A Phase 3 Randomized, Double-Blind Study Assessing the Efficacy and Safety of PF-06438179 and Infliximab in Combination with Methotrexate in Subjects with Moderately to Severely Active Rheumatoid Arthritis who have had an Inadequate Response to Methotrexate
A Phase 3 Randomized, Double-Blind Study Assessing the Efficacy and Safety of PF-06438179 and Infliximab in Combination with Methotrexate in Subjects with Moderately to Severely Active Rheumatoid Arthritis who have had an Inadequate Response to Methotrexate.
This is a Phase 3, multi-national, randomized, double blind, two-arm, parallel group study designed to evaluate the safety, efficacy, and immunogenicity of infliximab-Pfizer versus infliximab-EU in combination with methotrexate when administered intravenously to treat subjects with moderately to severely active RA who have had an inadequate response to methotrexate therapy. This study is also designed to evaluate clinical response, safety and immunogenicity after study drug transitioning from infliximab-EU to infliximab-Pfizer after 30 or 54 weeks of infliximab-EU treatment. The primary endpoint is ACR20 response at Week 14 of study treatment. Evaluation at both earlier time points (Weeks 2, 4, 6, 12) and later time points (Weeks 22 and 30) will be used to support the primary endpoint analysis.
|2010 - 2016||Health Technology Development||Drug Discovery and Development|
|Start Date||Duration in Months||Target Completion Date||Actual Completion Date|
|Pfizer Inc.||Private Business||NCR||N/A|
|PAREXEL Clinical Research (Philippines) Ltd. Corp.||Private Business||NCR||CDRR-NCR-CRO-4|
|Name||Institution and Institution Address|
|Raida Flores||Raida.Flores@parexel.com||15th Floor Philamlife Bldg. 8767 Paseo De Roxas Makati City|
|Name||Institution and Institution Address|
|Maaliddin Biruar, MD||Maaliddin.Biruar@parexel.com||15th Floor Philamlife Bldg. 8767 Paseo De Roxas Makati City|
|Allan E. Lanzon, MD||Rheumatology||Mary Mediatrix Medical Center|
|Andrei Rhoniel M. Rodriguez, MD||Rheumatology||Makati Medical Center|
|Bernadette Heizel Manapat-Reyes, MD||Rheumatology||University of the Philippines - Philippine General Hospital|
|Edgar Ramiterre, MD||Rheumatology||Southern Philippines Medical Center|
|Juan Javier T. Lichauco, MD||Rheumatology||St. Luke's Medical Center - Global City|
|Manuel Emerson S. Donaldo, MD||Rheumatology||Chong Hua Hospital|
|Michael L. Tee, MD||Rheumatology||Medical Center Manila|
|Project Location||Institutional Ethics Review Board|
|Mary Mediatrix Medical Center||Mary Mediatrix Medical Center Research Ethics Review Committee|
|Makati Medical Center||Makati Medical Center Institutional Review Board|
|University of the Philippines - Philippine General Hospital||N/A|
|Southern Philippines Medical Center||DOH XI Cluster Ethics Review Committee|
|St. Luke's Medical Center - Global City||N/A|
|Chong Hua Hospital||Chong Hua Hospital Institutional Review Board|
|Medical Center Manila||Manila Medical Ethics Review Committee|
ACR20 response (≥20% improvement by ACR criteria) at Week 14.
Categorical and continuous measures of clinical efficacy, including ACR20 (other than Week 14), ACR50, ACR70, change in DAS28-CRP (Disease Activity Score-28;
4 components based on hs-CRP), DAS remission (≤2.6), EULAR (European League Against Rheumatism) response and ACR/EULAR remission.
Safety measures characterized by type, incidence, severity, timing, seriousness and relatedness of adverse events and laboratory abnormalities.
Change from baseline in individual components of ACR response (including HAQ-DI).
Incidence and titers of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) in response to infliximab-Pfizer and infliximab-EU.
Serum drug concentrations.
more patients are eligible for the study
Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male and female subjects aged 18 years or older at the time of informed consent. Where required by regulations, consent from a legal representative is required for all subjects who are younger than 20 years of age.
4. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 6 months after the last dose of assigned treatment.
A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
Female subjects who are not of childbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum FSH level in the laboratory’s reference range for postmenopausal females.
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
c. Have medically confirmed ovarian failure.
All other female subjects (including females with tubal ligations and females that do NOT have a documented hysterectomy or bilateral oophorectomy) will be considered to be of childbearing potential.
5. Diagnosis of rheumatoid arthritis (RA) based on 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria (see Appendix 1) for RA for at least a 4 month duration.
6. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA (see Appendix 2).
7. Moderately to severely active RA disease as defined by the following criteria:
a. 6 tender joints (of 68 assessed) at both Screening and Baseline, and
b. 6 swollen joints (of 66 assessed) at both Screening and Baseline, and
c. Hs-CRP ≥10 mg/L (≥1 mg/dL) at Screening, performed by a central laboratory.
Subjects who do not meet this entry criteria but satisfy all other study entry criteria may have serum hs-CRP concentration re-tested once within 14 days and, if the repeat hs-CRP concentration is ≥10 mg/L (≥1 mg/dL), will be eligible to enroll into the study provided all other inclusion/exclusion criteria are met.
8. Stable dose of oral or parenteral methotrexate of 10 to 25 mg/week. Subjects who cannot tolerate 10 to 25 mg/week methotrexate may take a lower dose of as low as 7.5 mg/week.
In geographic regions where specified by local guidance or standard of care, a stable dose of as low as 6 mg/week is allowed. Subjects must have received methotrexate for at least 12 weeks and be on a stable dose for at least 4 weeks prior to first dose of study drug.
9. Stable dose of oral folic or folinic acid (≥5 mg per week) supplementation for at least 21 days prior to the first dose of study drug.
10. If receiving an oral corticosteroid, subjects must be on a stable dose of 10 mg/day of prednisone (or equivalent) for 4 weeks prior to the first dose of study drug, without any intramuscular (IM) or intra-articular (IA) corticosteroids within the 4 weeks prior to the first dose of study drug.
11. If receiving a NSAID/Cox-2 inhibitor, subject must be on a stable dose of only one NSAID/Cox-2 inhibitor drug for 4 weeks prior to the first dose of study drug at a dosage less than or equal to the maximum recommended dose in the product information. In
addition, a cardiovascular dose of aspirin (≤325 mg/day) is permitted. Topical NSAIDs (in addition to one NSAID/Cox-2 inhibitor drug) are allowed, prior to and during the study . Topical NSAIDs should not be used within 24 hours prior to joint assessments.
Subjects presenting with any of the following will not be included in the study:
1. Pregnant females and breastfeeding females; males and females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 6 months after last dose of
investigational product. Females must not breastfeed for at least 6 months after last dose of investigational product.
2. Clinically significant laboratory abnormalities at Screening, including but not limited to inadequate bone marrow, liver, renal and immune system functions as defined by the following lab criteria:
a. Hemoglobin (Hgb) b. Absolute neutrophil count (ANC) 1500 cells/mm3.
c. White blood cell count <3.0 x 109/L.
d. Platelets e. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) 2 times the upper limit of normal.
f. Bilirubin 1.5 times the upper limit of normal.
g. Serum creatinine 1.5 mg/dL.
h. Beta-D-Glucan = positive (Japan Only, see Appendix 14).
Subjects who do not meet a lab entry criteria but satisfy all other study entry criteria may have the lab re-tested within 14 days and, if within the required range, will be eligible to enroll into the study provided all other inclusion/exclusion criteria are met.
3. Evidence or history of moderate or severe heart failure (NYHA class III/IV, see Appendix 11 for NYHA classification of congestive heart failure) and subjects who are contraindicated for treatment with infliximab in accordance with the approved local label.
4. Evidence of current or recent history of uncontrolled, clinically significant infectious, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease.
5. Evidence or history of seizures, or nervous system demyelinating diseases (including multiple sclerosis, optic neuritis, Guillain-Barré syndrome).
6. Evidence or history of a malignancy within the past 5 years with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ with no evidence of recurrence.
7. History of any lymphoproliferative disorder (eg, Epstein Barr Virus (EBV) related lymphoproliferative disorder, lymphoma, leukemia).
8. History of recurrent (more than one episode) limited herpes zoster or disseminated (a single episode) herpes zoster or herpes simplex. History of disseminated or recurrent infection of EBV or human papilloma virus (HPV) (a single, limited episode in the past is not exclusionary).
9. Infection requiring hospitalization or parenteral antimicrobial therapy judged clinically significant by the investigator within 6 months prior to first dose of study drug.
10. History of an infected joint prosthesis at any time.
11. History of recurrent inflammatory joint disease other than RA (eg, post infectious arthritis, gout, etc.) or history of any other autoimmune rheumatic diseases (eg, vasculopathies, spondyloarthropathies, etc.) other than Sjogren’s syndrome.
12. Evidence of untreated or inadequately treated latent, or inadequately treated or active infection with tuberculosis (TB) as defined by one or more of the following:
a. Positive TB test at Screening (QuantiFERON®-TB Gold In-Tube Test).
Note: If a false positive TB result is suspected by the investigator at Screening (eg, when the screening chest radiography result is negative for TB and workup for non-pulmonary TB is negative, although the Screening QuantiFERON®-TB is positive), the subject should be referred to a TB specialist, pulmonologist or infectious disease specialist for further evaluation before initiating study treatment.
Prior to enrolling a subject who is suspected of having a false positive QuantiFERON®-TB test result, the investigator must discuss the case with the Medical Monitor.
b. History of either untreated or inadequately treated latent or active TB. Subjects previously treated for latent TB infection must have completed a successful course of treatment in accordance with local guidelines. Subjects detected with latent TB infection at Screening may be rescreened and randomized after having completed a
successful course of treatment in accordance with local guidelines. Subjects currently receiving treatment for active or latent TB are excluded.
13. Chest radiography with evidence of active TB, fungal infections, or other clinically significant abnormalities taken at Screening or within 12 weeks prior to first dose of study drug on Day 1.
14. Any current or prior treatment for the following DMARDs within the relevant washout period:
a. Washout for 12 weeks prior to first dose of study drug with immunosuppressive drugs, including alkylating agents (eg, cyclophosphamide and chlorambucil), mycophenolate mofetil, azathioprine, or 6-mercaptopurine. Washout for 12 weeks
prior to first dose of study drug with leflunomide. Alternatively, with the following elimination procedure, discontinue at least 4 weeks prior to first dose of study drug:
Elimination procedure upon discontinuation of leflunomide: Administer cholestyramine 8 grams TID for 11 days. (The 11 days do not need to be consecutive unless there is a need to lower the plasma level rapidly).
b. Washout for 8 weeks prior to first dose of study drug with gold therapy [auranofin or injectable gold (aurothioglucose or aurothiomalate), tofacitinib, tacrolimus, cyclosporine, and D-penicillamine.
c. Washout for 4 weeks prior to first dose of study drug with sulfasalazine and antimalarial drugs.
d. Washout for at least 4 weeks or 5 half-lives, whichever is longer, prior to first dose of study drug for Investigational treatments for RA not specifically mentioned.
15. Current or prior treatment with infliximab or lymphocyte depleting therapies (eg, Rituximab, Campath). Prior exposure to biologic therapy for RA (with the exception of up to 2 doses of one biologic therapy for RA, including anti-TNF therapies (other than infliximab). For prior exposure to a biologic therapy for RA, a washout period of at least 12 weeks or 5 half lives (whichever is longer) is required prior to the first dose of study drug.
16. Known requirement for treatment with prohibited concomitant medications during study.
17. Significant trauma or surgical procedure within 4 weeks prior to first dose of study drug.
18. Known or Screen test positive human immunodeficiency virus (HIV). Positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) at Screening. Subjects with positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) results are not
eligible to participate in the study. Subjects with negative HBcAb and HBsAg results but positive hepatitis B surface antibody (HBsAb) due to hepatitis B immunization are eligible to participate in the study. Subjects with positive hepatitis C antibody (HCVAb) and negative confirmatory HCV riboneucleic acid (RNA) results at Screening will be eligible to participate in the study.
19. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
20. Positive urine drug test at Screening for substances of abuse that is not due to prescribed medication.
If a subject, residing in a country where certain substances of abuse are available without a prescription, has a positive urine drug test and the Investigator considers the substance is being used appropriately, the subject may be eligible for the study provided the subject meets all other eligibility criteria. However, subject eligibility must be discussed with the study team prior to randomization.
21. Past or current history of addiction or dependence on non-prescribed substances within 12 months prior to Screening.
22. History of allergic or hypersensitivity reaction to active or inactive components of the study drug or any murine, chimeric or human proteins.
23. Exposure to any live vaccines within 4 weeks prior to administration of the first dose of study drug or lack of willingness to avoid exposure to any live vaccines during the trial and for at least 3 months after the last dose of study drug.
24. Participation in other studies involving investigational drug(s) (Phase 1-4) within at least 4 weeks or 5 half-lives from last dose, whichever is longer, before the current study begins and/or during study participation.
25. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the
judgment of the investigator, would make the subject inappropriate for entry into this study.
26. Unwilling or unable to comply with the Life Style Guidelines described in this protocol.
27. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.
Infliximab (marketed under the brand name REMICADE®) is a chimeric human-murine IgG1 kappa monoclonal antibody specific for TNFα and is approved for use in both the United States (US) and the European Union (EU).
|2015-04-24||Amendments related to the protocol||Informed consent|
|2015-07-15||Amendments related to the protocol||Informed consent|
|2016-06-14||Amendments related to the protocol||Informed consent|
|2017-02-28||Amendments related to the protocol||Informed consent|
To compare the efficacy between infliximab-Pfizer and infliximab-EU in subjects with moderately to severely active RA who are treated with infliximab in combination with methotrexate.
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