Arthritis, Rheumatoid
Conditions
Brief summary
The primary objective of this trial is to evaluate the long-term safety of BI 695500 in adult patients with moderately to severely active rheumatoid arthritis (RA) who have successfully completed treatment in Trial 1301.1.
Interventions
DRUGBI 695500
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 82 Years
Healthy volunteers
No
Inclusion criteria
1. Must give written informed consent and be willing to follow this Clinical Trial Protocol. 2. Male or female patients, with moderately to severely active RA who have previously participated in the double-blind randomized clinical Trial 1301.1. 3. Current treatment for RA on an outpatient basis: 1. Patients must continue to receive and tolerate oral or parenteral methotrexate (MTX) therapy at a dose of 15-25 mg per week (dose may be as low as 10 mg per week if the patient is unable to tolerate a higher dose). 2. Patients must be willing to receive oral folic acid (at least 5 mg/week or as per local practice) or folinic acid (at least 1 mg per week or as per local practice) or equivalent during the entire trial. 3. If receiving current treatment with oral corticosteroids (other than intra-articular or parenteral), the dose must not exceed 10 mg/day prednisolone or equivalent. During the 4 weeks prior to Baseline (Day 1) the dose must remain stable. 4. Intra-articular and parenteral corticosteroids are not permitted throughout the trial, with the exception of IV administration of 100 mg methylprednisolone 30 to 60 minutes prior to each infusion as part of the trial procedures. 5. Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable throughout the trial. 6. Patients may be taking oral hydroxychloroquine provided that the dose is not greater than 400 mg/day, or chloroquine provided that the dose is not greater than 250 mg/day. These doses must have been stable for a minimum of 12 weeks prior to Day 1. The hydroxychloroquine or chloroquine treatment will need to be continued at a stable dose with the same formulation until the end of the trial. 4. For participants of reproductive potential (males and females), use of a medically acceptable method of contraception during the trial, i.e., a combination of 2 forms of effective contraception (defined as hormonal contraception, intrauterine device, condom with spermicide, etc.). Females of childbearing potential must also agree to use an acceptable method of contraception (see above) for 12 months following completion or discontinuation from the trial medication.
Exclusion criteria
1. Patients receiving current treatment with corticosteroids must not be receiving a dose exceeding 10 mg/day prednisone or equivalent. 2. Serious underlying medical conditions, which, per the investigator¿s discretion, could impair the ability of the patient to participate in the trial (including but not limited to ongoing severe infection, severe immunosuppression, severe heart failure, uncontrolled hypertension, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease). 3. Pregnancy or breast feeding. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit. 4. Patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the New York Heart Association (NYHA) classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease; or uncontrolled hypertension. 5. Treatment with IV or intramuscular corticosteroids. The only exception will be the administration of 100 mg IV methylprednisolone 30 to 60 minutes before each infusion as part of the trial procedures. 6. Any condition or treatment (including biologic therapies) that, in the opinion of the investigator, may place the patient at unacceptable risk during the trial. 7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2.5 times upper limit of normal (ULN). 8. Hemoglobin \<8.0 g/dL. 9. Levels of Immunoglobulin G(IgG) \<5.0 g/L. 10. Absolute neutrophil count \<1500/µL. 11. Platelet count \<75000/µL.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase | Week 48 | This outcome measure presents percentage of patients with drug related adverse events during the treatment phase. Treatment Emergent Adverse Events (TEAEs) were defined as Adverse Events (AEs) that started or worsened in severity on or after the first dose of trial medication in this extension study \[1301.4\] and prior to the last date of trial medication + 180 days \[inclusive\]. Drug-related events were those considered by the investigator to have a causal relationship to trial medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Trial 1301.1 in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 48 of Clinical Trial 1301.4 | Baseline in clinical trial 1301.1 up to Week 48 in clinical trial 1301.4. | DAS-28 (ESR)\*\* is an index containing a 28-joint count for tenderness (TJC28), 28 joint count for swelling (SJC28), natural logarithm of ESR (inflammation) (Ln\[ESR\]) and a general health component (GH) which is the patient's global assessment of disease activity and was used to describe the severity of RA. The DAS28 (ESR) Score is calculated as: DAS28(ESR) = 0.56\*√(TJC28) + 0.28\*√(SJC28) + 0.70\*ln(ESR) + 0.014\*(GH). DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. A clinically important change in DAS28 score is defined as an improvement in DAS28 score of at least 1.2. The mean change from baseline (in clinical trial 1301.1) at Week 48 in the DAS28 (ESR) score is presented. |
| The Percentage of Patients Meeting the ACR20 [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Baseline in clinical trial 1301.1 up to Week 48 in clinical trial 1301.4. | A subject has an ACR20 response if all of the following occur: * a \> 20% improvement in the swollen joint count (66 joints) * a \> 20% improvement in the tender joint count (68 joints) * a \> 20% improvement in at least 3 of the following assessments: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's assessment of physical function, as measured by the Health Assessment Questionnaire - Disability Index, or Acute phase reactant (CRP). The number of subjects meeting the ACR20 response criteria at Week 48 is presented. |
| The Percentage of Patients Who Meet the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Definition of Remission [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Baseline in clinical trial 1301.1 up to Week 48 in clinical trial 1301.4. | To meet the ACR/EULAR Remission criteria\*, the subject needed to satisfy the following criteria: * TCJ (68 joints) \< 1 * SJC (66 joints) \< 1 * CRP \< 1 milligrams per decilitre * patient global assessment \< 10. The patient global assessment for the definition of ACR/EULAR Remission was defined with a visual analog scale in millimetres (0-100).\*\* The number of subjects meeting the ACR/EULAR Remission definition at Week 48 is presented. |
| The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Week 48 | This outcome measure presents percentage of patients who meet the EULAR response \[good response, moderate response, or no response\] \[based on DAS28 improvement since baseline in trial 1301.1\] at Week 48 of trial 1301.4. |
Countries
Belgium, Bulgaria, Germany, Greece, Netherlands, Poland, Portugal, Spain, United States
Participant flow
Pre-assignment details
97 subjects were screened for eligibility to participate in this extension trial. 91 subjects met all inclusion and exclusion criteria and were assigned to receive treatment.
Participants by arm
| Arm | Count |
|---|---|
| BI 695500 The subjects were administered BI 695500, concentrate for solution for infusion, 10 mg/mL by intravenous infusion. Two 1000 mg infusions were separated by 2 weeks.
Each patient was treated with BI 695500 on Days 1 and 15, with a possible further two infusions at Weeks 24 and 26 for eligible responders. | 30 |
| Rituxan From 1301.1 The Rituxan from 1301.1 recommended dose for use in patients with Rheumatoid Arthritis is 1000 mg by IV infusion followed by a second 1000 mg IV infusion 2 weeks later. | 29 |
| MabThera From 1301.1 The MabThera from 1301.1 recommended dose for use in patients with Rheumatoid Arthritis is 1000 mg by IV infusion followed by a second 1000 mg IV infusion 2 weeks later. | 29 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1 | Lost to Follow-up | 1 | 0 | 0 |
| Period 2 | Adverse Event | 1 | 0 | 0 |
| Period 2 | Lost to Follow-up | 2 | 0 | 0 |
| Period 2 | Other not defined above | 0 | 2 | 2 |
| Period 2 | Physician Decision | 0 | 0 | 1 |
| Period 2 | Study terminated by sponsor | 8 | 14 | 16 |
| Period 2 | Withdrawal by Subject | 1 | 3 | 2 |
Baseline characteristics
| Characteristic | BI 695500 | Rituxan From 1301.1 | MabThera From 1301.1 | Total |
|---|---|---|---|---|
| Age, Continuous | 54.6 Years STANDARD_DEVIATION 11.23 | 56.3 Years STANDARD_DEVIATION 11.02 | 56.8 Years STANDARD_DEVIATION 8.95 | 55.9 Years STANDARD_DEVIATION 10.38 |
| Sex: Female, Male Female | 21 Participants | 24 Participants | 22 Participants | 67 Participants |
| Sex: Female, Male Male | 9 Participants | 5 Participants | 7 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 30 | 8 / 29 | 9 / 29 |
| serious Total, serious adverse events | 0 / 30 | 2 / 29 | 2 / 29 |
Outcome results
Primary
The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase
This outcome measure presents percentage of patients with drug related adverse events during the treatment phase. Treatment Emergent Adverse Events (TEAEs) were defined as Adverse Events (AEs) that started or worsened in severity on or after the first dose of trial medication in this extension study \[1301.4\] and prior to the last date of trial medication + 180 days \[inclusive\]. Drug-related events were those considered by the investigator to have a causal relationship to trial medication.
Time frame: Week 48
Population: Safety Randomized Analysis Set (SAFRD): All subjects randomized in 1301.1 \[excluding open-label safety run-in subjects of trial 1301.1\] who receive at least one dose of trial medication and subjects will be classified according to treatment received in trial 1301.1. 2 subjects from 1301.1 safety run-in also received treatment in 1301.4, thus 88.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 695500 | The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase | 16.7 Percentage of patients |
| Rituxan From 1301.1 | The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase | 6.9 Percentage of patients |
| MabThera From 1301.1 | The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase | 3.4 Percentage of patients |
Secondary
Change From Baseline in Clinical Trial 1301.1 in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 48 of Clinical Trial 1301.4
DAS-28 (ESR)\*\* is an index containing a 28-joint count for tenderness (TJC28), 28 joint count for swelling (SJC28), natural logarithm of ESR (inflammation) (Ln\[ESR\]) and a general health component (GH) which is the patient's global assessment of disease activity and was used to describe the severity of RA. The DAS28 (ESR) Score is calculated as: DAS28(ESR) = 0.56\*√(TJC28) + 0.28\*√(SJC28) + 0.70\*ln(ESR) + 0.014\*(GH). DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. A clinically important change in DAS28 score is defined as an improvement in DAS28 score of at least 1.2. The mean change from baseline (in clinical trial 1301.1) at Week 48 in the DAS28 (ESR) score is presented.
Time frame: Baseline in clinical trial 1301.1 up to Week 48 in clinical trial 1301.4.
Population: The Full Analysis Set (FAS) consisted of all subjects from the randomised set of clinical trial 1301.1 who received at least one dose of trial medication and had data recorded for at least 1 DAS28 (ESR or C-reactive Protein \[CRP\]) or American College of Rheumatology 20% response criteria (ACR20).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 695500 | Change From Baseline in Clinical Trial 1301.1 in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 48 of Clinical Trial 1301.4 | -2.0 Units on Scale |
| Rituxan From 1301.1 | Change From Baseline in Clinical Trial 1301.1 in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 48 of Clinical Trial 1301.4 | -2.0 Units on Scale |
| MabThera From 1301.1 | Change From Baseline in Clinical Trial 1301.1 in Disease Activity Score 28 (DAS28) (Erythrocyte Sedimentation Rate [ESR]) at Week 48 of Clinical Trial 1301.4 | -1.6 Units on Scale |
Secondary
The Percentage of Patients Meeting the ACR20 [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4
A subject has an ACR20 response if all of the following occur: * a \> 20% improvement in the swollen joint count (66 joints) * a \> 20% improvement in the tender joint count (68 joints) * a \> 20% improvement in at least 3 of the following assessments: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's assessment of physical function, as measured by the Health Assessment Questionnaire - Disability Index, or Acute phase reactant (CRP). The number of subjects meeting the ACR20 response criteria at Week 48 is presented.
Time frame: Baseline in clinical trial 1301.1 up to Week 48 in clinical trial 1301.4.
Population: The FAS consisted of all subjects from the randomised set of clinical trial 1301.1 who received at least one dose of trial medication and had data recorded for at least 1 DAS28 (ESR or CRP) or ACR20.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 695500 | The Percentage of Patients Meeting the ACR20 [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | 3.7 Percentage of patients |
| Rituxan From 1301.1 | The Percentage of Patients Meeting the ACR20 [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | 4.3 Percentage of patients |
| MabThera From 1301.1 | The Percentage of Patients Meeting the ACR20 [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | 4.0 Percentage of patients |
Secondary
The Percentage of Patients Who Meet the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Definition of Remission [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4
To meet the ACR/EULAR Remission criteria\*, the subject needed to satisfy the following criteria: * TCJ (68 joints) \< 1 * SJC (66 joints) \< 1 * CRP \< 1 milligrams per decilitre * patient global assessment \< 10. The patient global assessment for the definition of ACR/EULAR Remission was defined with a visual analog scale in millimetres (0-100).\*\* The number of subjects meeting the ACR/EULAR Remission definition at Week 48 is presented.
Time frame: Baseline in clinical trial 1301.1 up to Week 48 in clinical trial 1301.4.
Population: The FAS consisted of all patients from the randomised set of clinical trial 1301.1 who received at least one dose of trial medication and had data recorded for at least 1 DAS28 (ESR or CRP) or ACR20.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 695500 | The Percentage of Patients Who Meet the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Definition of Remission [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | 0.0 Percentage of patients |
| Rituxan From 1301.1 | The Percentage of Patients Who Meet the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Definition of Remission [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | 0.0 Percentage of patients |
| MabThera From 1301.1 | The Percentage of Patients Who Meet the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Definition of Remission [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | 0.0 Percentage of patients |
Secondary
The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4
This outcome measure presents percentage of patients who meet the EULAR response \[good response, moderate response, or no response\] \[based on DAS28 improvement since baseline in trial 1301.1\] at Week 48 of trial 1301.4.
Time frame: Week 48
Population: FAS. Subjects who did not complete Week 48 are not presented.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BI 695500 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Good response | 0.0 Percentage of patients |
| BI 695500 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Moderate response | 3.3 Percentage of patients |
| BI 695500 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | No response | 13.3 Percentage of patients |
| BI 695500 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Missing | 43.3 Percentage of patients |
| Rituxan From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Missing | 15.4 Percentage of patients |
| Rituxan From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Good response | 0.0 Percentage of patients |
| Rituxan From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | No response | 15.4 Percentage of patients |
| Rituxan From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Moderate response | 7.7 Percentage of patients |
| MabThera From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Missing | 14.3 Percentage of patients |
| MabThera From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Moderate response | 0.0 Percentage of patients |
| MabThera From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | No response | 14.3 Percentage of patients |
| MabThera From 1301.1 | The Percentage of Patients Who Meet the EULAR Response [Good Response, Moderate Response, or no Response] [Based on DAS28 Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4 | Good response | 0.0 Percentage of patients |