A Study of Certolizumab Pegol as Additional Therapy in Chinese Patients With Active Rheumatoid Arthritis

Study Overview
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Brief Summary
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This study will evaluate the safety & efficacy of Certolizumab Pegol (CZP) as additional medication to Methotrexate (MTX) in Chinese subjects with Rheumatoid Arthritis. 400 patients will be randomized to receive either CZP + MTX or placebo + MTX. Anticipated time in the study is about 32 weeks.

Detailed Description
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This is a phase 3, multicenter, double-blind, placebo-controlled, parallel group, randomized, 24-week study to evaluate the safety and efficacy of Certolizumab Pegol (CZP) as additional medication to Methotrexate (MTX) in Chinese subjects with active Rheumatoid Arthritis (RA) who have an incomplete response to Methotrexate. This study is designed to determine whether CZP 400 mg at Weeks 0, 2, and 4 followed by CZP 200 mg every 2 weeks (Q2W) in combination with MTX demonstrates superiority, in terms of greater improvement in relief of the signs and symptoms of RA, compared with MTX alone. Approximately 535 subjects will be screened to randomize 400 subjects into this study, at approximately 25 centers in the People's Republic of China. There will be 2 treatment groups, with 300 subjects in the CZP+MTX group and 100 subjects in the PBO+MTX group. For each subject, the study duration will last a maximum of approximately 38 weeks. Subjects who complete study RA0044 and subjects who fail to achieve an American College of Rheumatology 20 % Response Criteria (ACR20) response at Week 12 that is confirmed at Week 14 and thus are withdrawn from this study at Week 16, are permitted to receive treatment with CZP in the open-label extension study, RA0078. The secondary objectives are to assess the dose regimen of CZP in combination with MTX compared with MTX alone in the safety and tolerability, ability to improve physical function, and health outcomes measures in Chinese subjects with active RA; also to characterize the pharmacokinetic (PK) profile and immunogenicity of CZP in combination with MTX.

Official Title
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A Phase 3, Multi-center, Double-blind, Placebo-controlled, Parallel Group, Randomized 24-week Study to Evaluate the Safety and Efficacy of Certolizumab Pegol (CZP) as Additional Medication to Methotrexate in Chinese Subjects With Active Rheumatoid Arthritis Who Have an Incomplete Response to Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Certolizumab Pegol
* Drug: Methotrexate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form (ICF) is signed and dated by the subject or by the legal representative Subject is considered reliable and capable of adhering to the protocol (eg, able to understand and complete questionnaires), visit schedule, and medication intake according to the judgment of the Investigator Subject is male or female, and at least 18 years of age at the Screening Visit Subjects must have a diagnosis of adult onset Rheumatoid Arthritis RA of at least 6 months duration as defined by the 1987 American College of Rheumatology (ACR) classification criteria (Arnett et al, 1988). Subjects must have active RA disease as defined by: ≥6 tender joints at Screening and Baseline ≥6 swollen joints at Screening and Baseline Fulfilling 1 of the following 2 criteria during the Screening Period: European League Against Rheumatism (ESR) (Westergren) ≥30 mm/hour, or C-reactive protein (CRP) >15 mg/L Subjects must have a normal chest x ray within 3 months prior to the Baseline Visit Female subjects with childbearing potential should have a negative pregnancy test at Screening and at Baseline and should have a medically accepted method of contraception used during the entire duration of the study and for 10 weeks after the last dose of Certolizumab Pegol (CZP). Male subjects must agree to ensure they use adequate contraception during the study and for at least 10 weeks after the subject receives their last dose of study medication Subjects must have received treatment with Methotrexate (MTX) (with or without folic acid) for at least 3 months prior to the Baseline Visit. The dose and route of administration of MTX must have been stable for at least 2 months prior to the Baseline Visit. The minimum stable dose of MTX allowed is 10 mg weekly Exclusion Criteria: Rheumatoid Arthritis disease-related exclusions: Subjects have a diagnosis of any other inflammatory arthritis (eg, psoriatic arthritis or ankylosing spondylitis) Subjects have a secondary, noninflammatory type of arthritis (eg, Osteoarthritis or Fibromyalgia) that in the Investigator's opinion is symptomatic enough to interfere with evaluation of the effect of study medication on the subject's primary diagnosis of Rheumatoid Arthritis (RA) Subjects have a history of an infected joint prosthesis at any time with that prosthesis still in situ Subjects have >3 arthroplasties due to RA and/or Steinbrocker IV functional capacity Concomitant medication exclusions: Subjects must be free of prohibited medication, Analgesics (including Paracetamol and Acetominophen), NSAIDs /COX-2 Inhibitors, Oral corticosteroids, DMARDs, etc. as detailed in protocol Previous clinical studies and previous biological therapy exclusions Subjects have previously participated in this study or subject has previously been assigned to treatment in a study of the medication under investigation in this study Subjects have participated in another study of an investigational medicinal product (or a medical device) within the previous 3 months or are currently participating in another study of an investigational medicinal product (or a medical device) Subjects have received any experimental nonbiological therapy, within or outside a clinical study in the 3 months or within 5 half lives (whichever is longer) prior to Baseline Visit Subjects have received any biological therapy for RA within 3 months or within 5 half lives (whichever is longer) prior to Baseline Visit, except for Etanercept and Anakinra where only a 1 month washout prior to the Baseline Visit is necessary Subjects have received Rituximab or Tocilizumab Subjects have received Yunke (technetium-99 conjugated with methylene diphosphonate) other than for diagnostic purpose within 5 years prior to Baseline Subjects have received previous treatment with a biological therapy for RA that resulted in a severe hypersensitivity reaction or an anaphylactic reaction Subjects who failed to respond to previous treatment with a Tumor Necrosis Factor (TNF) blocking drug are excluded. Subjects who initially responded to a maximum of 2 TNF blocking agents but who later discontinued the agent(s) due to loss of efficacy or other reasons may be included Medical history exclusions: Female subjects who are breast feeding, pregnant, or plan to become pregnant during the study or for 3 months following last dose of study medication Subjects with a history of chronic infection, recent serious or life threatening infection (within 6 months, including herpes zoster), or a current sign or symptom that may indicate an infection (eg, fever, cough) Subjects with a history or active systemic/respiratory infection due to fungal, parasitic, or mycotic pathogens including but not limited to histoplasmosis, coccidiosis, paracoccidiosis, pneumocystis, blastomyces, aspergillus, and nontuberculous mycobacteria (NTMB) Radiographic evidence suggestive of any of these infections is sufficient grounds for exclusion Subjects with known Tuberculosis (TB) infection, at high risk of acquiring TB infection, or Latent Tuberculosis (LTB) infection are excluded Subjects at a high risk of infection (eg, leg ulcers, indwelling urinary catheter, persistent or recurrent chest infections, and subjects that are permanently bedridden or wheelchair bound) Subjects with a positive Hepatitis B surface antigen (HBsAg) test and/or Hepatitis C virus antibody (anti HCV) test result Subjects with positive human immunodeficiency virus (HIV) test Subjects receiving any live (includes attenuated) vaccination within 56 days prior to Baseline (eg, injectable influenza and pneumococcal vaccines are allowed, but nasal influenza vaccine is not) Subjects with a history of a lymphoproliferative disorder including lymphoma or signs and symptoms suggestive of lymphoproliferative disease at any time Subjects with an active malignancy of any type or a history of malignancy (other than carcinoma of the cervix or basal cell carcinoma successfully treated more than 5 years prior to Screening) Subjects with a history of blood dyscrasias, eg, leukemia or hemophilia where the blood constituents are abnormal or are present in abnormal quantity Subjects with class III or IV congestive heart failure New York Heart Association (NYHA) 1994 Subjects with a history of, or suspected, demyelinating disease of the central nervous system (eg, multiple sclerosis or optic neuritis) Subjects with a current or recent history, as determined by the Investigator, of severe, progressive, and/or uncontrolled renal, hepatic, hematological, GI, endocrine, pulmonary, cardiac, neurological, or cerebral disease which would interfere with the subject's participation in the study. Abnormal laboratory parameters as detailed in protocol that require exclusion of a subject Subjects with a history of an adverse reaction to Polyethylene Glycol (PEG) or a protein based medicinal product or known hypersensitivity to any components of the study medication or comparative drugs as stated in this protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Certolizumab Pegol + Methotrexate<br>Subjects will receive loading doses of CZP 400 mg (200 mg / prefilled syringe [PFS], ie, 2 injections) at Baseline, and Weeks 2 and 4; then CZP 200 mg (1 injection) Q2W until Week 22. All subjects will continue their treatment on Methotrexate (MTX), with or without folic acid, at the same dose and route of administration as at entry (unless there is a need to reduce the dose for reasons of toxicity, minimum dose permitted 10 mg per week). | Biological: Certolizumab Pegol<br>* Active substance: Certolizumab Pegol Pharmaceutical Form: Prefilled syringes Concentration: 200 mg/ml Route of administration: Subcutaneous injection<br>* Other names: Cimzia;Drug: Methotrexate<br>* Active substance: Methotrexate Pharmaceutical form: Tablet Concentration: Maximum dose 10 mg per week Route of administration: Oral<br>|
| Placebo Comparator: Placebo + Methotrexate<br>Subjects will receive Placebo (1mL / prefilled syringe [PFS], ie, 2 injections) at Baseline, and Weeks 2 and 4; then Placebo (1 injection) Q2W until Week 22. All subjects will continue their treatment on Methotrexate (MTX), with or without folic acid, at the same dose and route of administration as at entry (unless there is a need to reduce the dose for reasons of toxicity, minimum dose permitted 10 mg per week). | Drug: Methotrexate<br>* Active substance: Methotrexate Pharmaceutical form: Tablet Concentration: Maximum dose 10 mg per week Route of administration: Oral<br>Other: Placebo<br>* Active substance: Placebo Pharmaceutical form: Prefilled syringes Concentration: 0.9 % saline Route of Administration: Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Meeting the American College of Rheumatology 20 % Response Criteria (ACR20) at Week 24 | The assessments are based on a 20 % or greater improvement from Baseline to Week 24 in the number of tender joints, in the number of swollen joints, and a 20 % or greater improvement in at least 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Meeting the American College of Rheumatology 50 % Response Criteria (ACR50) at Week 24 | The assessments are based on a 50 % or greater improvement from Baseline to Week 24 in the number of tender joints, in the number of swollen joints, and a 50 % or greater improvement in at least 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). | Week 24 | 
| Percentage of Subjects Meeting the American College of Rheumatology 70 % Response Criteria (ACR70) at Week 24 | The assessments are based on a 70 % or greater improvement from Baseline to Week 24 in the number of tender joints, in the number of swollen joints, and a 70 % or greater improvement in at least 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). | Week 24 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24 | The HAQ-DI assesses the degree of difficulty experienced in 8 domains of daily living activities using 20 questions. Each domain consists of 2 or 3 items. For each question, the level of difficulty is scored from 0 to 3. A total score is computed from the item scores using the scoring rules provided by the index's author. HAQ-DI scores range from 0 to 3. Lower scores indicate less disability. Negative values indicate improvement from Baseline. | Baseline, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, TNFα antagonist, Certolizumab Pegol, Chinese patients