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

Study Overview
=================
Brief Summary
-----------------
This is a Phase I/III Study to Evaluate Efficacy, Pharmacokinetics and Safety between CT-P13 SC and CT-P13 IV in Patients with Active Rheumatoid Arthritis (RA).

Detailed Description
-----------------
A new subcutaneous infliximab formulation is developed by Celltrion, Inc. as an alternative to the intravenous regimen where subcutaneous infliximab injection typically takes less than 2 minutes. The availability of a subcutaneous formulation of infliximab would increase the treatment options available to patients, particularly those wishing to self-administer their therapy. This Phase I/III Study randomized, double-blinded (Part 2 only), multicenter, parallel-group study was designed to evaluate Efficacy, Pharmacokinetics and Safety between Subcutaneous CT-P13 and Intravenous CT-P13 in Patients with Active RA.

Official Title
-----------------
A Randomized, Parallel-Group, Phase I/III Study to Evaluate Efficacy, Pharmacokinetics and Safety Between Subcutaneous CT-P13 and Intravenous CT-P13 in Patients With Active Rheumatoid Arthritis

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Biological: CT-P13
* Biological: CT-P13
* Biological: CT-P13
* Biological: CT-P13
* Biological: CT-P13
* Biological: CT-P13


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient is male or female between 18 and 75 years old, inclusive. Patient has a diagnosis of RA according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for at least 6 months Patient has active disease as defined by the presence of 6 or more swollen joints (of 28 assessed), 6 or more tender joints (of 28 assessed) and serum C-reactive protein (CRP) concentration >0.6 mg/dL Patient who completed at least 3 months of treatment of oral or parenteral dosing with Methotrexate between 12.5 to 25 mg/kg (between 10 to 25 mg/week in Korea) and on stable dosing with Methotrexate for at least 4 weeks prior to the first administration of the study drug. Exclusion Criteria: Patient who has previously received a biological agent for the treatment of RA and/or a TNFα inhibitor for the treatment of other disease Patient who has allergies to any of the excipients of infliximab or any other murine and/or human proteins or patient with a hypersensitivity to immunoglobulin product Patient who had current or past history of chronic infection with hepatitis C or human immunodeficiency virus (HIV)-1 or -2 or current infection with hepatitis B Patient who had acute infection requiring oral antibiotics within 2 weeks or parenteral injection of antibiotics within 4 weeks prior to the first administration of the study drug, other serious infection within 6 months prior to the first administration of study drug or recurrent herpes zoster or other chronic or recurrent infection within 6 weeks prior to the first administration of the study drug. Patient who had an indeterminate result for interferon-γ release assay (IGRA) or latent tuberculosis (TB) at Screening. For Part 2, if IGRA result was indeterminate at Screening, 1 retest was possible during the screening. If the repeated IGRA result was negative, the patient could be included in the study.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1: CT-P13 IV 3 mg/kg<br>CT-P13 Intravenous (IV) (Infliximab), 3 mg/kg by IV infusion every 8 weeks (Part 1) | Biological: CT-P13<br>* CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose every 8 weeks<br>* Other names: Infliximab;|
| Experimental: Cohort 2: CT-P13 SC 90 mg<br>CT-P13 Subcutaneous (SC) (Infliximab), 90 mg by SC injection every other week (Part 1) | Biological: CT-P13<br>* CT-P13 (90 mg) by single SC injection every other week<br>* Other names: Infliximab;|
| Experimental: Cohort 3: CT-P13 SC 120 mg<br>CT-P13 SC (Infliximab), 120 mg by SC injection every other week (Part 1) | Biological: CT-P13<br>* CT-P13 (120 mg) by single SC injection every other week<br>* Other names: Infliximab;|
| Experimental: Cohort 4: CT-P13 SC 180 mg<br>CT-P13 SC (Infliximab), 180 mg by SC injection every other week (Part 1) | Biological: CT-P13<br>* CT-P13 (180 mg) by double SC 90 mg injections every other week<br>* Other names: Infliximab;|
| Experimental: Arm 1: CT-P13 SC 120 mg<br>CT-P13 SC (Infliximab), 120 mg by SC injection every other week with placebo intravenous infusion at Weeks 6, 14 and 22 (Part 2) | Biological: CT-P13<br>* CT-P13 (120 mg) by single SC injection every other week with placebo IV at Weeks 6, 14 and 22.<br>* Other names: Infliximab;|
| Active Comparator: Arm 2: CT-P13 IV 3 mg/kg<br>CT-P13 IV (Infliximab), 3 mg/kg by IV infusion every 8 weeks with placebo subcutaneous injection at Week 6 and every 2 weeks thereafter up to Week 28 (Part 2) | Biological: CT-P13<br>* CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose every 8 weeks with placebo SC at Week 6 and every other week thereafter up to Week 28<br>* Other names: Infliximab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve (AUCτ) of Infliximab at Steady State (Part 1) | 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. | 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) | 
| Change From Baseline of Disease Activity Score Using 28 Joint Counts (DAS28) (CRP) at Week 22 (Part 2) | 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. | Week 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Actual Value of Disease Activity Score Using 28 Joint Counts (DAS28 [CRP]) (Part 2) | 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. | Baseline, Week 2, Week 6, Week 14, Week 22, Week 30, and Week 54 | 
| Number of Patients Achieving Clinical Response According to American College of Rheumatology 20% Response (ACR20) (Part 2) | 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). | Week 2, Week 6, Week 14, Week 22, Week 30, and Week 54 | 
| Observed Trough Serum Concentration (Ctrough) of Infliximab (Part 2) | 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. | 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 | 
| Mean Actual Value in Serum CRP Concentration (Pharmacodynamic Parameter) (Part 2) | 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. | Baseline, Week 2, Week 6, Week 14, Week 22, Week 30, Week 38, Week 46, and Week 54 |