CT-P13 3.5

CELLTRION Inc.

23, Academy-ro, Yeonsu-gu, Incheon, Korea, Republic of, 22014

Su Eun Song, Clinical Operation Department, CELLTRION Inc., +82 32 850 5776, SuEun.Song@celltrion.com

Sung Hyun Kim, Clinical Planning Department, CELLTRION Inc., +82 32 850 5778, SungHyun.Kim@celltrion.com

No

No

No

Final

15 Apr 2019

Yes

21 May 2018

Yes

15 Apr 2019

No

Part 1 •To find the optimal dose of CT-P13 subcutaneous (SC) over the first 30 weeks as determined by the area under the concentration-time curve (AUCτ) at steady state between Week 22 and Week 30 Part 2 •To demonstrate that CT-P13 SC is noninferior to CT-P13 intravenous (IV) at Week 22, in terms of efficacy, as determined by clinical response according to change from baseline in disease activity measured by Disease Activity Score using 28 joint counts (DAS28) (C-reactive protein [CRP])

The CT-P13 SC via prefilled syringe (PFS) was injected by the investigator or his/her designee at each study center visit at the time points specified in the schedule of events. CT-P13 SC via PFS was injected at a slow, steady rate. For each new injection, a different injection site was used. The same injection sites could be used only if the other sites were unavailable due to safety reasons and in that case, it was recommended that the new injection was given at least 3 cm away from the most recent area injected. After proper training in injection technique, patients could self-inject with CT-P13 SC via PFS if their investigator determined that it was appropriate. For patients in specific countries in Part 2, CT-P13 SC via auto-injector (AI) was self-injected by the patients after proper training in AI injection technique. If healthcare professional determined or the patient requested it, additional training was given prior to the self-injection of CT-P13 SC via PFS or AI. Hypersensitivity was assessed by vital sign monitoring on each visit day at the time points: Prior to the beginning of the study drug administration and 1h after the end of the study drug administration. Hypersensitivity was assessed at the time points from Week 0 to Week 30 in Part 2: Prior to the beginning of the SC formulation injection and 1h after the end of the IV formulation infusion. Hypersensitivity was monitored by routine continuous clinical monitoring, incl. patient-reported signs and symptoms. In case of hypersensitivity, emergency equipment (adrenaline, antihistamines, corticosteroids, and respiratory support incl. inhalational therapy, oxygen, and artificial ventilation) was available and any types of ECG could have been performed. For patients who experienced or developed life-threatening treatment-related anaphylactic reactions, infliximab treatment was stopped immediately and the patient withdrawn from the study.

12 Sep 2016

No

Yes

Bosnia and Herzegovina: 21

Chile: 8

Korea, Republic of: 5

Peru: 44

Russian Federation: 78

Ukraine: 62

Poland: 114

Spain: 4

Bulgaria: 29

Estonia: 9

Hungary: 13

Latvia: 4

391

173

0

0

0

0

0

0

337

54

0

Part 1 + Part 2 (overall period)

Randomised - controlled

Blinding was not included in Part 1 of the study because it was an open-label study. Part 2 was blinded during the study. All the patient and physician and predefined blinded team remained blinded until all patients had completed the study and the database had been finalized for study termination. The blindness has been maintained throughout the study period except the appointed unblinded teams. The blind should not be broken under normal circumstances.

Yes

CT-P13 (infliximab)

Infliximab

Solution for infusion

Intravenous use

CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then administered with further 7 doses of CT-P13 IV at Week 6 and every 8 weeks thereafter. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

CT-P13 (infliximab)

Infliximab

Solution for injection

Subcutaneous use

CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (90 mg) by SC injection via PFS with a 2-week interval from Week 6. The dose of SC 90 mg was adjusted to SC 120 mg every 2 weeks after Week 30 in applicable patients in Cohort 2: CT-P13 SC 90 mg. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

CT-P13 (infliximab)

Infliximab

Solution for injection

Subcutaneous use

CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (120 mg) by SC injection via PFS with a 2-week interval from Week 6. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

CT-P13 (infliximab)

Infliximab

Solution for injection

Subcutaneous use

CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (180 mg) by SC injection via PFS with a 2-week interval from Week 6. The dose of SC 180 mg was adjusted to SC 120 mg every 2 weeks after Week 30 in applicable patients in Cohort 4: CT-P13 SC 180 mg. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

CT-P13 (infliximab)

Infliximab

Solution for injection

Subcutaneous use

CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (120 mg) by SC injection via PFS with a 2-week interval from Week 6 up to Week 54 with placebo IV at Weeks 6, 14 and 22. Patients in specific countries were administered CT-P13 SC via AI at Week 46 and every 2 weeks up to Week 54, and were switched back to CT-P13 SC via PFS at Week 56 and every 2 weeks up to Week 64. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

CT-P13 (infliximab)

Infliximab

Solution for infusion

Intravenous use

CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then administered with further 3 doses of CT-P13 IV at Week 6 and every 8 weeks thereafter (Weeks 6, 14 and 22) with placebo SC at Week 6 and every 2 weeks up to Week 28. CT-P13 IV was switched to CT-P13 SC via PFS at Week 30, and further doses with CT-P13 SC every other week were given up to Week 54 (up to Week 44 for specific countries). Patients in specific countries were administered CT-P13 SC via AI at Week 46 and every 2 weeks up to Week 54, and were switched back to CT-P13 SC via PFS at Week 56 and every 2 weeks up to Week 64. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

Cohort 1: CT-P13 IV 3 mg/kg (Part 1)

Cohort 2: CT-P13 SC 90 mg (Part 1)

Cohort 3: CT-P13 SC 120 mg (Part 1)

Cohort 4: CT-P13 SC 180 mg (Part 1)

Arm 1: CT-P13 SC 120 mg (Part 2)

Arm 2: CT-P13 IV 3 mg/kg (Part 2)

All-randomised population (Part 2)

The all-randomised population consisted of all randomly assigned patients at Week 6, regardless of whether or not any study drug dosing was completed. It was also applied for Part 1.

Efficacy population (Part 2)

The efficacy population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one efficacy evaluation result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 2, the efficacy analysis set consisted of the patients who were included in efficacy population and had DAS28 (CRP) result at Week 22.

Pharmacokinetics population (Part 2)

The PK population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PK concentration result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 1, the PK analysis set consisted of the patients who received all doses (full) of study drug up to Week 30 (prior to Week 30) in the PK population.

Pharmacodynamics population (Part 2)

The PD population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PD result (rheumatoid factor, anti-cyclic citrullinated peptide [anti-CCP], CRP, or erythrocyte sedimentation rate) after Week 6 or thereafter treatment. It was also applied for Part 1.

Safety population (Part 2)

The safety population consisted of all patients who received at least one dose (partial or full) of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter. It was also applied for Part 1.

Cohort 1: CT-P13 IV 3 mg/kg (Part 1)

Cohort 2: CT-P13 SC 90 mg (Part 1)

Cohort 3: CT-P13 SC 120 mg (Part 1)

Cohort 4: CT-P13 SC 180 mg (Part 1)

Arm 1: CT-P13 SC 120 mg (Part 2)

Arm 2: CT-P13 IV 3 mg/kg (Part 2)

All-randomised population (Part 2)

The all-randomised population consisted of all randomly assigned patients at Week 6, regardless of whether or not any study drug dosing was completed. It was also applied for Part 1.

Efficacy population (Part 2)

The efficacy population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one efficacy evaluation result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 2, the efficacy analysis set consisted of the patients who were included in efficacy population and had DAS28 (CRP) result at Week 22.

Pharmacokinetics population (Part 2)

The PK population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PK concentration result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 1, the PK analysis set consisted of the patients who received all doses (full) of study drug up to Week 30 (prior to Week 30) in the PK population.

Pharmacodynamics population (Part 2)

The PD population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PD result (rheumatoid factor, anti-cyclic citrullinated peptide [anti-CCP], CRP, or erythrocyte sedimentation rate) after Week 6 or thereafter treatment. It was also applied for Part 1.

Safety population (Part 2)

The safety population consisted of all patients who received at least one dose (partial or full) of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter. It was also applied for Part 1.

The primary efficacy endpoint was the mean change (decrease) from baseline of DAS28 (CRP) at Week 22 (ANCOVA) for the efficacy population. All patients included in the efficacy population were analyzed according to the treatment they received. The least squares means and standard errors, estimate of treatment difference (CT-P13 SC 120 mg - CT-P13 IV 3 mg/kg), and 2-sided 95% CI obtained from the ANCOVA model.

Primary

At Week 22

Primary efficacy analysis were analyzed using an ANCOVA considering the treatment as fixed effect and country, serum CRP concentration at Week 2 (≤0.6 mg/dL vs. >0.6 mg/dL), and body weight at Week 6 (≤100 kg vs. >100 kg) as covariates. The non-inferiority was to be concluded if the lower limit of the two-sided 95% CI for the difference in the mean change (decrease) from baseline of DAS28 (CRP) at Week 22 was greater than the pre-specified non-inferiority margin of -0.6.

Arm 2: CT-P13 IV 3 mg/kg (Part 2) v Arm 1: CT-P13 SC 120 mg (Part 2)

330

Pre-specified

0.27

2-sided

For Part 1, the primary PK endpoint of the AUCτ 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. AUCτ is calculated at Week 22 for the IV cohort, Week 22 and 26 for Group A of SC cohorts, and Week 24 and 28 for Group B of SC cohorts.

Primary

From Week 22 to Week 30. Week 24, 26 and 28 are not applicable for cohort 1.

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. All enrolled patients received CT-P13 IV infusions at Weeks 0 and 2. Then, patients in CT-P13 SC group were administered with CT-P13 SC at Week 6 and every 2 weeks thereafter up to Week 54. Patients in the CT-P13 IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22 (Weeks 14 and 22). And then, CT-P13 IV was switched to CT-P13 SC at Week 30, and further doses with CT-P13 SC were given up to Week 54. All patients in the PD population were analyzed according to the treatment they received. The actual PD population was 168 for CT-P13 SC arm and 175 for CT-P13 IV arm. One patient in the CT-P13 IV arm who was mis-randomized was analyzed as CT-P13 SC arm.

Secondary

Up to Week 54

For evaluation of pharmacokinetics (PK), the secondary endpoint was defined as the analysis of trough concentration 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 enrolled patients received CT-P13 IV infusions at Weeks 0 and 2. Patients in SC group were administered with CT-P13 SC at Week 6 and every 2 weeks thereafter up to Week 54. Patients in IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22. Then, CT-P13 IV was switched to CT-P13 SC at Week 30, and further doses with CT-P13 SC were given up to Week 54. 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. All patients in PK population were analyzed according to the treatment they received.

Secondary

Up to Week 54. Not applicable visits are as follows: Arm 1 - Week 6 and 14; Arm 2 - Week 12, 20, 24, 26 and 28.

For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of actual value in disease activity measured by DAS28 (CRP) up to Week 54 (efficacy population) between 2 treatment groups. The results up to Week 6 represented the efficacy of CT-P13 IV loading dose (3 mg/kg) regardless of randomized treatment group (CT-P13 SC or CT-P13 IV) in both treatment groups. Patients in the CT-P13 IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22. And then, CT-P13 IV was switched to CT-P13 SC at Week 30. All patients in the efficacy population were analyzed according to the treatment they received.

Secondary

Up to Week 54

For evaluation of efficacy, the secondary endpoint was defined as proportions of patients achieving clinical response according to ACR20 (20% response, as defined by the 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 group (CT-P13 SC or CT-P13 IV) in both treatment groups. Patients in the CT-P13 IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22. And then, CT-P13 IV was switched to CT-P13 SC at Week 30. All patients in the efficacy population were analyzed according to the treatment they received.

Secondary

Up to Week 54

Adverse events were assessed from the date the informed consent form was signed until the last assessment date or End-of-Study visit (Treatment period).

The investigator was responsible for reporting all AEs that were observed or reported during the study, regardless of their relationship to the study drug or clinical significance. A participant is counted once if they reported 1 or more events. Only the most severe events is counted. TEAEs collected from Part 2 are shown in this table.

20.0

Arm 1: CT-P13 SC 120 mg (Part 2)

Arm 2: CT-P13 IV 3 mg/kg (Part 2)