Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid Arthritis

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01955733
• Collaborator: (none)
• Enrollment: 91
• Locations: 43
• Arm: 1
• Actual Duration (Months): 41.3
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Arthritis, Rheumatoid	Drug: BI 695500	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 91 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of BI 695500 in Patients With Moderately to Severely Active Rheumatoid Arthritis: an Open-label Extension Trial
• Actual Study Start Date: May 31, 2013
• Actual Primary Completion Date: Nov 18, 2015
• Actual Study Completion Date: Nov 7, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 695500 BI 695500, Two infusions separated by 2 weeks, Intravenous infusion	Drug: BI 695500

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

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 [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.

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 82 Years
• Sexes Eligible for Study: All
• Accepts 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:

4. 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).

5. 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.

6. 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.

7. 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.

8. Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable throughout the trial.

9. 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.

10. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1301.4.5585 Boehringer Ingelheim Investigational Site	Birmingham	Alabama	United States
2	1301.4.5727 Boehringer Ingelheim Investigational Site	Glendale	Arizona	United States
3	1301.4.5725 Boehringer Ingelheim Investigational Site	Phoenix	Arizona	United States
4	1301.4.5761 Boehringer Ingelheim Investigational Site	Little Rock	Arkansas	United States
5	1301.4.5765 Boehringer Ingelheim Investigational Site	El Cajon	California	United States
6	1301.4.5553 Boehringer Ingelheim Investigational Site	Lakewood	California	United States
7	1301.4.5527 Boehringer Ingelheim Investigational Site	Long Beach	California	United States
8	1301.4.5771 Boehringer Ingelheim Investigational Site	San Diego	California	United States
9	1301.4.5797 Boehringer Ingelheim Investigational Site	Santa Maria	California	United States
10	1301.4.5807 Boehringer Ingelheim Investigational Site	Upland	California	United States
11	1301.4.5809 Boehringer Ingelheim Investigational Site	Pembroke Pines	Florida	United States
12	1301.4.5567 Boehringer Ingelheim Investigational Site	Tampa	Florida	United States
13	1301.4.5561 Boehringer Ingelheim Investigational Site	Chicago	Illinois	United States
14	1301.4.5721 Boehringer Ingelheim Investigational Site	Columbia	Maryland	United States
15	1301.4.5811 Boehringer Ingelheim Investigational Site	Cumberland	Maryland	United States
16	1301.4.5507 Boehringer Ingelheim Investigational Site	Worcester	Massachusetts	United States
17	1301.4.5715 Boehringer Ingelheim Investigational Site	Grand Rapids	Michigan	United States
18	1301.4.5787 Boehringer Ingelheim Investigational Site	Omaha	Nebraska	United States
19	1301.4.5525 Boehringer Ingelheim Investigational Site	Toms River	New Jersey	United States
20	1301.4.5779 Boehringer Ingelheim Investigational Site	Brooklyn	New York	United States
21	1301.4.5717 Boehringer Ingelheim Investigational Site	Charlotte	North Carolina	United States
22	1301.4.5801 Boehringer Ingelheim Investigational Site	Dayton	Ohio	United States
23	1301.4.5549 Boehringer Ingelheim Investigational Site	Memphis	Tennessee	United States
24	1301.4.5729 Boehringer Ingelheim Investigational Site	Nashville	Tennessee	United States
25	1301.4.5757 Boehringer Ingelheim Investigational Site	Carrollton	Texas	United States
26	1301.4.5789 Boehringer Ingelheim Investigational Site	Corpus Christi	Texas	United States
27	1301.4.5705 Boehringer Ingelheim Investigational Site	Houston	Texas	United States
28	1301.4.5597 Boehringer Ingelheim Investigational Site	McKinney	Texas	United States
29	1301.4.5795 Boehringer Ingelheim Investigational Site	Beckley	West Virginia	United States
30	1301.4.0303 Boehringer Ingelheim Investigational Site	Kortrijk		Belgium
31	1301.4.0609 Boehringer Ingelheim Investigational Site	Plovdiv		Bulgaria
32	1301.4.1705 Boehringer Ingelheim Investigational Site	Magdeburg		Germany
33	1301.4.1807 Boehringer Ingelheim Investigational Site	Athens		Greece
34	1301.4.3305 Boehringer Ingelheim Investigational Site	Sneek		Netherlands
35	1301.4.3909 Boehringer Ingelheim Investigational Site	Bialystok		Poland
36	1301.4.3907 Boehringer Ingelheim Investigational Site	Bydgoszcz		Poland
37	1301.4.3915 Boehringer Ingelheim Investigational Site	Krakow		Poland
38	1301.4.3919 Boehringer Ingelheim Investigational Site	Warszawa		Poland
39	1301.4.3917 Boehringer Ingelheim Investigational Site	Wroclaw		Poland
40	1301.4.4013 Boehringer Ingelheim Investigational Site	Amadora		Portugal
41	1301.4.4007 Boehringer Ingelheim Investigational Site	Lisboa		Portugal
42	1301.4.4809 Boehringer Ingelheim Investigational Site	Sevilla		Spain
43	1301.4.4813 Boehringer Ingelheim Investigational Site	Sevilla		Spain

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01955733
• Other Study ID Numbers: 1301.4; 2013-002622-23
• First Posted: Oct 7, 2013
• Last Update Posted: Jan 18, 2018
• Last Verified: Dec 1, 2017

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	BI 695500	Rituxan From 1301.1	MabThera From 1301.1
Arm/Group Description	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.	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.	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.
Period Title: Period 1
STARTED	33	29	29
COMPLETED	32	29	29
NOT COMPLETED	1	0	0
Period Title: Period 1
STARTED	32	29	29
COMPLETED	20	10	8
NOT COMPLETED	12	19	21

Baseline Characteristics

Arm/Group Title	BI 695500	Rituxan From 1301.1	MabThera From 1301.1	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	30	29	29	88
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54.6 (11.23)	56.3 (11.02)	56.8 (8.95)	55.9 (10.38)
Sex: Female, Male (Count of Participants)
Female	21 70%	24 82.8%	22 75.9%	67 76.1%
Male	9 30%	5 17.2%	7 24.1%	21 23.9%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Patients With Drug Related Adverse Events During the Treatment Phase
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 695500	Rituxan From 1301.1	MabThera From 1301.1
Arm/Group Description	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.	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.	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.
Measure Participants	30	29	29
Number [Percentage of patients]	16.7	6.9	3.4

2. Secondary Outcome

Title	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
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 695500	Rituxan From 1301.1	MabThera From 1301.1
Arm/Group Description	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.	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.	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.
Measure Participants	30	26	28
Least Squares Mean (90% Confidence Interval) [Units on Scale]	-2.0	-2.0	-1.6

3. Secondary Outcome

Title	The Percentage of Patients Meeting the ACR20 [Based on Improvement Since Baseline in Trial 1301.1] at Week 48 of Trial 1301.4
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 695500	Rituxan From 1301.1	MabThera From 1301.1
Arm/Group Description	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.	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.	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.
Measure Participants	30	26	28
Number [Percentage of patients]	3.7	4.3	4.0

4. Secondary Outcome

Title	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
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 695500	Rituxan From 1301.1	MabThera From 1301.1
Arm/Group Description	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.	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.	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.
Measure Participants	30	26	28
Number [Percentage of patients]	0.0	0.0	0.0

5. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

FAS. Subjects who did not complete Week 48 are not presented.

Arm/Group Title	BI 695500	Rituxan From 1301.1	MabThera From 1301.1
Arm/Group Description	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.	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.	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.
Measure Participants	30	26	28
Good response	0.0	0.0	0.0
Moderate response	3.3	7.7	0.0
No response	13.3	15.4	14.3
Missing	43.3	15.4	14.3

Adverse Events

Time Frame	TEAEs were collected from the first dose of study medication in this extension study [1301.4] and prior to the last date of study medication + 6 months [180 days].
Adverse Event Reporting Description	AEs are presented for the Safety Randomised Analysis Set (SAF) which consisted of all randomised subjects who received at least one dose of trial medication in this extension study [1301.4].
Arm/Group Title	BI 695500		Rituxan From 1301.1		MabThera From 1301.1
Arm/Group Description	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.		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.		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.
All Cause Mortality
	BI 695500		Rituxan From 1301.1		MabThera From 1301.1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	BI 695500		Rituxan From 1301.1		MabThera From 1301.1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		2/29 (6.9%)		2/29 (6.9%)
Infections and infestations
Cellulitis	0/30 (0%)		0/29 (0%)		2/29 (6.9%)
Injury, poisoning and procedural complications
Femur fracture	0/30 (0%)		1/29 (3.4%)		0/29 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	0/30 (0%)		0/29 (0%)		1/29 (3.4%)
Metabolic acidosis	0/30 (0%)		0/29 (0%)		1/29 (3.4%)
Nervous system disorders
Cerebral microangiopathy	0/30 (0%)		1/29 (3.4%)		0/29 (0%)
Metabolic encephalopathy	0/30 (0%)		0/29 (0%)		1/29 (3.4%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/30 (0%)		1/29 (3.4%)		0/29 (0%)
Vascular disorders
Deep vein thrombosis	0/30 (0%)		1/29 (3.4%)		0/29 (0%)
Other (Not Including Serious) Adverse Events
	BI 695500		Rituxan From 1301.1		MabThera From 1301.1
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/30 (23.3%)		8/29 (27.6%)		9/29 (31%)
Infections and infestations
Sinusitis	1/30 (3.3%)		1/29 (3.4%)		2/29 (6.9%)
Urinary tract infection	3/30 (10%)		2/29 (6.9%)		4/29 (13.8%)
Viral upper respiratory tract infection	3/30 (10%)		2/29 (6.9%)		2/29 (6.9%)
Pharyngitis	0/30 (0%)		0/29 (0%)		2/29 (6.9%)
Metabolism and nutrition disorders
Hypercholesterolaemia	1/30 (3.3%)		2/29 (6.9%)		1/29 (3.4%)
Psychiatric disorders
Insomnia	0/30 (0%)		2/29 (6.9%)		0/29 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/30 (6.7%)		1/29 (3.4%)		0/29 (0%)

Limitations/Caveats

Further development of BI 695500 has been stopped and the program was therefore prematurely discontinued on 03Sep2015. The decision was made by the Sponsor based on a strategic review of company's product portfolio and not due to any safety concern.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.