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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) (REFLECTIONS)

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ClinicalTrials.gov Identifier: NCT01526057
Recruitment Status : Completed
First Posted : February 3, 2012
Results First Posted : November 19, 2019
Last Update Posted : November 19, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Biological: PF-05280586 Biological: MabThera Biological: Rituxan Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 220 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : March 20, 2012
Actual Primary Completion Date : August 13, 2013
Actual Study Completion Date : May 7, 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Rituximab

Arm Intervention/treatment
Experimental: A - PF-05280586 Biological: PF-05280586
1000 mg, IV on days 1 and 15

Active Comparator: B - Rituximab EU Biological: MabThera
1000 mg, IV on days 1 and 15

Active Comparator: C- Rituximab-US Biological: Rituxan
1000 mg, IV on days 1 and 15




Primary Outcome Measures :
  1. Maximum Serum Concentration (Cmax) of Rituximab [ Time Frame: 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.

  2. AUC 0-inf of Rituximab [ Time Frame: 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.


Secondary Outcome Measures :
  1. Rituximab AUC From Time 0 to 2 Weeks (AUC 0-2wk) [ Time Frame: 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.

  2. Rituximab AUC From Time 0 to the Time of the Last Quantifiable Concentration (AUC 0-T) [ Time Frame: 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.

  3. CD19+ B-cell Count AUC From Time 0 to the Last Measurement at Time T (AUC 0-T,B-cell) [ Time Frame: 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.

  4. Minimum Post-Baseline CD19+ B-cell Count (/uL) [ Time Frame: 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.

  5. Time to Minimum Post-Baseline CD19+ B-cell Count (Weeks) [ Time Frame: 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.

  6. Duration of B-cell Depletion (τB-cell) (Days) [ Time Frame: 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.

  7. Percentage of Participants With CD19+ B-cell Count Recovery [ Time Frame: 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.

  8. Area Under the CD19+ B-cell Count Concentration-time Profile (AUC 0-T, B-cell) [ Time Frame: 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.

  9. Baseline and Change From Baseline in Circulating Immunoglobulin-M (IgM) by Visit (Grams Per Liter (g/L]) [ Time Frame: 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.

  10. Percent (%) Change From Baseline in Circulating IgM by Visit (g/L) [ Time Frame: Baseline and Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21 and 25 ]
    The percentage change from Baseline in circulating IgM by visit.

  11. Percentage of Participants With American College of Rheumatology (ACR) 20% Improvement (ACR20) Response by Visit [ Time Frame: 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.


  12. Percentage of Participants With ACR 70% Improvement (ACR70) Response by Visit [ Time Frame: 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.


  13. Percentage of Participants With ACR 50% Improvement (ACR50) Response by Visit [ Time Frame: 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.


  14. Percentage of Participants by Anti-drug Antibody (ADA) Status [ Time Frame: 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.

  15. Percentage of Participants With Neutralizing Antibody (NAb) in Participants With a Positive ADA by Visit [ Time Frame: Day 1 up to Day 169 ]
  16. Change From Baseline in Disease Activity Score Based on 28-Joint Count and C-Reactive Protein (DAS28-CRP) [ Time Frame: 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.

  17. Percent Change From Baseline in DAS28-CRP by Visit [ Time Frame: 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.

  18. Percentage of Participants With Good European League Against Rheumatism (EULAR) Response Based on Disease Activity Score Based on 28-Joint Count (DAS28) by Visit [ Time Frame: 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.

  19. Percentage of Participants With Moderate EULAR Response Based on Disease Activity Score Based on DAS28 by Visit [ Time Frame: 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.

  20. Percentage of Participants With No EULAR Response Based on DAS28 by Visit [ Time Frame: 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.

  21. Percentage of Participants With Low Disease Activity Score (DAS <=3.2) by Visit [ Time Frame: 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.

  22. Percentage of Participants With DAS Remission (DAS <2.6) by Visit [ Time Frame: 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.

  23. Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) by Visit [ Time Frame: 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.

  24. Percent Change From Baseline in HAQ-DI Score by Visit [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01526057


Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01526057    
Other Study ID Numbers: B3281001
ICON 9002/010
2011-002896-40 ( EudraCT Number )
First Posted: February 3, 2012    Key Record Dates
Results First Posted: November 19, 2019
Last Update Posted: November 19, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Keywords provided by Pfizer:
rheumatoid arthritis
rituximab
methotrexate
anti-TNF
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents