FKB327-002

FUJIFILM KYOWA KIRIN BIOLOGICS Co., Ltd.

1-6-1 Ohtemachi, Chiyoda-ku, Tokyo, Japan, 100-8185

Clinical-Trials@fk-b.com, Clinical Trial Information, Fujifilm Kyowa Kirin Biologics Co., Ltd., EU Branch, +44 1896 668 173, Clinical-Trials@fk-b.com

Clinical-Trials@fk-b.com, Clinical Trial Information, Fujifilm Kyowa Kirin Biologics Co., Ltd., EU Branch, +44 1896 668 173, Clinical-Trials@fk-b.com

No

No

No

Final

12 Jul 2016

Yes

12 Jul 2016

Yes

12 Jul 2016

No

Primary: • To assess the efficacy of FKB327 compared with Humira®, when each was administered in combination with methotrexate (MTX). Secondary: • To compare the safety profiles of FKB327 and Humira, each in combination with MTX treatment. • To assess the efficacy profiles of FKB327 and Humira over time, including initial onset of effect. • To compare the proportions of patients on FKB327 and Humira, who develop anti-drug antibodies (ADAs) and to summarise the distribution of the level of ADA activity between patients on FKB327 and Humira. • To compare the steady state pharmacokinetics (PK) of FKB327 and Humira administered by multiple dosing in patients with rheumatoid arthritis (RA) receiving concomitant treatment with MTX.

The study was performed in compliance with European Union (EU) Directives 2001/20/EC and 2005/28/EC, the Declaration of Helsinki (South Africa Revision, 1996), Good Manufacturing Practice (GMP), and Good Clinical Practice (GCP). The study was designed in accordance with the EU guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010) and other relevant guidelines for similar biological medicinal products. Participants were given as long as they wished to read the patient information and informed consent form (ICF), and to ask as many questions as they wanted. Each participant had an opportunity to discuss the study in private with a fully registered physician who was familiar with the study. The physician observed the participant's signature, then countersigned the consent form. The participant gave consent freely and in writing. During the study participants were monitored closely. In addition, the investigator and sponsor formally reviewed safety results at agreed intervals. Participants could be withdrawn from the study if that was in their best interest and the study physician ensured that participants received any medical treatment that they needed.

05 Jan 2015

No

No

Poland: 134

Romania: 28

Spain: 10

Bulgaria: 14

Czech Republic: 67

Germany: 26

Canada: 7

Chile: 41

Peru: 100

Russian Federation: 109

Ukraine: 114

United States: 78

728

279

0

0

0

0

0

0

601

125

2

Overall trial (overall period)

Randomised - controlled

Patients will be randomised to receive either FKB327 40 mg eow or Humira 40 mg eow in a 1:1 ratio. A blinded kit containing a single dose of either FKB327 or Humira was supplied by the Sponsor. The person preparing the injection (pharmacist or other suitably qualified member of staff not otherwise involved in the study) was unblinded once the treatment kit was opened.

Yes

FKB327

FKB327

Solution for injection

Subcutaneous use

Patients were administered subcutaneous (sc) FKB327 40 mg every other week (eow)

Humira

Humira

Solution for injection

Subcutaneous use

Patients were administered subcutaneous (sc) Humira 40 mg every other week (eow).

FKB327

Humira

Safety analysis set

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.

Full Analysis Set

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. The FAS was used for the primary efficacy analysis and other efficacy endpoints and analyses. Patients were analysed according to the randomised treatment in the primary analysis.

Per-Protocol Analysis set

The Per-protocol Analysis Set (PPAS) was defined as the set of patients in the FAS that had not deviated sufficiently from the protocol as to impact on the primary efficacy endpoint.

Pharmacokinetic analysis set

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.

FKB327

Humira

Safety analysis set

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.

Full Analysis Set

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. The FAS was used for the primary efficacy analysis and other efficacy endpoints and analyses. Patients were analysed according to the randomised treatment in the primary analysis.

Per-Protocol Analysis set

The Per-protocol Analysis Set (PPAS) was defined as the set of patients in the FAS that had not deviated sufficiently from the protocol as to impact on the primary efficacy endpoint.

Pharmacokinetic analysis set

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.

The primary efficacy endpoint is 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])

Primary

Week 24.

The primary hypothesis to be tested was that FKB327 is biosimilar to Humira. The difference and its 95% CI for primary endpoint between FKB327 and Humira were estimated. If the 95% CI fell entirely between pre-specified equivalence margin (+-13%), then FKB327 was considered equivalent to Humira.

FKB327 v Humira

721

Pre-specified

-1.3

2-sided

The DAS28 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.

Secondary

DAS28-CRP scores from Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24.

The key 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.

FKB327 v Humira

721

Pre-specified

0.01

2-sided

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 AssessmentQuestionnaire Disability Index [HAQ-DI]).

Secondary

Weeks 2, 4, 8, 12, 16, 20, and 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]).

Secondary

Weeks 2, 4, 8, 12, 16, 20, and 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]).

Secondary

Weeks 2, 4, 8, 12, 16, 20, and 24.

Counts of swollen joints from amongst 68/66 selected joints were to be performed by a trained and qualified joint assessor using standardised techniques recommended by the European League Against Rheumatism (EULAR).

Secondary

Base line to Week 24

Counts of tender from amongst 68/66 selected joints were to be performed by a trained and qualified joint assessor as scheduled using standardised techniques recommended by the European League Against Rheumatism (EULAR).

Secondary

Baseline to 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.

Secondary

Baseline to Week 24

Patient global assessment of disease activity visual analogue scale (VAS; ranging from very well to extremely bad) was assessed on 100-point scales. This VAS was to be completed by the patient themselves and results were recorded on an ePRO tablet device.

Secondary

Base line to Week 24

Physician global assessment of disease activity visual analogue scale (VAS; ranging from very low to very high) was assessed on 100-point scales. This VAS was to be completed by the physician themselves and results were recorded on an ePRO tablet device.

Secondary

Baseline to Week 24

Patient assessment of pain was assessed on 100-point scales. This VAS were to be completed by the patient themselves and results were recorded on an ePRO tablet device.

Secondary

Baseline to 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. The HAQ-DI questionnaire was to be completed on the ePRO device by the patient themselves.

Secondary

Baseline to 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 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).

Secondary

Baseline to 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).

Secondary

Baseline to Week 24

Blood samples for the assessment of ADA activity were to be collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12, and 24.

Secondary

Baseline to last sampling day

Blood samples for the quantification of adalimumab concentration in serum were to be collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12 and 20, and Week 24. Samples were to be taken prior to dosing (trough samples). Concentrations of MTX were not assessed.

Secondary

Baseline to Week 24

Patients were carefully monitored for AEs from signing of informed consent until Week 24 (for patients who will enter the open-label extension), Week 26 (for patients who did not enter the open-label extension), or the Early Termination visit.

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

17.1

FKB327

Humira