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)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: PF-05280586
* Biological: MabThera
* Biological: Rituxan


Participation Criteria
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Eligibility Criteria
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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

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A - PF-05280586<br> | Biological: PF-05280586<br>* 1000 mg, IV on days 1 and 15<br>|
| Active Comparator: B - Rituximab EU<br> | Biological: MabThera<br>* 1000 mg, IV on days 1 and 15<br>|
| Active Comparator: C- Rituximab-US<br> | Biological: Rituxan<br>* 1000 mg, IV on days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| Duration of B-cell Depletion (τB-cell) (Days) | The τB-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) | 
| 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 | 
| 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) | 
| 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) | 
| 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 | 
| 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 | 
| 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) | 
| 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 | 
| 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. | 
| Percentage of Participants With Neutralizing Antibody (NAb) in Participants With a Positive ADA by Visit |  | Day 1 up to Day 169 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rheumatoid arthritis, rituximab, methotrexate, anti-TNF