Rheumatoid Arthritis
Conditions
Brief summary
This single arm study will investigate the pattern of B cell depletion in synovial tissue and peripheral blood of patients with active RA, after MabThera (1000mg iv x 2 on days 1 and 15) + methotrexate (10-25mg/week po) treatment. The clinical efficacy and pharmacokinetic profile of MabThera after treatment and retreatment will also be investigated. The anticipated time on study treatment is 2+ years, and the target sample size is \<100 individuals.
Interventions
DRUGrituximab [MabThera/Rituxan]
1000mg iv on days 1 and 15
DRUGMethotrexate
10-25mg po weekly
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* adult patients 18-80 years of age; * RA for \>=3 months; * receiving outpatient treatment; * failed treatment with \>=1 DMARD (but not anti TNF or other biologic therapy); * inadequate response to methotrexate, having taken and tolerated it for \>=12 weeks, with a stable dose for \>=4 weeks.
Exclusion criteria
* rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA; * history of, or current, inflammatory joint disease other than RA, or other systemic autoimmune disorder; * diagnosis of RA before the age of 16; * bone/joint surgery within 12 weeks of study; * prior use of anti-TNF or other biologic therapy, an anti-alpha 4 integrin, or any cell-depleting therapies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Absolute B Cell Cluster Differential 19 Positive (CD19+) Counts in Synovial Tissues | Weeks 12, 24, and 36 | The change from baseline in absolute B cell (CD19+) counts at each visit calculated as (B cell count at visit minus B cell count at baseline) for synovial tissues. |
| Change From Baseline in Absolute B Cell CD19+ Counts in Peripheral Blood | Weeks 4, 12, 24, 36, and 48 | The change from baseline in absolute B cell (CD19+) count at each visit calculated as (B cell count at visit minus B cell count at baseline) for peripheral blood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Levels of Key Cytokines (Interleukin [IL]-1beta [β], Tumor Necrosis Factor [TNF]-Alpha [α], IL-4, IL-6, IL-10, and IL-13) in Blood (Serum) | Days 15 and 183 and Weeks 4, 12, 24, 36, and 48 | The change in levels of key cytokines (IL-1β, TNF-α, IL-4, IL-6, IL-10, and IL-13) in blood (serum) on Days 15 and 183 and at Weeks 4, 12, 24, 36, and 48, relative to baseline. |
| Change From Baseline in Levels of Key Cytokines in (IL-1β, TNF-α, IL-6, and IL-10) in Synovial Tissues | Weeks 12, 24, and 36 | The change in levels of key cytokines in (IL-1β, TNF-α, IL-6, and IL-10) in synovial tissues at Weeks 12, 24, and 36, relative to baseline. |
| Change From Baseline in Myelocytomatosis Oncogene (C-myc) and BCL2-associated X Protein (BAX) in Peripheral Blood | Days 15 and 183 | The change in ribonucleic acid (RNA) expression of markers of apoptosis (C-myc and BAX) in peripheral blood at Days 15 and 183, relative to baseline. |
| Percentage of Participants Achieving American College of Rheumatology 20 Percent (20%) 50%, and 70% (ACR20/50/70) Response | Week 48 | ACR20/50/70 response is greater than or equal to (≥) 20%, 50%, or 70% improvement, respectively, in tender joint count (TJC) and swollen joint count (SJC); and improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient 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). |
| Change From Baseline in Disease Activity Score Based on 28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) Score | Weeks 12, 24, 36, and 48 | The change in DAS28-ESR at Weeks 12, 24, 36, and 48, relative to baseline. DAS28-ESR was calculated from SJC and TJC using 28-joint count, ESR (millimeters per hour \[mm/hour\]) and patient global assessment of disease activity (participant-rated arthritis activity assessment). Total score range: 0-9.4, higher score equals (=) more disease activity. DAS28-ESR less than or equal to (≤) 3.2 implied low disease activity and greater than (\>)3.2 to 5.1 implied moderate to high disease activity, and DAS28-ESR \<2.6 = remission. |
| Change From Baseline in Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Synovial Tissues | Weeks 12, 24, and 36 | The change in absolute counts of cells expressing the key B cell markers (CD20+ and CD22+) in absolute B cell (CD19+) counts in synovial tissues at Weeks 12, 24, and 36, relative to baseline. |
| Change From Baseline in ACR Core Set | Week 48 | The changes from baseline in the ACR core set parameters at Week 48. Change from baseline to Week 48 over time in ACR core set: SJC, TJC, physician's global assessment of disease activity, patient's global assessment of disease activity, patient's assessment of pain, HAQ, ESR, and CRP. ACR20/50/70 response: ≥20%/50%/70% improvement in SJC; ≥20%/50%/70% improvement in TJC; and ≥20%/50%/70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; physician's global assessment of disease activity, participant's assessment of disease activity, participant assessment of functional disability via a HAQ, and CRP at each visit. |
| Change From Baseline in Modified Total Sharp Score (mTSS) | Weeks 24 and 48 | mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement. |
| Change From Baseline in Erosion Score | Weeks 24 and 48 | Changes from baseline in modified Sharp radiographic erosion score from baseline to Weeks 24 and 48. The change in score at week X (where X=Week 24 or Week 48, as appropriate) calculated as: Change = week X score minus screening score. |
| Change From Baseline in Joint Space Narrowing (JSN) Score | Weeks 24 and 48 | Changes from baseline in modified Sharp radiographic JSN score from baseline to Weeks 24 and 48. The change in score at week X (where X=Week 24 or Week 48, as appropriate) calculated as: Change = week X score minus screening score. |
| Percentage of Participants Achieving Response by European League Against Rheumatism (EULAR) Category | Weeks 24, 36, and 48 | 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 Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Peripheral Blood | Weeks 4,12, 24, 36, and 48 | The change in absolute counts of cells expressing the key B cell markers (CD20+ and CD22+) in absolute B cell (CD19+) counts in peripheral blood at Weeks 4,12, 24, 36, and 48, relative to baseline. |
Countries
Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab + MTX Participants received rituximab 1000 mg via IV infusion on Days 1 and 15 and also on Days 169 and 183 (for those meeting retreatment criteria) or PRN if retreatment criteria were not met; premedication with MP 100 mg IV was administered at least 30 minutes prior to each rituximab infusion. Participants also received MTX 10-25 mg/week (oral or parenteral) for up to 48 weeks and folate (≥5 mg/week) given as either a single weekly dose or as divided dose for up to 48 weeks. | 0 |
| Total | 0 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Study terminated by Sponsor | 3 |
Baseline characteristics
| Characteristic | — |
|---|---|
| Region of Enrollment Netherlands | — participants |
| Sex: Female, Male Female | — Participants |
| Sex: Female, Male Male | — Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Change From Baseline in Absolute B Cell CD19+ Counts in Peripheral Blood
The change from baseline in absolute B cell (CD19+) count at each visit calculated as (B cell count at visit minus B cell count at baseline) for peripheral blood.
Time frame: Weeks 4, 12, 24, 36, and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Primary
Change From Baseline in Absolute B Cell Cluster Differential 19 Positive (CD19+) Counts in Synovial Tissues
The change from baseline in absolute B cell (CD19+) counts at each visit calculated as (B cell count at visit minus B cell count at baseline) for synovial tissues.
Time frame: Weeks 12, 24, and 36
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Peripheral Blood
The change in absolute counts of cells expressing the key B cell markers (CD20+ and CD22+) in absolute B cell (CD19+) counts in peripheral blood at Weeks 4,12, 24, 36, and 48, relative to baseline.
Time frame: Weeks 4,12, 24, 36, and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Synovial Tissues
The change in absolute counts of cells expressing the key B cell markers (CD20+ and CD22+) in absolute B cell (CD19+) counts in synovial tissues at Weeks 12, 24, and 36, relative to baseline.
Time frame: Weeks 12, 24, and 36
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in ACR Core Set
The changes from baseline in the ACR core set parameters at Week 48. Change from baseline to Week 48 over time in ACR core set: SJC, TJC, physician's global assessment of disease activity, patient's global assessment of disease activity, patient's assessment of pain, HAQ, ESR, and CRP. ACR20/50/70 response: ≥20%/50%/70% improvement in SJC; ≥20%/50%/70% improvement in TJC; and ≥20%/50%/70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; physician's global assessment of disease activity, participant's assessment of disease activity, participant assessment of functional disability via a HAQ, and CRP at each visit.
Time frame: Week 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Disease Activity Score Based on 28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) Score
The change in DAS28-ESR at Weeks 12, 24, 36, and 48, relative to baseline. DAS28-ESR was calculated from SJC and TJC using 28-joint count, ESR (millimeters per hour \[mm/hour\]) and patient global assessment of disease activity (participant-rated arthritis activity assessment). Total score range: 0-9.4, higher score equals (=) more disease activity. DAS28-ESR less than or equal to (≤) 3.2 implied low disease activity and greater than (\>)3.2 to 5.1 implied moderate to high disease activity, and DAS28-ESR \<2.6 = remission.
Time frame: Weeks 12, 24, 36, and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Erosion Score
Changes from baseline in modified Sharp radiographic erosion score from baseline to Weeks 24 and 48. The change in score at week X (where X=Week 24 or Week 48, as appropriate) calculated as: Change = week X score minus screening score.
Time frame: Weeks 24 and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Joint Space Narrowing (JSN) Score
Changes from baseline in modified Sharp radiographic JSN score from baseline to Weeks 24 and 48. The change in score at week X (where X=Week 24 or Week 48, as appropriate) calculated as: Change = week X score minus screening score.
Time frame: Weeks 24 and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Levels of Key Cytokines in (IL-1β, TNF-α, IL-6, and IL-10) in Synovial Tissues
The change in levels of key cytokines in (IL-1β, TNF-α, IL-6, and IL-10) in synovial tissues at Weeks 12, 24, and 36, relative to baseline.
Time frame: Weeks 12, 24, and 36
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Levels of Key Cytokines (Interleukin [IL]-1beta [β], Tumor Necrosis Factor [TNF]-Alpha [α], IL-4, IL-6, IL-10, and IL-13) in Blood (Serum)
The change in levels of key cytokines (IL-1β, TNF-α, IL-4, IL-6, IL-10, and IL-13) in blood (serum) on Days 15 and 183 and at Weeks 4, 12, 24, 36, and 48, relative to baseline.
Time frame: Days 15 and 183 and Weeks 4, 12, 24, 36, and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Modified Total Sharp Score (mTSS)
mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.
Time frame: Weeks 24 and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Change From Baseline in Myelocytomatosis Oncogene (C-myc) and BCL2-associated X Protein (BAX) in Peripheral Blood
The change in ribonucleic acid (RNA) expression of markers of apoptosis (C-myc and BAX) in peripheral blood at Days 15 and 183, relative to baseline.
Time frame: Days 15 and 183
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Percentage of Participants Achieving American College of Rheumatology 20 Percent (20%) 50%, and 70% (ACR20/50/70) Response
ACR20/50/70 response is greater than or equal to (≥) 20%, 50%, or 70% improvement, respectively, in tender joint count (TJC) and swollen joint count (SJC); and improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient 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).
Time frame: Week 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.
Secondary
Percentage of Participants Achieving Response by European League Against Rheumatism (EULAR) Category
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.
Time frame: Weeks 24, 36, and 48
Population: No participant data were analyzed. Study was terminated after enrollment of 3 participants as it was decided that it would not be appropriate to expose further participants to study drug since the objectives and data sought from this study had been published from other, independent sources and given the recruitment difficulties encountered.