Arthritis, Rheumatoid
Conditions
Keywords
Rheumatoid, Arthritis
Brief summary
The purpose of the study is to compare the effectiveness and safety of FKB327 in comparison to Humira® in rheumatoid arthritis patients who have inadequate disease control on methotrexate.
Interventions
Sponsors
Fujifilm Kyowa Kirin Biologics Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female aged 18 years or over 2. Patients have been diagnosed with Rheumatoid Arthritis (RA) for at least 3 months 3. Patient has active RA 4. Patient has taken a stable dose of methotrexate for at least 3 months
Exclusion criteria
1. Patient has been previously treated with adalimumab 2. Patient has been previously treated or has ongoing treatment with prohibited medications 3. Patient has been immunised with a live or attenuated vaccine in past 4 weeks 4. Patient has positive result for HIV, HBV, HCV or TB infection Other Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| American College of Rheumatology (ACR) 20 Response Rate | Week 24 | The primary efficacy endpoint was the ACR20 response rate at Week 24. An ACR20 response meant that the patient achieved a 20% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health Assessment Questionnaire Disability Index \[HAQ-DI\]) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 | The DAS28-CRP assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum CRP, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad). The DAS28-CRP is a number on a scale from 0 to 10 indicating the current activity of the patient's RA. A higher score indicates higher disease activity. |
| ACR20 Response Rates Over Time | Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 | An ACR20 response meant that the patient achieved a 20% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health Assessment Questionnaire Disability Index \[HAQ-DI\]) |
| ACR50 Response Rates Over Time | Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 | An ACR50 response meant that the patient achieved a 50% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health AssessmentQuestionnaire Disability Index \[HAQ-DI\]) |
| ACR70 Response Rates Over Time | Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24 | An ACR70 response meant that the patient achieved a 70% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health AssessmentQuestionnaire Disability Index \[HAQ-DI\]) |
| Swollen Joint Count | Baseline and Week 24 | Counts of swollen joints from amongst 66 selected joints performed by a trained and qualified joint assessor using standardised techniques recommended by the European League Against Rheumatism (EULAR). Joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66 with higher scores indicating severe disease. Swollen joint count is a value of the individual ACR core set variables. |
| Tender Joint Count | Baseline and Week 24 | Counts of tender joints from amongst 68 selected joints were performed by a trained and qualified joint assessor using standardised techniques recommended by the European League Against Rheumatism (EULAR). Joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68 with higher scores indicating severe disease.Tender joint count is a value of the individual ACR core set variables. |
| Analysis of Serum C-Reactive Protein (CRP) Concentration | Baseline and Week 24 | Analysis of serum C-Reactive Protein (CRP) concentrations for inclusion in the ACR20/50/70 and DAS28-CRP scores was performed by a central laboratory. Elevation of CRP is a nonspecific marker of inflammation. Values above 10 mg/L were considered to be abnormally high. Decrease in level of CRP indicates reduction in inflammation. |
| DAS28-CRP Score Over Time | Baseline and Week 24 | The DAS28 score is a combined index that has been developed to measure the disease activity in patients with RA and has been extensively validated for its use in clinical studies. The DAS28-CRP assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum CRP, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad). The individual results are summed using a formula. The DAS28 is a number on a scale from 0 to 10 indicating the current activity of the patient's RA. A higher score indicates higher disease activity. |
| DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR) | Baseline, Week 12 and Week 24 | The DAS28 score is a combined index that has been developed to measure the disease activity in patients with RA and has been extensively validated for its use in clinical studies. The DAS28-ESR assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum ESR, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad). The individual results are summed using a formula. The DAS28 is a number on a scale from 0 to 10 indicating the current activity of the patient's RA. A higher score indicates higher disease activity. |
| Patient Assessment of Disease Activity | Baseline and Week 24 | Patient assessment of disease activity visual analogue scale (VAS) will be assessed on 100-point scales (ranging from very well (0) to extremely bad (100)).The patient assessment of disease activity VAS will contribute to the calculation of the DAS28 score. The patient assessment of disease activity VAS will contribute to the calculation of ACR20, ACR50 and ACR70 response. |
| Physician Assessment of Disease Activity | Baseline and Week 24 | Physician assessment of disease activity visual analogue scale (VAS) will be assessed on 100-point scale (ranging from very low (0) to very high (100)). The physician assessment of disease activity VAS will contribute to the calculation of ACR20, ACR50 and ACR70 response. |
| Patient's Assessment of Pain | Baseline and Week 24 | An injection site pain visual analogue score (VAS) will be administered to the patient. To determine the extent of the pain, patients will be asked to place a small vertical mark on a horizontal scale from 0 to 100, the ends of which are labelled with the extreme responses to be measured (No pain at 0 and Intolerable pain at 100). Patient's assessment of pain is a value of the individual ACR core set variables. |
| Health Assessment Questionnaire Disability Index (HAQ-DI) | Baseline and Week 24 | The HAQ-DI is a 20-question, self-administered instrument that measures the patient's functional ability on a 4-level difficulty scale (0 to 3, with 0 representing normal or no difficulty and 3 representing inability to perform). Eight categories of functioning are included: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. This scale is sensitive to change and is a good predictor of future disability. HAQ-DI is a value of the individual ACR core set variables. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Baseline and last sampling day | Blood samples for the assessment of ADA activity were collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12, and 24. |
| Trough Adalimumab Concentration | Week 2, Week 4, Week 12, Week 20, and Week 24 | Blood samples for the quantification of adalimumab concentration in serum were collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12 and 20, and Week 24. Samples were taken prior to dosing (trough samples). |
Countries
Bulgaria, Canada, Chile, Czechia, Germany, Peru, Poland, Romania, Russia, Spain, Ukraine, United States
Participant flow
Recruitment details
Patients were enrolled in 109 sites in 12 countries in 3 geographical regions: North America, Europe and Rest of World. The first participant enrolled on 05 January 2015 and the last participant completed on 12 July 2016.
Pre-assignment details
Screening details: Patients were randomised in a 1:1 ratio to receive either FKB327 40 mg eow or Humira 40 mg eow using the following stratification factors: prior biological treatment for Rheumatoid Arthritis (RA) (yes/no) and Screening disease activity (DAS28-CRP ≤5.1/\>5.1).
Participants by arm
| Arm | Count |
|---|---|
| FKB327 Patients were administered subcutaneous (sc) FKB327 40 mg every other week (eow). The treatment period was 22 weeks. | 366 |
| Humira® Patients were administered subcutaneous (sc) Humira 40 mg every other week (eow). The treatment period was 22 weeks. | 362 |
| Total | 728 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 9 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Lost to Follow-up | 4 | 4 |
| Overall Study | Protocol deviation | 2 | 3 |
| Overall Study | Screen failure | 0 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 16 |
Baseline characteristics
| Characteristic | FKB327 | Humira® | Total |
|---|---|---|---|
| Age, Continuous | 53 years | 53.6 years | 53.3 years |
| Age, Customized <18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized >65 years | 64 Participants | 63 Participants | 127 Participants |
| Age, Customized Between 18 and 65 years | 302 Participants | 299 Participants | 601 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 51 Participants | 48 Participants | 99 Participants |
| Race (NIH/OMB) White | 311 Participants | 308 Participants | 619 Participants |
| Region of Enrollment Bulgaria | 7 participants | 7 participants | 14 participants |
| Region of Enrollment Canada | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Chile | 20 participants | 21 participants | 41 participants |
| Region of Enrollment Czech Republic | 33 participants | 34 participants | 67 participants |
| Region of Enrollment Germany | 14 participants | 12 participants | 26 participants |
| Region of Enrollment Peru | 51 participants | 49 participants | 100 participants |
| Region of Enrollment Poland | 67 participants | 67 participants | 134 participants |
| Region of Enrollment Romania | 15 participants | 13 participants | 28 participants |
| Region of Enrollment Russia | 57 participants | 52 participants | 109 participants |
| Region of Enrollment Spain | 4 participants | 6 participants | 10 participants |
| Region of Enrollment Ukraine | 56 participants | 58 participants | 114 participants |
| Region of Enrollment United States | 39 participants | 39 participants | 78 participants |
| Sex: Female, Male Female | 281 Participants | 284 Participants | 565 Participants |
| Sex: Female, Male Male | 85 Participants | 78 Participants | 163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 366 | 0 / 362 |
| other Total, other adverse events | 26 / 366 | 29 / 362 |
| serious Total, serious adverse events | 15 / 366 | 19 / 362 |
Outcome results
Primary
American College of Rheumatology (ACR) 20 Response Rate
The primary efficacy endpoint was the ACR20 response rate at Week 24. An ACR20 response meant that the patient achieved a 20% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health Assessment Questionnaire Disability Index \[HAQ-DI\])
Time frame: Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FKB327 | American College of Rheumatology (ACR) 20 Response Rate | 72.5 Percentage of participants |
| Humira® | American College of Rheumatology (ACR) 20 Response Rate | 74.3 Percentage of participants |
Comparison: The difference and its 90% Confidence Interval (CI) for primary endpoint between FKB327 and Humira were estimated. If the 90% CI fell entirely between pre-specified equivalence margin (-12% to +15%), then FKB327 was considered equivalent to Humira.90% CI: [-7.3, 3.6]
Secondary
ACR20 Response Rates Over Time
An ACR20 response meant that the patient achieved a 20% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health Assessment Questionnaire Disability Index \[HAQ-DI\])
Time frame: Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment.Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FKB327 | ACR20 Response Rates Over Time | Week 8 | 64.6 percentage of responders |
| FKB327 | ACR20 Response Rates Over Time | Week 16 | 74.6 percentage of responders |
| FKB327 | ACR20 Response Rates Over Time | Week 4 | 51 percentage of responders |
| FKB327 | ACR20 Response Rates Over Time | Week 20 | 78 percentage of responders |
| FKB327 | ACR20 Response Rates Over Time | Week 12 | 69.2 percentage of responders |
| FKB327 | ACR20 Response Rates Over Time | Week 24 | 77.1 percentage of responders |
| FKB327 | ACR20 Response Rates Over Time | Week 2 | 37.3 percentage of responders |
| Humira® | ACR20 Response Rates Over Time | Week 24 | 79.3 percentage of responders |
| Humira® | ACR20 Response Rates Over Time | Week 2 | 31 percentage of responders |
| Humira® | ACR20 Response Rates Over Time | Week 4 | 52.4 percentage of responders |
| Humira® | ACR20 Response Rates Over Time | Week 8 | 67.7 percentage of responders |
| Humira® | ACR20 Response Rates Over Time | Week 12 | 72.2 percentage of responders |
| Humira® | ACR20 Response Rates Over Time | Week 16 | 74.9 percentage of responders |
| Humira® | ACR20 Response Rates Over Time | Week 20 | 77.8 percentage of responders |
Secondary
ACR50 Response Rates Over Time
An ACR50 response meant that the patient achieved a 50% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health AssessmentQuestionnaire Disability Index \[HAQ-DI\])
Time frame: Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FKB327 | ACR50 Response Rates Over Time | Week 8 | 28.9 percentage of responders |
| FKB327 | ACR50 Response Rates Over Time | Week 16 | 39.4 percentage of responders |
| FKB327 | ACR50 Response Rates Over Time | Week 4 | 17.3 percentage of responders |
| FKB327 | ACR50 Response Rates Over Time | Week 20 | 45.5 percentage of responders |
| FKB327 | ACR50 Response Rates Over Time | Week 12 | 37.6 percentage of responders |
| FKB327 | ACR50 Response Rates Over Time | Week 24 | 49 percentage of responders |
| FKB327 | ACR50 Response Rates Over Time | Week 2 | 5 percentage of responders |
| Humira® | ACR50 Response Rates Over Time | Week 24 | 49.4 percentage of responders |
| Humira® | ACR50 Response Rates Over Time | Week 2 | 8.8 percentage of responders |
| Humira® | ACR50 Response Rates Over Time | Week 4 | 17.8 percentage of responders |
| Humira® | ACR50 Response Rates Over Time | Week 8 | 30.9 percentage of responders |
| Humira® | ACR50 Response Rates Over Time | Week 12 | 35.1 percentage of responders |
| Humira® | ACR50 Response Rates Over Time | Week 16 | 44.7 percentage of responders |
| Humira® | ACR50 Response Rates Over Time | Week 20 | 46 percentage of responders |
Secondary
ACR70 Response Rates Over Time
An ACR70 response meant that the patient achieved a 70% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. * Acute phase reactant (CRP) * Patient global assessment of disease activity * Physician global assessment of disease activity * Patient pain scale * Disability/functional questionnaire (patient completed Health AssessmentQuestionnaire Disability Index \[HAQ-DI\])
Time frame: Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FKB327 | ACR70 Response Rates Over Time | Week 12 | 15.4 percentage of responders |
| FKB327 | ACR70 Response Rates Over Time | Week 2 | 0.3 percentage of responders |
| FKB327 | ACR70 Response Rates Over Time | Week 16 | 17.4 percentage of responders |
| FKB327 | ACR70 Response Rates Over Time | Week 20 | 20.9 percentage of responders |
| FKB327 | ACR70 Response Rates Over Time | Week 8 | 11.3 percentage of responders |
| FKB327 | ACR70 Response Rates Over Time | Week 24 | 21.3 percentage of responders |
| FKB327 | ACR70 Response Rates Over Time | Week 4 | 4.5 percentage of responders |
| Humira® | ACR70 Response Rates Over Time | Week 24 | 25.1 percentage of responders |
| Humira® | ACR70 Response Rates Over Time | Week 2 | 2.3 percentage of responders |
| Humira® | ACR70 Response Rates Over Time | Week 4 | 6.9 percentage of responders |
| Humira® | ACR70 Response Rates Over Time | Week 8 | 10.7 percentage of responders |
| Humira® | ACR70 Response Rates Over Time | Week 12 | 13.2 percentage of responders |
| Humira® | ACR70 Response Rates Over Time | Week 20 | 23.6 percentage of responders |
| Humira® | ACR70 Response Rates Over Time | Week 16 | 19 percentage of responders |
Secondary
Analysis of Serum C-Reactive Protein (CRP) Concentration
Analysis of serum C-Reactive Protein (CRP) concentrations for inclusion in the ACR20/50/70 and DAS28-CRP scores was performed by a central laboratory. Elevation of CRP is a nonspecific marker of inflammation. Values above 10 mg/L were considered to be abnormally high. Decrease in level of CRP indicates reduction in inflammation.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Analysis of Serum C-Reactive Protein (CRP) Concentration | Baseline | 25.12 mg/L | Standard Deviation 26.746 |
| FKB327 | Analysis of Serum C-Reactive Protein (CRP) Concentration | Week 24 | 10.98 mg/L | Standard Deviation 16.819 |
| Humira® | Analysis of Serum C-Reactive Protein (CRP) Concentration | Baseline | 26.73 mg/L | Standard Deviation 28.534 |
| Humira® | Analysis of Serum C-Reactive Protein (CRP) Concentration | Week 24 | 11.78 mg/L | Standard Deviation 18.528 |
Secondary
DAS28-CRP Score Over Time
The DAS28 score is a combined index that has been developed to measure the disease activity in patients with RA and has been extensively validated for its use in clinical studies. The DAS28-CRP assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum CRP, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad). The individual results are summed using a formula. The DAS28 is a number on a scale from 0 to 10 indicating the current activity of the patient's RA. A higher score indicates higher disease activity.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | DAS28-CRP Score Over Time | Baseline | 6.05 units on a scale | Standard Deviation 0.913 |
| FKB327 | DAS28-CRP Score Over Time | Week 24 | 3.47 units on a scale | Standard Deviation 1.298 |
| Humira® | DAS28-CRP Score Over Time | Baseline | 6.06 units on a scale | Standard Deviation 0.852 |
| Humira® | DAS28-CRP Score Over Time | Week 24 | 3.47 units on a scale | Standard Deviation 1.336 |
Secondary
DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR)
The DAS28 score is a combined index that has been developed to measure the disease activity in patients with RA and has been extensively validated for its use in clinical studies. The DAS28-ESR assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum ESR, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad). The individual results are summed using a formula. The DAS28 is a number on a scale from 0 to 10 indicating the current activity of the patient's RA. A higher score indicates higher disease activity.
Time frame: Baseline, Week 12 and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR) | Baseline | 6.52 units on a scale | Standard Deviation 0.941 |
| FKB327 | DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR) | Week 12 | 4.24 units on a scale | Standard Deviation 1.382 |
| FKB327 | DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR) | Week 24 | 3.82 units on a scale | Standard Deviation 1.384 |
| Humira® | DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR) | Baseline | 6.56 units on a scale | Standard Deviation 0.902 |
| Humira® | DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR) | Week 12 | 4.24 units on a scale | Standard Deviation 1.353 |
| Humira® | DAS28 Score Based on Erythrocyte Sedimentation Rate (DAS28-ESR) | Week 24 | 3.85 units on a scale | Standard Deviation 1.371 |
Secondary
Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score
The DAS28-CRP assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum CRP, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad). The DAS28-CRP is a number on a scale from 0 to 10 indicating the current activity of the patient's RA. A higher score indicates higher disease activity.
Time frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Baseline | 6.05 units on a scale | Standard Deviation 0.913 |
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 2 | 4.92 units on a scale | Standard Deviation 1.07 |
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 4 | 4.44 units on a scale | Standard Deviation 1.317 |
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 8 | 4.11 units on a scale | Standard Deviation 1.295 |
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 12 | 3.81 units on a scale | Standard Deviation 1.32 |
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 16 | 3.68 units on a scale | Standard Deviation 1.304 |
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 20 | 3.58 units on a scale | Standard Deviation 1.329 |
| FKB327 | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 24 | 3.47 units on a scale | Standard Deviation 1.298 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 24 | 3.47 units on a scale | Standard Deviation 1.336 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Baseline | 6.06 units on a scale | Standard Deviation 0.852 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 12 | 3.85 units on a scale | Standard Deviation 1.339 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 2 | 4.86 units on a scale | Standard Deviation 1.203 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 20 | 3.57 units on a scale | Standard Deviation 1.388 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 4 | 4.43 units on a scale | Standard Deviation 1.383 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 16 | 3.67 units on a scale | Standard Deviation 1.419 |
| Humira® | Disease Activity Score 28 (DAS28) Based on C-reactive Protein (DAS28-CRP) Score | Week 8 | 4.09 units on a scale | Standard Deviation 1.397 |
Comparison: The secondary hypothesis involved equivalence of the difference between FKB327 and Humira in DAS28-CRP at Week 24. Based on the repeated measures analysis model, the difference and its 95% CI in the least-squares means (LSMs) for DAS28-CRP at Week 24 between FKB327 and Humira were estimated. If the 95% CI fell entirely between the pre-specified margin (+/- 0.6), then FKB327 was considered equivalent to Humira.95% CI: [-0.16, 0.18]
Secondary
Health Assessment Questionnaire Disability Index (HAQ-DI)
The HAQ-DI is a 20-question, self-administered instrument that measures the patient's functional ability on a 4-level difficulty scale (0 to 3, with 0 representing normal or no difficulty and 3 representing inability to perform). Eight categories of functioning are included: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. This scale is sensitive to change and is a good predictor of future disability. HAQ-DI is a value of the individual ACR core set variables.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Health Assessment Questionnaire Disability Index (HAQ-DI) | Baseline | 1.78 units on a scale | Standard Deviation 0.544 |
| FKB327 | Health Assessment Questionnaire Disability Index (HAQ-DI) | Week 24 | 1.21 units on a scale | Standard Deviation 0.696 |
| Humira® | Health Assessment Questionnaire Disability Index (HAQ-DI) | Baseline | 1.8 units on a scale | Standard Deviation 0.538 |
| Humira® | Health Assessment Questionnaire Disability Index (HAQ-DI) | Week 24 | 1.26 units on a scale | Standard Deviation 0.719 |
Secondary
Patient Assessment of Disease Activity
Patient assessment of disease activity visual analogue scale (VAS) will be assessed on 100-point scales (ranging from very well (0) to extremely bad (100)).The patient assessment of disease activity VAS will contribute to the calculation of the DAS28 score. The patient assessment of disease activity VAS will contribute to the calculation of ACR20, ACR50 and ACR70 response.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Patient Assessment of Disease Activity | Baseline | 68 units on a scale | Standard Deviation 17.98 |
| FKB327 | Patient Assessment of Disease Activity | Week 24 | 35.2 units on a scale | Standard Deviation 24.04 |
| Humira® | Patient Assessment of Disease Activity | Baseline | 68.2 units on a scale | Standard Deviation 18.18 |
| Humira® | Patient Assessment of Disease Activity | Week 24 | 33.2 units on a scale | Standard Deviation 23.4 |
Secondary
Patient's Assessment of Pain
An injection site pain visual analogue score (VAS) will be administered to the patient. To determine the extent of the pain, patients will be asked to place a small vertical mark on a horizontal scale from 0 to 100, the ends of which are labelled with the extreme responses to be measured (No pain at 0 and Intolerable pain at 100). Patient's assessment of pain is a value of the individual ACR core set variables.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Patient's Assessment of Pain | Baseline | 66.8 units on a scale | Standard Deviation 18.71 |
| FKB327 | Patient's Assessment of Pain | Week 24 | 34.7 units on a scale | Standard Deviation 23.86 |
| Humira® | Patient's Assessment of Pain | Baseline | 67.7 units on a scale | Standard Deviation 18.56 |
| Humira® | Patient's Assessment of Pain | Week 24 | 33.6 units on a scale | Standard Deviation 23.86 |
Secondary
Physician Assessment of Disease Activity
Physician assessment of disease activity visual analogue scale (VAS) will be assessed on 100-point scale (ranging from very low (0) to very high (100)). The physician assessment of disease activity VAS will contribute to the calculation of ACR20, ACR50 and ACR70 response.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Physician Assessment of Disease Activity | Baseline | 68.4 units on a scale | Standard Deviation 14.58 |
| FKB327 | Physician Assessment of Disease Activity | Week 24 | 21.5 units on a scale | Standard Deviation 17.29 |
| Humira® | Physician Assessment of Disease Activity | Baseline | 66.2 units on a scale | Standard Deviation 15.48 |
| Humira® | Physician Assessment of Disease Activity | Week 24 | 21.5 units on a scale | Standard Deviation 16.97 |
Secondary
Swollen Joint Count
Counts of swollen joints from amongst 66 selected joints performed by a trained and qualified joint assessor using standardised techniques recommended by the European League Against Rheumatism (EULAR). Joints were classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66 with higher scores indicating severe disease. Swollen joint count is a value of the individual ACR core set variables.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Swollen Joint Count | Baseline | 16.3 Count / Score | Standard Deviation 9.1 |
| FKB327 | Swollen Joint Count | Week 24 | 3.8 Count / Score | Standard Deviation 6.04 |
| Humira® | Swollen Joint Count | Baseline | 16 Count / Score | Standard Deviation 8.96 |
| Humira® | Swollen Joint Count | Week 24 | 3.5 Count / Score | Standard Deviation 5.23 |
Secondary
Tender Joint Count
Counts of tender joints from amongst 68 selected joints were performed by a trained and qualified joint assessor using standardised techniques recommended by the European League Against Rheumatism (EULAR). Joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68 with higher scores indicating severe disease.Tender joint count is a value of the individual ACR core set variables.
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. Patients were analysed according to the randomised treatment in the primary analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FKB327 | Tender Joint Count | Baseline | 26.2 Count / Score | Standard Deviation 14.49 |
| FKB327 | Tender Joint Count | Week 24 | 8.5 Count / Score | Standard Deviation 10.56 |
| Humira® | Tender Joint Count | Baseline | 25.9 Count / Score | Standard Deviation 14.52 |
| Humira® | Tender Joint Count | Week 24 | 8.1 Count / Score | Standard Deviation 9.36 |
Other Pre-specified
Percentage of Patients Developing Anti-drug Antibodies (ADAs)
Blood samples for the assessment of ADA activity were collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12, and 24.
Time frame: Baseline and last sampling day
Population: The Safety Analysis Set was defined as the set of patients who received at least 1 dose of randomised treatment. The Safety Analysis Set was used for all safety analyses. Patient safety data were analysed according to treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FKB327 | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Baseline (Negative) | 95.4 percentage of patients |
| FKB327 | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Last sampling day (Positive) | 61.7 percentage of patients |
| FKB327 | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Baseline (Missing) | 0.3 percentage of patients |
| FKB327 | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Last sampling day (Negative) | 38.3 percentage of patients |
| FKB327 | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Baseline (Positive) | 4.4 percentage of patients |
| Humira® | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Last sampling day (Negative) | 40.9 percentage of patients |
| Humira® | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Baseline (Positive) | 5.5 percentage of patients |
| Humira® | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Baseline (Negative) | 94.2 percentage of patients |
| Humira® | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Baseline (Missing) | 0.3 percentage of patients |
| Humira® | Percentage of Patients Developing Anti-drug Antibodies (ADAs) | Last sampling day (Positive) | 59.1 percentage of patients |
Other Pre-specified
Trough Adalimumab Concentration
Blood samples for the quantification of adalimumab concentration in serum were collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12 and 20, and Week 24. Samples were taken prior to dosing (trough samples).
Time frame: Week 2, Week 4, Week 12, Week 20, and Week 24
Population: The Pharmacokinetic Analysis Set (PKAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and had at least 1 serum adalimumab concentration result after receiving randomised treatment.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| FKB327 | Trough Adalimumab Concentration | Week 4 | 3450.6 ng/mL |
| FKB327 | Trough Adalimumab Concentration | Week 20 | 4369.8 ng/mL |
| FKB327 | Trough Adalimumab Concentration | Week 12 | 4316.3 ng/mL |
| FKB327 | Trough Adalimumab Concentration | Week 24 | 4126 ng/mL |
| FKB327 | Trough Adalimumab Concentration | Week 2 | 2434.6 ng/mL |
| Humira® | Trough Adalimumab Concentration | Week 24 | 3758.2 ng/mL |
| Humira® | Trough Adalimumab Concentration | Week 2 | 2089.1 ng/mL |
| Humira® | Trough Adalimumab Concentration | Week 4 | 2932.1 ng/mL |
| Humira® | Trough Adalimumab Concentration | Week 12 | 3851.5 ng/mL |
| Humira® | Trough Adalimumab Concentration | Week 20 | 3873 ng/mL |