A Phase I/III Study to Evaluate Efficacy, PK and Safety Between CT-P13 SC and CT-P13 IV in Patients With Active RA

For Part 1, the primary pharmacokinetic (PK) endpoint of the AUCτ (area under the concentration-time curve) at steady state between Week 22 and Week 30 was analyzed in patients who received all doses (full) of study drug up to Week 30 (prior to Week 30) in the PK population. All patients in SC cohorts were randomly assigned at Week 14 in a 1:1 ratio to either Group A or B for PK monitoring visit period (Week 22 and Week 30). Therefore, AUCτ was calculated at Week 22 for Cohort 1: CT-P13 IV 3 mg/kg, Weeks 22 and 26 for Group A of SC cohorts, and Weeks 24 and 28 for Group B of SC cohorts.

Time frame: Weeks 22 (pre-dose to 216 hours post-dose), 24 (14 days after start of administration [SOA] at Week 22), 26 (pre-dose) and 28 (42 days after SOA at Week 22), and Week 30 (pre-dose)

Population: The PK population consisted of the all-randomized population who received at least 1 full dose of study drug at Week 6 or thereafter and who had at least 1 PK concentration result after Week 6 treatment. Among them, patients who had AUCτ result at steady state were included for the primary analysis.

For Part 2, the primary efficacy endpoint was to demonstrate that CT-P13 SC 120 mg is non-inferior to CT-P13 IV 3 mg/kg at Week 22, as determined by clinical response according to mean change from baseline in DAS28 (CRP) at Week 22, using Analysis of Covariance (ANCOVA). Change from baseline for ANCOVA was defined as decrease from baseline and calculated as (DAS28 \[CRP\] at baseline - DAS28 \[CRP\] at Week 22). DAS28 (CRP) was calculated using the following formula: DAS28 (CRP) equals(=) (0.56 multiplied by \[\*\] the square root \[√\] of TJC28 \[tender joint count\]) plus (+) (0.28 \* √ of SJC28 \[swollen joint count\]) + (0.36 \* the natural logarithm \[ln\](CRP \[mg/L\] + 1)) + (0.014 \* patient global disease activity \[GH\] on visual analogue assessment \[VAS\]) + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 indicating the current activity of patients with RA. DAS28 (CRP) score above 5.1 indicates high disease activity, whereas DAS28 (CRP) score below 3.2 indicates low disease activity.

Time frame: Week 22

Population: Efficacy population consisted of all randomly assigned patients who received at least 1 full dose of study drug at Week 6 or thereafter and had at least 1 efficacy result after Week 6. Among them, patients who had DAS28 (CRP) at Week 22 were included for the analysis. All patients were analyzed according to the treatment they received.

For evaluation of pharmacodynamic (PD), the secondary endpoint was defined as concentration of CRP between 2 treatment groups up to Week 54. The blood samples for CRP were collected at Weeks 0, 2 and 6, and every 8 weeks up to Week 54. Patient who received the other treatment than that to which they were assigned at any point was defined as mis-randomized. One patient in IV group was mis-randomized and analyzed as SC group for PD analysis.

Time frame: Baseline, Week 2, Week 6, Week 14, Week 22, Week 30, Week 38, Week 46, and Week 54

Population: The PD population consisted of all randomized population who received at least 1 full dose of study drug at Week 6 or thereafter and had at least 1 PD result (rheumatoid factor, anti-cyclic citrullinated peptide, CRP or ESR) after Week 6 treatment. All patients in PD population were analyzed according to the treatment they received.

The secondary endpoint was defined as descriptive statistics of actual value in disease activity measured by DAS28 (CRP) up to Week 54. The results up to Week 6 represented the efficacy of CT-P13 IV loading dose (3 mg/kg) regardless of randomized treatment arm (CT-P13 SC or CT-P13 IV) in both treatment arms. DAS28 (CRP) was calculated according to the following formula: DAS28 (CRP) = (0.56\* √ of TJC28) + (0.28 \* √ of SJC28) + (0.36 \* ln(CRP \[mg/L\] + 1)) + (0.014 \* GH on VAS) + 0.96. DAS28 (CRP) provides a number on a scale from 0 to 10 indicating the current activity of the patients with RA. DAS28 (CRP) score above 5.1 indicates high disease activity, whereas DAS28 (CRP) score below 3.2 indicates low disease activity.

Time frame: Baseline, Week 2, Week 6, Week 14, Week 22, Week 30, and Week 54

Population: The efficacy population consisted of all randomly assigned patients who received at least 1 full dose of study drug (CT-P13 IV or CT-P13 SC) at Week 6 or thereafter, and who had at least 1 efficacy evaluation result after Week 6 and thereafter treatment. All patients in efficacy population were analyzed according to the treatment they received.

The secondary endpoint was defined as number of patients achieving clinical response according to ACR20 (20% response, defined by ACR) between CT-P13 SC and CT-P13 IV groups. The results up to Week 6 represented the efficacy of CT-P13 IV loading dose (3 mg/kg) regardless of randomized treatment arm (CT-P13 SC or CT-P13 IV). Responder according to the ACR20 criteria defined as, if they are fulfilled, a decrease of at least 20% in number of tender joints and swollen joints (0-28), and 20% improvement in 3 of the followings: patient assessment of pain on VAS (0-100 mm), patient global assessment of disease activity on VAS (0-100 mm) and physician global assessment of disease activity on VAS (0-100 mm), health assessment questionnaire disability index and CRP or ESR (erythrocyte sedimentation rate).

Time frame: Week 2, Week 6, Week 14, Week 22, Week 30, and Week 54

Population: The efficacy population consisted of all randomly assigned patients who received at least 1 full dose of study drug (CT-P13 IV or CT-P13 SC) at Week 6 or thereafter, and who had at least 1 efficacy evaluation result after Week 6 and thereafter treatment. All patients in efficacy population were analyzed according to the treatment they received.

For evaluation of pharmacokinetics (PK), the secondary endpoint was defined as the analysis of trough concentration (concentration before the next study drug administration) of Infliximab up to Week 54. The samples were collected at Weeks 0, 2 and 6, and every 8 weeks up to Week 54. During PK monitoring visit (Weeks 22-30), samples were collected every 2 weeks according steady state PK sampling time point. All patients were randomly assigned at Week 14 in a 1:1:1:1 ratio to one of 4 groups (Groups A, B, C or D) for PK monitoring visit period. No PK results were obtained at Weeks 6 and 14 for SC group and Weeks 12, 20, 24, 26 and 28 for IV group due to 2 weeks and 8 weeks dosing interval, respectively.

Time frame: SC group: Weeks 0, 2, 12, 20, 22, 24, 26, 28, 36, 44, and 52; IV group: Weeks 0, 2, 6, 14, 22, 36, 44, and 52

Population: The PK population consisted of all randomly assigned patients who received at least 1 full dose of study drug (CT-P13 IV, CT-P13 SC) at Week 6 or thereafter and who had at least 1 PK concentration result after Week 6 or thereafter treatment. All patients in PK population were analyzed according to the treatment they received.