52 | 46.9 Years STANDARD_DEVIATION 16.22 |
| Sex: Female, Male Female | 42 Participants | 4 Participants | 9 Participants | 2 Participants | 57 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 1 Participants | 8 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 10 | 4 / 10 | 12 / 50 | 8 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 2 / 50 | 0 / 10 |
Outcome results
Primary
Response to Treatment (ACR20) in Adult Patients With Established Rheumatoid Arthritis (RA)
At each post-dose visit, an ACR20 responder was defined as someone who achieved at least 20% improvement in the tender and the swollen 28-joint count, and 20% improvement 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))
Time frame: 6 weeks and 12 weeks
Population: The Safety Analysis Set consisted of all subjects who received at least one dose of study medication. The analysis used last observation carried forward (LOCF) imputation for missing values.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ACZ885 (Canakinumab) : RA Patients | Response to Treatment (ACR20) in Adult Patients With Established Rheumatoid Arthritis (RA) | ACR20 response rate at 6 weeks | 17 Participants |
| ACZ885 (Canakinumab) : RA Patients | Response to Treatment (ACR20) in Adult Patients With Established Rheumatoid Arthritis (RA) | ACR20 response rate at 12 weeks | 27 Participants |
| Placebo Comparator: RA Patients | Response to Treatment (ACR20) in Adult Patients With Established Rheumatoid Arthritis (RA) | ACR20 response rate at 6 weeks | 2 Participants |
| Placebo Comparator: RA Patients | Response to Treatment (ACR20) in Adult Patients With Established Rheumatoid Arthritis (RA) | ACR20 response rate at 12 weeks | 2 Participants |
Secondary
Efficacy of ACZ885 by Assessing the Response to Treatment Using the Simple Disease Index (SDAI)
SDAI is derived by the number of swollen joints and tender joints using the 28-joint count (tender28 and swollen28). SDAI measures the high sensitivity C-reactive protein (hsCRP) level, patient's global disease activity (PGDA) and evaluator's global disease activity (EGDA). PGDA and EGDA are measured on a 100 mm Visual Analogue Scale (VAS), ranging from no arthritis activity to maximal arthritis activity. SDAI = tender28 + swollen28 + CRP + (PGDA/10) + (EGDA/10). Lower scores indicate less disease activity.
Time frame: 6 weeks and 12 weeks
Population: The Safety Analysis Set consisted of all subjects who received at least one dose of study medication. The analysis used last observation carried forward (LOCF) imputation for missing values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ACZ885 (Canakinumab) : RA Patients | Efficacy of ACZ885 by Assessing the Response to Treatment Using the Simple Disease Index (SDAI) | 6 Weeks | 32.623 Scores on a scale | Standard Deviation 13.6218 |
| ACZ885 (Canakinumab) : RA Patients | Efficacy of ACZ885 by Assessing the Response to Treatment Using the Simple Disease Index (SDAI) | 12 Weeks | 29.163 Scores on a scale | Standard Deviation 13.0927 |
| Placebo Comparator: RA Patients | Efficacy of ACZ885 by Assessing the Response to Treatment Using the Simple Disease Index (SDAI) | 6 Weeks | 33.841 Scores on a scale | Standard Deviation 15.0053 |
| Placebo Comparator: RA Patients | Efficacy of ACZ885 by Assessing the Response to Treatment Using the Simple Disease Index (SDAI) | 12 Weeks | 32.412 Scores on a scale | Standard Deviation 12.2633 |
Secondary
Efficacy of ACZ885 (Canakinumab) by Assessing the Response to Treatment Using the Disease Activity Score (DAS28)
DAS28 is derived by the number of swollen joints and tender joints using the 28-joint count (tender28 and swollen28). DAS28 measures the C-reactive protein (CRP) (in mg/L) and the patient's general health (GH). GH is measured on a 100 mm Visual Analogue Scale (VAS), ranging from no arthritis activity to maximal arthritis activity. DAS28 = 0.56\*√(tender28) + 0.28\*√(swollen28) + 0.36\*log\_e(CRP+1) + 0.014\*PGDA + 0.96. Lower scores indicate less disease activity.
Time frame: 6 weeks and 12 weeks
Population: The Safety Analysis Set consisted of all subjects who received at least one dose of study medication. The analysis used last observation carried forward (LOCF) imputation for missing values.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ACZ885 (Canakinumab) : RA Patients | Efficacy of ACZ885 (Canakinumab) by Assessing the Response to Treatment Using the Disease Activity Score (DAS28) | 6 Weeks | 5.088 Scores on a scale | Standard Deviation 1.1148 |
| ACZ885 (Canakinumab) : RA Patients | Efficacy of ACZ885 (Canakinumab) by Assessing the Response to Treatment Using the Disease Activity Score (DAS28) | 12 Weeks | 4.853 Scores on a scale | Standard Deviation 1.1879 |
| Placebo Comparator: RA Patients | Efficacy of ACZ885 (Canakinumab) by Assessing the Response to Treatment Using the Disease Activity Score (DAS28) | 6 Weeks | 5.397 Scores on a scale | Standard Deviation 1.0591 |
| Placebo Comparator: RA Patients | Efficacy of ACZ885 (Canakinumab) by Assessing the Response to Treatment Using the Disease Activity Score (DAS28) | 12 Weeks | 5.400 Scores on a scale | Standard Deviation 0.9321 |