A Study to Compare FKB327 Long-term Safety, Efficacy and Immunogenicity With Humira® in Rheumatoid Arthritis Patients

Period I: Patients were carefully monitor for Adverse Events from signing of informed consent until week 30 and thereafter during Period II of the study. For patients who discontinued early, a follow-up period of 4 weeks was added to the Early Termination Visit.

The investigator actively asked the patients for Adverse Events. Patients spontaneously reported Adverse Events to the Investigator during clinic visits or in between visits.

From week 30 all subjects were transferred to receive FKB327 treatment. Adverse Events were contentiously monitored and recorded during Period II. For patients discontinuing the study prematurely, a follow-up period of 4 weeks was added to the Early Termination Visit. The data for Period II is based on the number of patients in the Safety Analysis Set that entered Period II.

A Serious Adverse Event (SAE) was defined in the Protocol as: Death; or a Life-threatening Adverse Event (AE); Inpatient Hospitalization; Persistant or significant disability or incapacity; A congenital anomaly/birth defect; An important medical event that may not have resulted in death, have been life-threatening, or required hospitalization, but may have jeopardized the patient and may have required medical intervention to prevent 1 of the outcomes listed in this definition.

SAEs were followed until resolution, the investigator confirmed the event was unlikely to resolve or the patient was recorded as lost to follow-up.

Period II: at week 30 all patients were transferred to receive FKB327.

Each subject was counted once within each System Organ Class (SOC) and Preferred Term (PT). Death defined as a fatal outcome of a (S)AE.

SAEs were followed until resolution, the investigator confirmed the event was unlikely to resolve or the patient was lost to follow-up.

Systolic Blood Pressure is part of Vital Signs which were part of the subject safety evaluations. Systolic Blood Pressure was measured at the following time-points: Week 0, Week 4, Week 8, Week 12, Week 24 and Week 80/End o Study (EOS). Systolic Blood Pressure with changes from Baseline_002 (NCT022600791) was summarized by treatment sequence over the whole study period for each visit.

Baseline_002 is defined as the last non-missing measurement collected prior to the first study medication administered at Week 0 from Study FKB327-002.

Diastolic Blood Pressure is part of Vital Signs which were part of the subject safety evaluations. Diastolic Blood Pressure was measured at the following time-points: Week 0, Week 4, Week 8, Week 12, Week 24 and Week 80/End o Study (EOS). Diastolic Blood Pressure with changes from Baseline_002 (NCT022600791) was summarized by treatment sequence over the whole study period for each visit measured.

Baseline_002 is defined as the last non-missing measurement collected prior to the first study medication administered at Week 0 from Study FKB327-002.

Pulse rate is part of Vital Signs which were part of the subject safety evaluations. Pulse rate was measured at the following time-points: Weeks 0, 4, 8, 12, 24 and 80/End of Study (EOS). Pulse Rate with changes from Baseline_002 (NCT022600791) was summarized by treatment sequence over the whole study period for each visit.

Baseline_002 is defined as the last non-missing measurement collected prior to the first study medication administered at Week 0 from Study FKB327-002.

Temperature measurements forms part of the vital signs which was one of the continuous safety measurements for the study primary endpoint.

Temperature was measured at week 0, week 4, week 8, week 12, week 24 and at week 80 or at End of Study (EOS).

Temperature with change from Baseline_002 were summarized by treatment sequence over the whole study period.

Baseline_002 is defined as the last non-missing measurement collected prior to the first study medication administration at Week 0 from Study FKB327-002 (NCT02260791).

Clinical Laboratory tests for hematology and serum chemistry were performed by the sites and analysed at a Central Laboratory. Urine dip-stick tests were performed by the sites. Laboratory samples were taken at the following time-points (weeks): 0; 4; 8; 12; 24; 30; 42; 54; 66; 76 and 80/End of Study (EOS). Each result outside its normal range was review and assessed by the investigator whether or not it was Clinically Significant (CS) or Not Clinically Significant (NCS) CS laboratory abnormalities were recorded as AEs.

The DAS28 score is a combined index that has been developed to measure the disease activity in patients with Rheumatoid arthritis (RA) and has been extensively validated for the use in clinical studies. The DAS28-CRP assessment involved evaluating the number of tender (TJC) and the swollen (SJC) joints (out of 28 specified joints), serum CRP, and patient global assessment of disease activity (Visual analogue scale (VAS) from 0-100, very well to extremely bad). The individual results are summarized using a formula. 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.

During the FKB327-003 study for Period I and Period II the DAS28-CRP score was compared to Baseline in study FKB327-002 (NCT02260791).

An ACR20 response means that the patient achieved a 20% improvement in Tender Joint Count (TJC) and Swollen Joint Count (SJC) and a 20% improvement in at least 3 of the other 5 Core Data Set elements listed below:

• Acute phase reactant (C-reactive protein, CRP) A high level of CRP in the blood is a marker of inflammation.
• Patient global assessment of disease activity assessed on a Visual Analog Scale (VAS) ranging from very well to extremely bad was assessed on a 100 point scale. (from 0 to 100)
• Physician global assessment of disease activity assessed on a VAS ranging from very low to very high was assessed on 100 point scale
• Patient pain scale assessed on a VAS ranging from very well to extremely bad was assessed on 100 point scale
• Disability/functional questionnaire (patient completed Heath Assessment Questionnaire Disability Index (HAQ-DI)) A higher response rate is a better outcome. The minimum possible value is 0% and the maximum possible value is 100%

An ACR50 response means that the patient achieved a 50% improvement in Tender Joint Count (TJC) and Swollen Joint Count (SJC) and in at least 3 of the other 5 Core Data Set elements listed below:

• Acute phase reactant (C-reactive protein, CRP) A high level of CRP in the blood is a marker of inflammation.
• Patient global assessment of disease activity assessed on a Visual Analog Scale (VAS) ranging from very well to extremely bad was assessed on a 100 point scale. (from 0 to 100)
• Physician global assessment of disease activity assessed on a VAS ranging from very low to very high was assessed on 100 point scale
• Patient pain scale assessed on a VAS ranging from very well to extremely bad was assessed on 100 point scale
• Disability/functional questionnaire (patient completed Heath Assessment Questionnaire Disability Index (HAQ-DI)) A higher response rate is a better outcome. The minimum possible value is 0% and the maximum possible value is 100%

An ACR70 response means that the patient achieved a 70% improvement in Tender Joint Count (TJC) and Swollen Joint Count (SJC) and in at least 3 of the other 5 Core Data Set elements listed below:

• Acute phase reactant (C-reactive protein,CRP) A high level of CRP in the blood is a marker of inflammation.
• Patient global assessment of disease activity assessed on a Visual Analog Scale (VAS) ranging from very well to extremely bad was assessed on a 100 point scale. (from 0 to 100)
• Physician global assessment of disease activity assessed on a VAS ranging from very low to very high was assessed on 100 point scale
• Patient pain scale assessed on a VAS ranging from very well to extremely bad was assessed on 100 point scale
• Disability/functional questionnaire (patient completed Heath Assessment Questionnaire Disability Index (HAQ-DI)) A higher response rate is a better outcome. The minimum possible value is 0% and the maximum possible value is 100%

Blood samples for assessment of Anti-Drug antibodies (ADA) were collected prior to dosing (trough samples) at Baseline (Week 0) and at Weeks 12, 24, 30, 54, 76 and 80/EOS.

All ADA activity was listed and summarized for each treatment sequence by time point during the overall treatment period as well as by treatment group for each period (Period I and Period II). Descriptive statistics included absolute counts (n) and percentage (%).

Blood samples for the quantification of adalimumab concentration in serum were collected prior to dosing (trough samples) at Baseline (Week 0), and at weeks 12, 24 , 30, 54, 76 and 80/EOS.