A Pharmacokinetic/Pharmacodynamic Study Comparing PF-05280586 To Rituximab In Subjects With Active Rheumatoid Arthritis With An Inadequate Response To TNF Inhibitors (REFLECTIONS B328-01)
- Conditions
- Rheumatoid Arthritis
- Interventions
- Biological: MabTheraBiological: PF-05280586Biological: Rituxan
- Registration Number
- NCT01526057
- Lead Sponsor
- Pfizer
- Brief Summary
In this study, patients with moderate to severe rheumatoid arthritis who are being treated with methotrexate will receive 2 intravenous treatments with either PF-05280586 or Rituxan (Rituximab) or MabThera (Rituximab). During the course of the study, the effects of the drugs will be assessed by sampling the levels of drug in the blood, blood cell counts, and by comparing these levels among the different treatments. Safety, tolerability and immunologic response also will be evaluated throughout.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 220
- Confirmed diagnosis of rheumatoid arthritis
- Meets Class I, II or III of the ACR 1991 Revised Criteria
- RA seropositivity
- Stable dose of methotrexate
- Inadequate response to TNF inhibitors
- Any prior treatment with lymphocyte depleting therapies
- History of active TB infection
- Known or screen test positive for specific viruses or indicators of viral infection
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description B - Rituximab EU MabThera - A - PF-05280586 PF-05280586 - C- Rituximab-US Rituxan -
- Primary Outcome Measures
Name Time Method AUC 0-inf of Rituximab Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion The AUC 0-inf refers to the concentration in serum of the drug over time. It represents the total drug exposure over time, from time 0 (the point of drug administration) extrapolated to infinity.
Maximum Serum Concentration (Cmax) of Rituximab Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion Cmax is the peak serum concentration of study drug (rituximab) after a dose has been administered.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Neutralizing Antibody (NAb) in Participants With a Positive ADA by Visit Day 1 up to Day 169 Percentage of Participants With American College of Rheumatology (ACR) 20% Improvement (ACR20) Response by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 ACR20 response: greater than or equal to (≥)20% improvement in tender joint count; ≥20% improvement in swollen joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire \[HAQ\]); and C-Reactive Protein (CRP).
Non-responder imputation categorized participants as having a non-response if they did not have data available at a visit due to missing data or study discontinuation. Participants who rolled over to the extension study were not included in the non-responder imputation from that point on.Percentage of Participants With ACR 70% Improvement (ACR70) Response by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT) ACR70 response: ≥70% improvement in tender joint count; ≥70% improvement in swollen joint count; and ≥70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.
Non-responder imputation categorized participants as having a non-response if they did not have data available at a visit due to missing data or study discontinuation. Participantss who rolled over to the extension study were not included in the non-responder imputation from that point on.Duration of B-cell Depletion (τB-cell) (Days) Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT) The τB-cell is defined as the time interval over which the B-cell count was \<0.3 cells/uL or the detection limit.
Percentage of Participants With CD19+ B-cell Count Recovery Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 The percentage of participants with CD19+ B-cell counts which fell to \<50% of Baseline value during treatment and which recovered to ≥50% of Baseline value at End of Treatment.
Area Under the CD19+ B-cell Count Concentration-time Profile (AUC 0-T, B-cell) Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT) The AUC 0-T, B-cell refers to the CD19+ B-cell count over time. It represents the total B-cells over time, from time 0 (the point of drug administration) to the last measured count at time T.
Percentage of Participants by Anti-drug Antibody (ADA) Status Days 1 up to Day 169. Presence of anti-rituximab antibodies in blood. Participants with a positive antibody status at any time during the study were defined as having overall positive antibody status; participants with a negative antibody status throughout the study were defined as having overall negative antibody status.
Percent Change From Baseline in HAQ-DI Score by Visit Baseline, Week 3, 5, 9, 13, 17, 21 and 25 HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.
Rituximab AUC From Time 0 to 2 Weeks (AUC 0-2wk) Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion The AUC 0-2wk refers to the concentration in serum of the drug over time. It represents the total drug exposure over time, from time 0 (the point of drug administration) to 2 weeks after drug administration.
Rituximab AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-T) Predose (Day 1) and 3, 4.25 (immediately before 1st infusion end), 72, 168, 335 (Day 15 within 1.5 hours before 2nd infusion), 337.5, 339.25 (Day 15 immediately before 2nd infusion end), 408, 504, 672, 1344, and 2016 hours after start of 1st infusion The AUC 0-T refers to the concentration in serum of the drug over time. It represents the total drug exposure over time, from time 0 (the point of drug administration) to the last measured concentration at time T.
Percentage of Participants With ACR 50% Improvement (ACR50) Response by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 ACR50 response: ≥50% improvement in tender joint count; ≥50% improvement in swollen joint count; and ≥50% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the HAQ); and CRP.
Non-responder imputation categorized participants as having a non-response if they did not have data available at a visit due to missing data or study discontinuation. Participants who rolled over to the extension study were not included in the non-responder imputation from that point on.Percent Change From Baseline in DAS28-CRP by Visit Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25 DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP less than or equal to (≤)3.2 implied low disease activity, DAS28-CRP greater than (\>)3.2 to ≤5.1 implied moderate to high disease activity, and DAS28-CRP less than (\<)2.6 implied remission.
Percentage of Participants With Moderate EULAR Response Based on Disease Activity Score Based on DAS28 by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline \>1.2 with DAS28 ≤3.2; moderate responders: change from baseline \>1.2 with DAS28 \>3.2 to ≤5.1 or change from baseline \>0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤0.6, or change from baseline \>0.6 and ≤1.2 with DAS28 \>5.1.
Percentage of Participants With DAS Remission (DAS <2.6) by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP \<2.6 implied remission. p-value of 9999 indicates p-value is not applicable.
CD19+ B-cell Count AUC From Time 0 to the Last Measurement at Time T (AUC 0-T,B-cell) Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT) The AUC 0-T,B-cell refers to the concentration in serum of B-cells. It represents the total B-cells over time from time 0 (the point of drug administration) to the last measurement taken at time T.
Minimum Post-Baseline CD19+ B-cell Count (/uL) Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT) The lowest CD19+ B-cell count measured in a participant's blood post-baseline.
Time to Minimum Post-Baseline CD19+ B-cell Count (Weeks) Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT) The amount of time in weeks from baseline to the lowest observed CD19+ B-cell count.
Baseline and Change From Baseline in Circulating Immunoglobulin-M (IgM) by Visit (Grams Per Liter (g/L]) Baseline and Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21 and 25 (EOT) The level of IgM in serum at Baseline and the change from Baseline at each subsequent visit.
Percent (%) Change From Baseline in Circulating IgM by Visit (g/L) Baseline and Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21 and 25 The percentage change from Baseline in circulating IgM by visit.
Change From Baseline in Disease Activity Score Based on 28-Joint Count and C-Reactive Protein (DAS28-CRP) Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25 DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP less than or equal to (≤)3.2 implied low disease activity, DAS28-CRP greater than (\>)3.2 to ≤5.1 implied moderate to high disease activity, and DAS28-CRP less than (\<)2.6 implied remission.
Percentage of Participants With Low Disease Activity Score (DAS <=3.2) by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 DAS28-CRP was calculated from the swollen joint count and tender joint count using the 28 joints count and CRP (mg/L). Total score range: 0 to 9.4, higher score indicated more disease activity. DAS28-CRP ≤3.2 implied low disease activity. p-value of 9999 indicates p-value is not applicable.
Percentage of Participants With Good European League Against Rheumatism (EULAR) Response Based on Disease Activity Score Based on 28-Joint Count (DAS28) by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline \>1.2 with DAS28 ≤3.2; moderate responders: change from baseline \>1.2 with DAS28 \>3.2 to ≤5.1 or change from baseline \>0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤0.6, or change from baseline \>0.6 and ≤1.2 with DAS28 \>5.1.
Percentage of Participants With No EULAR Response Based on DAS28 by Visit Weeks 3, 5, 9, 13, 17, 21 and 25 The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline \>1.2 with DAS28 ≤3.2; moderate responders: change from baseline \>1.2 with DAS28 \>3.2 to ≤5.1 or change from baseline \>0.6 to ≤1.2 with DAS28 ≤5.1; non-responders: change from baseline ≤0.6, or change from baseline \>0.6 and ≤1.2 with DAS28 \>5.1.
Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) by Visit Baseline, Week 3, 5, 9, 13, 17, 21 and 25 HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.
Trial Locations
- Locations (83)
Dartmouth Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
Mix Supplier S.A
🇨🇴Medellin, Antioquia, Colombia
IPS Centro Integral de Reumatologia del Cairbe, CIRCARIBE S.A.S.
🇨🇴Barranquilla, Atlantico, Colombia
Centro De Investigacion Y Atencion Integral Durango CIAID
🇲🇽Durango, Mexico
IPS Clinica General del Norte S.A.
🇨🇴Barranquilla, Colombia, Atlántico, Colombia
Centro de Alta Especialidad en Reumatologia e Investigacion del Potosi S.C.
🇲🇽San Luis Potosi, Mexico
State Institution of Healthcare "Regional Clinical Hospital for Wars' Veterans"
🇷🇺Kemerovo, Russian Federation
Llc Ava-Peter
🇷🇺St. Petersburg, Russian Federation
Regional State Budget Institution of Healthcare "Tomsk Regional Clinical Hospital"
🇷🇺Tomsk, Russian Federation
Ronald Reagan UCLA Medical Center
🇺🇸Los Angeles, California, United States
Klein & Associates, M.D., P.A.
🇺🇸Hagerstown, Maryland, United States
St. Vincent's Hospital (Melbourne)
🇦🇺Fitzroy, Victoria, Australia
The Chaim Sheba Medical Center Department of Internal Medicine B
🇮🇱Ramat Gan, Israel
State Budgetary Institution of Healthcare of Nizhegorodskiy Region
🇷🇺Nizhny Novgorod, Russian Federation
Schlosspark-Klinik GMBH, Internal Medicine II
🇩🇪Berlin, Germany
Cliditer, S.A. de C.V.
🇲🇽Mexico, D.f., Mexico
Centro de Reumatologia y Ortopedia
🇨🇴Barranquilla, Atlántico, Colombia
Bexley Wing - St. James's University Hospital
🇬🇧Leeds, UK, United Kingdom
Pharmacy Department, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust
🇬🇧Leeds, United Kingdom
Pharmacy Dispensing - Bexley Wing - St. James's University Hospital
🇬🇧Leeds, United Kingdom
GBUZ City Clinical Hospital #7
🇷🇺Kazan, Tatarstan, Russian Federation
"The University of Leeds,
🇬🇧Leeds, United Kingdom
Panorama Medical Centre
🇿🇦Panorama, Cape Town, South Africa
LLC CDCR "Healthy Joints"
🇷🇺Novosibirsk, Novosibirsk Region, Russian Federation
St. Petersburg state Healthcare lnstitution 'Clinical Rheumatology Hospital No25
🇷🇺Saint-Petersburg, Russian Federation
State Institute of Healthcare Samara Regional Clinical Hospital named after M.I.Kalinin
🇷🇺Samara, Russian Federation
Whipps Cross University Hospital
🇬🇧London, United Kingdom
Dr. Jan Fourie Medical Centre
🇿🇦Dundee, Kwa-zulu Natal, South Africa
Rheumatology Associates of North Alabama, PC
🇺🇸Huntsville, Alabama, United States
Mercy Clinic Hot Springs Communities
🇺🇸Hot Springs, Arkansas, United States
ArthroCare, Arthritis Care & Research, PC
🇺🇸Gilbert, Arizona, United States
UCLA David Geffen School of Medicine
🇺🇸Los Angeles, California, United States
Desert Medical Advances
🇺🇸Palm Desert, California, United States
New England Research Assoc. LLC
🇺🇸Trumbull, Connecticut, United States
Loyola Center for Health at Burr Ridge
🇺🇸Burr Ridge, Illinois, United States
Loyola Medical Medical Center Outpatient Center
🇺🇸Maywood, Illinois, United States
Clinical Pharmacology Study Group
🇺🇸Worcester, Massachusetts, United States
Illinois Bone and Joint Institute
🇺🇸Morton Grove, Illinois, United States
Loyola University Medical Center Pharmacy
🇺🇸Maywood, Illinois, United States
UMass Memorial Medical Center - Memorial Campus
🇺🇸Worcester, Massachusetts, United States
UMass Memorial Medical Center-Rheumatology Center-Memorial Campus
🇺🇸Worcester, Massachusetts, United States
Rheumatology/Arthritis Center
🇺🇸Lansing, Michigan, United States
Hickory Family Practice Associates
🇺🇸Hickory, North Carolina, United States
North Shore-LIJ Health System - Division of Rheumatology and Allergy-Clinical Immunology
🇺🇸Great Neck, New York, United States
PMG Research of Hickory, LLC - PI's Main Office (Subject visit, IP Storage, Infusion, & Lab Draws)
🇺🇸Hickory, North Carolina, United States
PMG Research of Hickory
🇺🇸Hickory, North Carolina, United States
The Arthritis Group
🇺🇸Philadelphia, Pennsylvania, United States
Altoona Center for Clinical Research
🇺🇸Duncansville, Pennsylvania, United States
Arthritis Clinic
🇺🇸Jackson, Tennessee, United States
Arthritis Associates, PLLC
🇺🇸Hixson, Tennessee, United States
Clinical Research Center of Reading, LLP
🇺🇸Wyomissing, Pennsylvania, United States
West Tennessee Research Institute
🇺🇸Jackson, Tennessee, United States
Metroplex Clinical Research Center
🇺🇸Dallas, Texas, United States
Southwest Rheumatology Research LLC.
🇺🇸Mesquite, Texas, United States
Rheumatology Research Unit
🇦🇺Maroochydore, Queensland, Australia
Centre de Rhumatologie de l'Est du Quebec
🇨🇦Rimouski, Quebec, Canada
Clinique Medicale du Phare
🇨🇦Rimouski, Quebec, Canada
Pharmacie Matte et Petit
🇨🇦Quebec, Canada
Clinica Medellin S.A Sede Centro
🇨🇴Medellin, Antioquia, Colombia
Rodrigo Botero S.A.S.
🇨🇴Medellin, Antioquia, Colombia
Centre de Recherche Musculo-Squelettique
🇨🇦Trois-Rivieres, Quebec, Canada
Centre de Rhumatologie St-Louis
🇨🇦Quebec, Canada
Clinica de la Costa Ltdz.
🇨🇴Barranquilla, Atlantico, Colombia
Cediul S.A.
🇨🇴Barranquilla, Atlantico, Colombia
Clinica Bonnadona - Prevenir S.A.
🇨🇴Barranquilla, Atlantico, Colombia
Sabbag Radiologos Ltda.
🇨🇴Barranquilla, Atlantico, Colombia
Congregacion de las Hemanas Franciscanas Misioneras de Maria Auxiliadora - Clinica La Asuncion
🇨🇴Barranquilla, Colombia, Atlántico, Colombia
Cerid S.A.
🇨🇴Barranquilla, Colombia, Atlántico, Colombia
Bronson Internal Medicine & Rheumatology
🇺🇸Battle Creek, Michigan, United States
Advances In Medicine
🇺🇸Rancho Mirage, California, United States
Loyola Center for health at Oakbrook Terrace North
🇺🇸Oakbrook Terrace, Illinois, United States
Box Arthritis & Rheumatology of the Carolinas, PLLC
🇺🇸Charlotte, North Carolina, United States
University of Alabama at Bermingham
🇺🇸Birmingham, Alabama, United States
University of Alabama at Birmingham - Arthritis Clinical Intervention Program (ACIP) SRC 076
🇺🇸Birmingham, Alabama, United States
University of South Florida - College of Medicine, Frank and Carol Morsani Center
🇺🇸Tampa, Florida, United States
University Of Nevada School Of Medicine
🇺🇸Las Vegas, Nevada, United States
Cincinnati Rheumatic Disease Study Group, Inc.
🇺🇸Cincinnati, Ohio, United States
Health Research of Oklahoma
🇺🇸Oklahoma City, Oklahoma, United States
Center For Clinical Trials Of Houston
🇺🇸Houston, Texas, United States
Arthritis Associates
🇺🇸Orlando, Florida, United States
Bluegrass Community Research, Inc.
🇺🇸Lexington, Kentucky, United States
The Queen Elizabeth Hospital, Department of Rheumatology
🇦🇺Woodville South, South Australia, Australia
Private Office
🇲🇽Guadalajara, Jalisco, Mexico