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)

Rheumatoid Arthritis Clinical Trial

— REFLECTIONS  

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01526057
• Other study ID #: B3281001
• Secondary ID: ICON 9002/010201
• Status: Completed
• Phase: Phase 2
• Start date: March 20, 2012
• Est. completion date: May 7, 2014

Study information

• Verified date: October 2019
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: May 7, 2014
• Est. primary completion date: August 13, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Biological:
• PF-05280586
1000 mg, IV on days 1 and 15
• MabThera
1000 mg, IV on days 1 and 15
• Rituxan
1000 mg, IV on days 1 and 15

Locations

Country	Name	City	State
Australia	St. Vincent's Hospital (Melbourne)	Fitzroy	Victoria
Australia	Rheumatology Research Unit	Maroochydore	Queensland
Australia	The Queen Elizabeth Hospital, Department of Rheumatology	Woodville South	South Australia
Canada	Centre de Rhumatologie St-Louis	Quebec
Canada	Pharmacie Matte et Petit	Quebec
Canada	Centre de Rhumatologie de l'Est du Quebec	Rimouski	Quebec
Canada	Clinique Medicale du Phare	Rimouski	Quebec
Canada	Centre de Recherche Musculo-Squelettique	Trois-Rivieres	Quebec
Colombia	Cediul S.A.	Barranquilla	Atlantico
Colombia	Centro de Reumatologia y Ortopedia	Barranquilla	Atlántico
Colombia	Clinica Bonnadona - Prevenir S.A.	Barranquilla	Atlantico
Colombia	Clinica de la Costa Ltdz.	Barranquilla	Atlantico
Colombia	IPS Centro Integral de Reumatologia del Cairbe, CIRCARIBE S.A.S.	Barranquilla	Atlantico
Colombia	Sabbag Radiologos Ltda.	Barranquilla	Atlantico
Colombia	Cerid S.A.	Barranquilla, Colombia	Atlántico
Colombia	Congregacion de las Hemanas Franciscanas Misioneras de Maria Auxiliadora - Clinica La Asuncion	Barranquilla, Colombia	Atlántico
Colombia	IPS Clinica General del Norte S.A.	Barranquilla, Colombia	Atlántico
Colombia	Clinica Medellin S.A Sede Centro	Medellin	Antioquia
Colombia	Mix Supplier S.A	Medellin	Antioquia
Colombia	Rodrigo Botero S.A.S.	Medellin	Antioquia
Germany	Schlosspark-Klinik GMBH, Internal Medicine II	Berlin
Israel	The Chaim Sheba Medical Center Department of Internal Medicine B	Ramat Gan
Mexico	Centro De Investigacion Y Atencion Integral Durango CIAID	Durango
Mexico	Private Office	Guadalajara	Jalisco
Mexico	Cliditer, S.A. de C.V.	Mexico	D.f.
Mexico	Centro de Alta Especialidad en Reumatologia e Investigacion del Potosi S.C.	San Luis Potosi
Russian Federation	GBUZ City Clinical Hospital #7	Kazan	Tatarstan
Russian Federation	State Institution of Healthcare "Regional Clinical Hospital for Wars' Veterans"	Kemerovo
Russian Federation	State Budgetary Institution of Healthcare of Nizhegorodskiy Region	Nizhny Novgorod
Russian Federation	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	Llc Ava-Peter	St. Petersburg
Russian Federation	Regional State Budget Institution of Healthcare "Tomsk Regional Clinical Hospital"	Tomsk
South Africa	Dr. Jan Fourie Medical Centre	Dundee	Kwa-zulu Natal
South Africa	Panorama Medical Centre	Panorama	Cape Town
United Kingdom	"The University of Leeds,	Leeds
United Kingdom	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	Whipps Cross University Hospital	London
United States	Bronson Internal Medicine & Rheumatology	Battle Creek	Michigan
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	Loyola Center for Health at Burr Ridge	Burr Ridge	Illinois
United States	Box Arthritis & Rheumatology of the Carolinas, PLLC	Charlotte	North Carolina
United States	Cincinnati Rheumatic Disease Study Group, Inc.	Cincinnati	Ohio
United States	Klein & Associates, M.D., P.A.	Cumberland	Maryland
United States	Metroplex Clinical Research Center	Dallas	Texas
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	ArthroCare, Arthritis Care & Research, PC	Gilbert	Arizona
United States	North Shore-LIJ Health System - Division of Rheumatology and Allergy-Clinical Immunology	Great Neck	New York
United States	Klein & Associates, M.D., P.A.	Hagerstown	Maryland
United States	Hickory Family Practice Associates	Hickory	North Carolina
United States	PMG Research of Hickory	Hickory	North Carolina
United States	PMG Research of Hickory, LLC - PI's Main Office (Subject visit, IP Storage, Infusion, & Lab Draws)	Hickory	North Carolina
United States	Arthritis Associates, PLLC	Hixson	Tennessee
United States	Mercy Clinic Hot Springs Communities	Hot Springs	Arkansas
United States	Center For Clinical Trials Of Houston	Houston	Texas
United States	Rheumatology Associates of North Alabama, PC	Huntsville	Alabama
United States	Arthritis Clinic	Jackson	Tennessee
United States	West Tennessee Research Institute	Jackson	Tennessee
United States	Rheumatology/Arthritis Center	Lansing	Michigan
United States	University Of Nevada School Of Medicine	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Bluegrass Community Research, Inc.	Lexington	Kentucky
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	UCLA David Geffen School of Medicine	Los Angeles	California
United States	Loyola Medical Medical Center Outpatient Center	Maywood	Illinois
United States	Loyola University Medical Center Pharmacy	Maywood	Illinois
United States	Southwest Rheumatology Research LLC.	Mesquite	Texas
United States	Illinois Bone and Joint Institute	Morton Grove	Illinois
United States	Loyola Center for health at Oakbrook Terrace North	Oakbrook Terrace	Illinois
United States	Health Research of Oklahoma	Oklahoma City	Oklahoma
United States	Arthritis Associates	Orlando	Florida
United States	Desert Medical Advances	Palm Desert	California
United States	The Arthritis Group	Philadelphia	Pennsylvania
United States	Advances In Medicine	Rancho Mirage	California
United States	University of South Florida - College of Medicine, Frank and Carol Morsani Center	Tampa	Florida
United States	New England Research Assoc. LLC	Trumbull	Connecticut
United States	Clinical Pharmacology Study Group	Worcester	Massachusetts
United States	UMass Memorial Medical Center - Memorial Campus	Worcester	Massachusetts
United States	UMass Memorial Medical Center-Rheumatology Center-Memorial Campus	Worcester	Massachusetts
United States	Clinical Research Center of Reading, LLP	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Colombia,  Germany,  Israel,  Mexico,  Russian Federation,  South Africa,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Serum Concentration (Cmax) of Rituximab	Cmax is the peak serum concentration of study drug (rituximab) after a dose has been administered.	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
Primary	AUC 0-inf of Rituximab	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.	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
Secondary	Rituximab AUC From Time 0 to 2 Weeks (AUC 0-2wk)	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.	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
Secondary	Rituximab AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-T)	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.	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
Secondary	CD19+ B-cell Count AUC From Time 0 to the Last Measurement at Time T (AUC 0-T,B-cell)	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.	Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
Secondary	Minimum Post-Baseline CD19+ B-cell Count (/uL)	The lowest CD19+ B-cell count measured in a participant's blood post-baseline.	Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
Secondary	Time to Minimum Post-Baseline CD19+ B-cell Count (Weeks)	The amount of time in weeks from baseline to the lowest observed CD19+ B-cell count.	Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
Secondary	Duration of B-cell Depletion (tB-cell) (Days)	The tB-cell is defined as the time interval over which the B-cell count was <0.3 cells/uL or the detection limit.	Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
Secondary	Percentage of Participants With CD19+ B-cell Count Recovery	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.	Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25
Secondary	Area Under the CD19+ B-cell Count Concentration-time Profile (AUC 0-T, B-cell)	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.	Baseline and Weeks 2, 3, 5, 9, 13, 17, 21 and 25 (EOT)
Secondary	Baseline and Change From Baseline in Circulating Immunoglobulin-M (IgM) by Visit (Grams Per Liter (g/L])	The level of IgM in serum at Baseline and the change from Baseline at each subsequent visit.	Baseline and Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21 and 25 (EOT)
Secondary	Percent (%) Change From Baseline in Circulating IgM by Visit (g/L)	The percentage change from Baseline in circulating IgM by visit.	Baseline and Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants With American College of Rheumatology (ACR) 20% Improvement (ACR20) Response by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants With ACR 70% Improvement (ACR70) Response by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25 (EOT)
Secondary	Percentage of Participants With ACR 50% Improvement (ACR50) Response by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants by Anti-drug Antibody (ADA) Status	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.	Days 1 up to Day 169.
Secondary	Percentage of Participants With Neutralizing Antibody (NAb) in Participants With a Positive ADA by Visit		Day 1 up to Day 169
Secondary	Change From Baseline in Disease Activity Score Based on 28-Joint Count and C-Reactive Protein (DAS28-CRP)	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.	Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percent Change From Baseline in DAS28-CRP by Visit	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.	Baseline and Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants With Good European League Against Rheumatism (EULAR) Response Based on Disease Activity Score Based on 28-Joint Count (DAS28) by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants With Moderate EULAR Response Based on Disease Activity Score Based on DAS28 by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants With No EULAR Response Based on DAS28 by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants With Low Disease Activity Score (DAS <=3.2) by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Percentage of Participants With DAS Remission (DAS <2.6) by Visit	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.	Weeks 3, 5, 9, 13, 17, 21 and 25
Secondary	Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) by Visit	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.	Baseline, Week 3, 5, 9, 13, 17, 21 and 25
Secondary	Percent Change From Baseline in HAQ-DI Score by Visit	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.	Baseline, Week 3, 5, 9, 13, 17, 21 and 25

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