A study comparing the pharmacokinetics and pharmacodynamics, and assessing the safety of PF-05280586 in subjects with active rheumatoid arthritis

• Register: EUCTR
• Last refreshed on: 27 October 2014
• Main ID: EUCTR2011-002896-40-DE
• Date of registration: 02/07/2012
• Prospective Registration: Yes
• Primary sponsor: Pfizer Inc., 235 East 42nd Street, New York, NY 10017 US
• Public title: A study comparing the pharmacokinetics and pharmacodynamics, and assessing the safety of PF-05280586 in subjects with active rheumatoid arthritis
• Scientific title: A RANDOMIZED, DOUBLE-BLIND, STUDY COMPARING THE PHARMACOKINETICS AND PHARMACODYNAMICS, AND ASSESSING THE SAFETY OF PF-05280586 AND RITUXIMAB IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS ON A BACKGROUND OF METHOTREXATE WHO HAVE HAD AN INADEQUATE RESPONSE TO ONE OR MORE TNF ANTAGONIST THERAPIES - REFLECTIONS B328-01
• Date of first enrolment: 23/10/2012
• Target sample size: 195
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-002896-40
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 3

Countries of recruitment

Argentina, Australia, Brazil, Canada, Colombia, France, Germany, Israel, Italy, Mexico, Peru, Poland, Russian Federation, South Africa, Spain, Taiwan, United Kingdom, United States

Contacts

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc.

• Name: Clinical Trials.gov Call Center
• Affiliation: Pfizer Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Age 18 years or older.
2. 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.
3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Confirmed diagnosis of rheumatoid arthritis (RA) based on 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis.
5. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA.
6. RA seropositivity as documented by a screening assessment for RF, and/or anti CCP.
7. Active disease as defined by:
a. =6 tender/painful joints (of 68 assessed) at screening and baseline, and
b. =6 swollen joints (of 66 assessed) at screening and baseline, and
c. hs-CRP > ULN at screening, performed by central laboratory
OR
Patient’s Global Assessment of Arthritis score =50, and
d. Screening DAS28-CRP >3.2.
8. Stable dose of oral or parenteral methotrexate 10-25 mg per week (depending on local practice and standard of care; in the case of prior poor tolerance, methotrexate doses as low as 7.5 mg per week are allowed). Subjects must have received methotrexate for at least 3 months, and with a stable dose for at least 4 weeks prior to first dose of study drug.
9. Inadequate response in the opinion of the investigator to 1 or more approved TNF antagonist therapies administered in accordance with local product label. Inadequate response is defined as:
a. Failure to achieve adequate clinical response during prior TNF antagonist therapy, or
b. Relapse following clinical response to TNF antagonist therapy, or
c. Adverse event to TNF antagonist therapy resulting in discontinuation from treatment.
Please refer to the Protocol for a full list of Inclusion Criteria
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 147
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 48

Exclusion criteria:
Subjects presenting with any of the following will not be included in the study:
1. Any prior treatment with lymphocyte depleting therapies such as, but not limited to rituximab [Rituxan®, MabThera®], alemtuzumab (Campath®), total lymphoid irradiation.
2. Pregnant females; breast feeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 12 months after last dose of investigational product. 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.
3. Inadequate bone marrow, liver, renal and immune system functions at screening visit as defined by:
a. Absolute neutrophil count (ANC) =1500 cells/mm^3.
b. Platelets <100 x 109/L.
c. Hemoglobin (Hgb) <8 g/dL.
d. Bilirubin =1.5 times the upper limit of normal (x ULN), unless a diagnosis of Gilbert’s Disease in which case =2.5 x ULN.
e. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =3 x ULN.
f. Serum creatinine =1.5 mg/dL.
g. Immunoglobulin G (IgG) or IgM < lower limit of normal (LLN).
4. 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. Screening TB according to local health authority guidance.
b. History of active TB infection.
• A Mantoux Purified Protein Derivative (PPD) test may be performed locally for subjects not having prior Bacille Calmette Guérin (BCG) vaccination and interpreted by the investigator according to local standards or country-specific guidelines. A QuantiFERON Gold®™ test is recommended and provided for subjects in this study with a history of BCG vaccination.
• Screening chest radiograph suggestive of active TB infection.
c. Untreated or inadequately treated latent TB infection. Subjects previously treated for potential latent TB must have completed a full course of treatment in accordance with local guidelines. Subjects may be randomized after receiving at least the first 1-month of course of the anticipated prophylactic treatment that must be continued to completion.
5. Known or screen test positive for any of the following viruses or indicators of viral infection:
a. Known positive for human immunodeficiency virus (HIV).
b. Test positive for hepatitis B surface antigen (HBsAg). c. Test positive for core antibody associated with positive HBV DNA.
d. Test positive for hepatitis C virus.
e. History of disseminated or recurrent herpes zoster (single, limited episode in the past is not exclusionary).
f. History of disseminated herpes simplex.
6. Primary or secondary immunodeficiency.
7. History of recurrent inflammatory joint disease other than rheumatoid arthritis (eg, other autoimmune diseases, vasculopathies, spondyloarthropathies, severe osteoarthritis, post infectious arthritis, gout).
8. History of lymphoproliferative disorder (eg, Epstein Barr Virus (EBV) related lymphoproliferative disorder, lymphoma, leukemia).
9. Infection requiring hospitalization, parenteral antimicrobial therapy, or judged clinically significant by the investigator within 3 months prior to first dose of study drug.
10. Vaccination with live or attenuated vaccines within 6 weeks prior to the first dose of study drug or plan/need to administer these vaccines during study participation or within 4 weeks following discon

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

RHEUMATOID ARTHRITIS
MedDRA version: 16.1 Level: LLT Classification code 10003268 Term: Arthritis rheumatoid System Organ Class: 100000004859

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: Rituximab-Pfizer
Product Code: PF-05280586
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Not Applicable
Current Sponsor code: PF-05280586
Other descriptive name: Not Applicable
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: MabThera®
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: Not Applicable
Other descriptive name: Not Applicable
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: Rituxan®
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Current Sponsor code: Not Applicable
Other descriptive name: Not Applicable
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Main Objective: To demonstrate the PK similarity of rituximab Pfizer, rituximab EU and rituximab-US in subjects with active rheumatoid arthritis on a background of methotrexate who have had an inadequate response to 1 or more TNF antagonist therapies.

Secondary Objective: • To utilize population PK/PD modeling approaches to integrate PK and PD data for the purpose of detecting potential differences in PK/PD profiles among rituximab-Pfizer, rituximab-EU and rituximab-US.
• To assess additional clinical response endpoints of rituximab Pfizer, rituximab EU and rituximab-US.
• To evaluate the overall safety, tolerability and immunogenicity of rituximab-Pfizer, rituximab-EU and rituximab-US.
• To evaluate health outcomes using HAQ DI in subjects receiving rituximab-Pfizer, rituximab-EU, and rituximab-US.

Timepoint(s) of evaluation of this end point: PK parameters Cmax, and AUC0-8. Timepoint: The parameters will be assessed after Day 85 for the primary endpoint.

Primary end point(s): PK parameters Cmax, and AUC0-8

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: PK parameters: AUC0-2wk Day 15: AUC0-8wk Day 57: AUC0-12wk Day 85
PD parameters: CD19+ B-cell count and IgM Day 1, 4, 8, 15, 22, 29, 57, 85, 113, 141, 169 and follow-up as needed every 3 months DAS28-CRP Day 15, 29, 57 and 85
• Type, incidence, severity, timing, seriousness, and relatedness of adverse events, and laboratory abnormalities throughout the study
• Incidence of anti drug antibodies and safety associated with immune response Day 1, 15, 29, 57, 85 and 169 with follow-up every 3 months if needed.
• Mean change from baseline in DAS28-CRP, EULAR response, LDAS, and DAS remission Day 15, 29, 57, 85, 113, 141 and 169.
• ACR response Day 169.

Secondary end point(s): • PK parameters AUC0-2wk, AUC0-8wk and AUC0-12wk.
• PD parameters of drug effect including CD19+ B-cell count, circulating IgM and kinetics of early clinical response using DAS28-CRP.
• Type, incidence, severity, timing, seriousness, and relatedness of adverse events, and laboratory abnormalities.
• Incidence of anti rituximab antibodies (ADA), including neutralizing antibodies (Nab), and safety associated with immune response.
• Mean change from baseline in DAS28-CRP, EULAR response (reduction =1.2), LDAS (=3.2), and DAS remission (<2.6).
• ACR response at End of Treatment (EOT).
• Outcome measure using HAQ DI.

Secondary ID(s)

NCT01526057

2011-002896-40-GB

B3281001

Source(s) of Monetary Support

Pfizer Inc., 235 East 42nd Street, New York, NY 10017