Atacicept in Combination With Rituximab in Subjects With Rheumatoid Arthritis (August III)

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00664521
• Collaborator: (none)
• Enrollment: 27
• Locations: 8
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study is to assess the safety and tolerability of combined treatment with atacicept and rituximab in subjects with active rheumatoid arthritis (RA) receiving re-treatment with rituximab.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Biological: Rituximab; Drug: Atacicept; Drug: Placebo matched to atacicept	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo Controlled, Multi-centre, Exploratory, Pilot, Phase II Trial of 150mg Atacicept Given Subcutaneously in Combination With Rituximab in Subjects With Rheumatoid Arthritis.
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab Plus Atacicept Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Biological: Rituximab; Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3.; Drug: Atacicept; Atacicept will be administered at a dose of 150 mg subcutaneously once a week from Week 7 to 32.
Placebo Comparator: Rituximab Plus Placebo Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.	Biological: Rituximab; Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3.; Drug: Placebo matched to atacicept; Placebo matched to atacicept will be administered subcutaneously once a week from Week 7 to 32.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to Week 64]

   An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.

2. Percentage of Participants With Immunoglobulin G (IgG) Level Less Than 3 Gram Per Liter (g/L) [Week 64]

3. Percent Change From Baseline in Vital Signs and Routine Safety Lab Parameters at Week 32 [Baseline, Week 32]

   Vital signs assessed included blood pressure (systolic and diastolic), pulse and body temperature. Routine safety lab parameters evaluated included red blood cell (RBC), hemoglobin, hematocrit, platelets, mean cellular hemoglobin (MCH), MCH concentration, MCH volume, white blood cell (WBC), lymphocytes, monocytes, eosinophils, basophils, neutrophils, gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), albumin, alkaline phosphatase (AP), aspartate aminotransferase (AST), bilirubin, calcium, creatinine, glucose, potassium, total protein, sodium, uric acid, and blood urea nitrogen. Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.

4. Percent Change From Baseline in Anti-tetanus and Anti-diphteria Immunization Titer at Week 32 [Baseline, Week 32]

   Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.

5. Percent Change From Baseline in Anti-pneumococcus Titer at Week 32 [Baseline, Week 32]

   Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.

Secondary Outcome Measures

1. Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP), ACR50-CRP and ACR70-CRP at Week 32 [Week 32]

   ACR20-CRP response: greater than or equal to (>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with >=20% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) acute-phase marker (CRP). ACR50-CRP and ACR70-CRP response are defined as >=50% and >=70% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) respectively together with >=50% and >=70% improvement in at least 3 of the following respectively: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) CRP.

2. Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) at Week 32 [Baseline, Week 32]

   DAS28-CRP incorporates non-graded joint counts for tenderness and swelling based on a total of 28 joints, CRP as a marker of inflammation, and a general health assessment using a 100 mm visual analog scale (the participant's global assessment of disease activity). DAS28 score ranges between 0 and 10 representing current disease activity. A value above 5.1 represents high disease activity, a value below 3.2 represents low disease activity, and a value below 2.6 represents remission.

3. Median Percentage Change From Baseline in Levels of Total, Mature and Memory B Cells [Baseline, Week 3, 7, 12, 16, 26 and 32]

   Flow cytometric analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of total, mature and memory B cell levels.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female subjects

• Greater than and equal to (>=) 18 years of age at the time of Informed Consent

• Who have rheumatoid arthritis satisfying American College of Rheumatology (ACR) criteria with a disease history of at least 12 months

• Subjects must have active disease defined by DAS28 >3.2

• Subjects must have received previous treatment with rituximab and must be candidates for re-treatment with rituximab

• Female subjects of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 4 weeks before study day 1 (SD1), during the treatment period and for 12 months after the last dose of rituximab, and must have a negative urine pregnancy test at the screening visit and SD1

• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Current neurological disease excluding migraine

• Inflammatory joint disease other than rheumatoid arthritis

• Any contraindication to rituximab as per national label

• Use of disease-modifying anti-rheumatic drugs (DMARDs; including methotrexate) for less than 3 months or change in dosing regimen within 28 days before SD1, or methotrexate dose regimen >25 mg/week

• Participation in any interventional clinical trial within 1 month before SD1 (or within 5 half-lives of the investigated compound before SD1, whichever is longer)

• Prednisone dose regimen >10 mg/day (or equivalent), or change in steroid dosing regimen within 28 days before SD1

• Active or latent tuberculosis within the year before screening or major infection requiring hospitalization or intravenous anti-infectives within 28 days before SD1

• Serum Immunoglobulin G (IgG) below 6 gram per liter (g/L)

• Known hypersensitivity to atacicept or to any of the components of the formulated atacicpet

• Known hypersensitivity to rituximab, to any of the components of the formulated rituximab or to murine proteins

• Breastfeeding or pregnancy

• Other protocol defined exclusion criteria could apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Nice		France
2	Research Site	Paris		France
3	Research Site	Strasbourg		France
4	Research Site	Amsterdam		Netherlands
5	Research Site	Malmö		Sweden
6	Research Site	Stockholm		Sweden
7	Research Site	Newcastle		United Kingdom
8	Research Site	Norwich		United Kingdom

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT00664521
• Other Study ID Numbers: 28155
• First Posted: Apr 23, 2008
• Last Update Posted: Dec 30, 2016
• Last Verified: Nov 1, 2016

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Rituximab

Study Results

Participant Flow

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Period Title: Overall Study
STARTED	18	9
COMPLETED	12	8
NOT COMPLETED	6	1

Baseline Characteristics

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo	Total
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.	Total of all reporting groups
Overall Participants	18	9	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.0 (11.0)	57.7 (11.5)	57.2 (11.0)
Gender (Count of Participants)
Female	12 66.7%	8 88.9%	20 74.1%
Male	6 33.3%	1 11.1%	7 25.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Time Frame	Baseline up to Week 64

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of atacicept or placebo.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	18	9
AEs	17 94.4%	9 100%
SAEs	6 33.3%	2 22.2%

2. Primary Outcome

Title	Percentage of Participants With Immunoglobulin G (IgG) Level Less Than 3 Gram Per Liter (g/L)
Time Frame	Week 64

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of atacicept or placebo. Here. "N" (Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	11	5
Number [percentage of participants]	0 0%	0 0%

3. Primary Outcome

Title	Percent Change From Baseline in Vital Signs and Routine Safety Lab Parameters at Week 32
Description	Vital signs assessed included blood pressure (systolic and diastolic), pulse and body temperature. Routine safety lab parameters evaluated included red blood cell (RBC), hemoglobin, hematocrit, platelets, mean cellular hemoglobin (MCH), MCH concentration, MCH volume, white blood cell (WBC), lymphocytes, monocytes, eosinophils, basophils, neutrophils, gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), albumin, alkaline phosphatase (AP), aspartate aminotransferase (AST), bilirubin, calcium, creatinine, glucose, potassium, total protein, sodium, uric acid, and blood urea nitrogen. Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Time Frame	Baseline, Week 32

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of atacicept or placebo. Here, "N" (Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure and 'n' signifies those participants who were evaluable for the specified category.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	12	9
Systolic Blood Pressure (n = 12, 9)	3.74 (11.76)	-6.29 (13.80)
Diastolic Blood Pressure (n = 12, 9)	1.09 (11.19)	4.89 (10.09)
Pulse (n = 12, 9)	10.21 (19.93)	-8.54 (11.98)
Temperature (n = 10, 8)	0.23 (1.05)	-0.44 (0.86)
RBC (n = 12, 9)	3.10 (5.30)	4.94 (7.18)
Hemoglobin (n = 12, 9)	2.55 (5.32)	4.93 (6.18)
Hematocrit (n = 12, 9)	2.39 (6.30)	6.05 (6.15)
Platelets (n = 12, 9)	-6.80 (21.21)	-2.49 (37.62)
MCH (n = 12, 9)	-0.32 (5.03)	0.22 (3.21)
MCH Concentration (n = 12, 9)	-0.18 (2.01)	-1.41 (1.47)
MCH Volume (n = 12, 9)	-0.06 (4.98)	1.39 (2.73)
WBC(n = 12, 9)	-14.59 (36.85)	-9.70 (19.15)
Lymphocytes (n = 12, 9)	0.27 (30.11)	-5.68 (23.00)
Monocytes (n = 12, 9)	5.01 (70.44)	1.88 (38.51)
Eosinophils (n = 12, 9)	34.11 (103.78)	-7.51 (34.58)
Basophils (n = 12, 9)	-20.45 (58.61)	32.41 (117.44)
Neutrophils (n = 12, 9)	-11.29 (57.75)	-13.09 (24.01)
GGT (n = 12, 9)	-3.21 (30.37)	10.17 (53.33)
ALT (n = 12, 9)	17.52 (27.89)	17.79 (53.23)
Albumin (n = 12, 9)	6.22 (6.34)	6.43 (8.10)
AP (n = 12, 9)	4.85 (18.86)	-5.41 (16.48)
AST (n = 12, 9)	14.53 (30.87)	6.73 (36.47)
Bilirubin Total (n = 12, 9)	15.09 (42.78)	4.76 (14.29)
Calcium (n = 12, 9)	-1.07 (5.04)	2.61 (4.72)
Creatinine (n = 12, 9)	-3.29 (10.30)	5.89 (5.26)
Glucose (n = 12, 9)	3.71 (18.55)	7.99 (22.71)
Potassium (n = 12, 9)	-0.93 (6.34)	4.67 (9.37)
Total Protein (n = 12, 9)	-2.83 (7.08)	4.17 (6.57)
Sodium (n = 12, 9)	1.21 (1.46)	0.25 (1.63)
Uric Acid (n = 12, 9)	-2.95 (12.60)	-0.72 (6.10)
Blood Urea Nitrogen (n = 12, 9)	1.63 (27.04)	-7.42 (26.02)

4. Primary Outcome

Title	Percent Change From Baseline in Anti-tetanus and Anti-diphteria Immunization Titer at Week 32
Description	Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Time Frame	Baseline, Week 32

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of atacicept or placebo. Here. "N" (Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	10	9
Anti-tetanus Immunization Titer	-17.98	0.00
Anti-diphtheria Immunization Titer	-33.68	8.41

5. Primary Outcome

Title	Percent Change From Baseline in Anti-pneumococcus Titer at Week 32
Description	Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value.
Time Frame	Baseline, Week 32

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of atacicept or placebo. Here, "N" (Number of Participants Analyzed) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	10	9
Median (Inter-Quartile Range) [percent change]	-18.49	0.00

6. Secondary Outcome

Title	Percentage of Participants Achieving American College of Rheumatology 20 Response Based on C-reactive Protein (ACR20-CRP), ACR50-CRP and ACR70-CRP at Week 32
Description	ACR20-CRP response: greater than or equal to (>=) 20 percent (%) improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) together with >=20% improvement in at least 3 of the following: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) acute-phase marker (CRP). ACR50-CRP and ACR70-CRP response are defined as >=50% and >=70% improvement in both tender joint counts (based on a total of 68 joints) and swollen joint counts (based on a total of 66 joints) respectively together with >=50% and >=70% improvement in at least 3 of the following respectively: 1) participant's assessment of pain; 2) participant's global assessment of disease activity; 3) physician's global assessment of disease activity; 4) participant's assessment of physical function; and 5) CRP.
Time Frame	Week 32

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	18	9
ACR20-CRP	33.3 185%	22.2 246.7%
ACR50-CRP	11.1 61.7%	11.1 123.3%
ACR70-CRP	5.6 31.1%	0 0%

7. Secondary Outcome

Title	Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) at Week 32
Description	DAS28-CRP incorporates non-graded joint counts for tenderness and swelling based on a total of 28 joints, CRP as a marker of inflammation, and a general health assessment using a 100 mm visual analog scale (the participant's global assessment of disease activity). DAS28 score ranges between 0 and 10 representing current disease activity. A value above 5.1 represents high disease activity, a value below 3.2 represents low disease activity, and a value below 2.6 represents remission.
Time Frame	Baseline, Week 32

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants. Here 'n' signifies those participants who were evaluable for the specified category.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	18	9
Baseline (n = 18, 9)	5.50 (0.99)	5.81 (1.04)
Change at Week 32 (n = 12, 9)	3.85 (0.98)	4.25 (1.10)

8. Secondary Outcome

Title	Median Percentage Change From Baseline in Levels of Total, Mature and Memory B Cells
Description	Flow cytometric analysis of lymphocyte populations using four-color fluorescence-activated cell sorting was performed for the analysis of total, mature and memory B cell levels.
Time Frame	Baseline, Week 3, 7, 12, 16, 26 and 32

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of atacicept or placebo. Here 'n' signifies those participants who were evaluable for the specified category.

Arm/Group Title	Rituximab Plus Atacicept	Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
Measure Participants	18	9
Total B cells (Week 3: n=18, 9)	-100.00	-100.00
Total B cells (Week 7: n=17, 8)	-100.00	-99.69
Total B cells (Week 12: n=16, 9)	-100.00	-100.00
Total B cells (Week 16: n=15, 9)	-100.00	-100.00
Total B cells (Week 26: n=12, 9)	-100.00	-94.74
Total B cells (Week 32: n=12, 9)	-86.99	-68.11
Mature B Cells (Week 3: n=18, 9)	-100.00	-100.00
Mature B Cells (Week 7: n=17, 8)	-100.00	-100.00
Mature B Cells (Week 12: n=16, 9)	-100.00	-100.00
Mature B Cells (Week 16: n=15, 9)	-100.00	-100.00
Mature B Cells (Week 26: n=12, 9)	-100.00	-100.00
Mature B Cells (Week 32: n=12, 9)	-99.35	-84.47
Memory B cells (Week 3: n=18, 9)	-100.00	-100.00
Memory B cells (Week 7: n=17, 8)	-100.00	-100.00
Memory B cells (Week 12: n=16, 9)	-100.00	-100.00
Memory B cells (Week 16: n=15, 9)	-100.00	-100.00
Memory B cells (Week 26: n=12, 9)	-100.00	-88.89
Memory B cells (Week 32: n=12, 9)	-83.33	-50.00

Adverse Events

Time Frame	Baseline up to Week 64
Arm/Group Title	Rituximab Plus Atacicept		Rituximab Plus Placebo
Arm/Group Description	Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by atacicept 150 mg subcutaneously once a week from Week 7 to 32.		Rituximab was administered as an intravenous infusion at a dose of 1000 milligram (mg) at Weeks 1 and 3, followed by placebo matched to atacicept subcutaneously once a week from Week 7 to 32.
All Cause Mortality
	Rituximab Plus Atacicept		Rituximab Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rituximab Plus Atacicept		Rituximab Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)		2/9 (22.2%)
Cardiac disorders
Atrial fibrillation	1/18 (5.6%)		0/9 (0%)
Cardiac arrest	1/18 (5.6%)		0/9 (0%)
Ventricular fibrillation	1/18 (5.6%)		0/9 (0%)
Eye disorders
Visual impairment	1/18 (5.6%)		0/9 (0%)
Immune system disorders
Drug hypersensitivity	1/18 (5.6%)		0/9 (0%)
Infections and infestations
Gastroenteritis	1/18 (5.6%)		0/9 (0%)
Injury, poisoning and procedural complications
Joint capsule rupture	1/18 (5.6%)		0/9 (0%)
Pelvic fracture	1/18 (5.6%)		0/9 (0%)
Musculoskeletal and connective tissue disorders
Arthropathy	1/18 (5.6%)		0/9 (0%)
Muscular weakness	1/18 (5.6%)		0/9 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioma	1/18 (5.6%)		0/9 (0%)
Nervous system disorders
Transient ischaemic attack	1/18 (5.6%)		1/9 (11.1%)
Demyelination	1/18 (5.6%)		0/9 (0%)
Nervous system disorder	1/18 (5.6%)		0/9 (0%)
Ruptured cerebral aneurysm	0/18 (0%)		1/9 (11.1%)
Other (Not Including Serious) Adverse Events
	Rituximab Plus Atacicept		Rituximab Plus Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/18 (94.4%)		9/9 (100%)
Blood and lymphatic system disorders
Hypochromic anaemia	1/18 (5.6%)		0/9 (0%)
Spontaneous haematoma	0/18 (0%)		1/9 (11.1%)
Cardiac disorders
Tachycardia	1/18 (5.6%)		0/9 (0%)
Eye disorders
Cataract	1/18 (5.6%)		0/9 (0%)
Dry eye	1/18 (5.6%)		0/9 (0%)
Eye pruritus	1/18 (5.6%)		0/9 (0%)
Vision blurred	1/18 (5.6%)		0/9 (0%)
Gastrointestinal disorders
Diarrhoea	2/18 (11.1%)		1/9 (11.1%)
Abdominal pain	2/18 (11.1%)		0/9 (0%)
Dry mouth	1/18 (5.6%)		0/9 (0%)
Nausea	1/18 (5.6%)		0/9 (0%)
Constipation	0/18 (0%)		1/9 (11.1%)
Enteritis	0/18 (0%)		1/9 (11.1%)
Gastritis	1/18 (5.6%)		0/9 (0%)
Glossodynia	0/18 (0%)		1/9 (11.1%)
Irritable bowel syndrome	1/18 (5.6%)		0/9 (0%)
Mouth ulceration	1/18 (5.6%)		0/9 (0%)
Vomiting	1/18 (5.6%)		0/9 (0%)
General disorders
Injection site reaction	7/18 (38.9%)		2/9 (22.2%)
Injection site erythema	4/18 (22.2%)		0/9 (0%)
Injection site pruritus	4/18 (22.2%)		0/9 (0%)
Injection site swelling	2/18 (11.1%)		0/9 (0%)
Fatigue	1/18 (5.6%)		1/9 (11.1%)
Pyrexia	1/18 (5.6%)		1/9 (11.1%)
Injection site pain	1/18 (5.6%)		0/9 (0%)
Asthenia	1/18 (5.6%)		0/9 (0%)
Device dislocation	0/18 (0%)		1/9 (11.1%)
Injection site irritation	1/18 (5.6%)		0/9 (0%)
Mucosal inflammation	0/18 (0%)		1/9 (11.1%)
Oedema peripheral	0/18 (0%)		1/9 (11.1%)
Immune system disorders
Drug hypersensitivity	1/18 (5.6%)		0/9 (0%)
Food allergy	1/18 (5.6%)		0/9 (0%)
Type I hypersensitivity	1/18 (5.6%)		0/9 (0%)
Infections and infestations
Upper respiratory tract infection	3/18 (16.7%)		3/9 (33.3%)
Influenza	2/18 (11.1%)		1/9 (11.1%)
Rhinitis	2/18 (11.1%)		0/9 (0%)
Urinary tract infection	1/18 (5.6%)		1/9 (11.1%)
Viral upper respiratory tract infection	1/18 (5.6%)		1/9 (11.1%)
Nasopharyngitis	1/18 (5.6%)		0/9 (0%)
Herpes virus infection	0/18 (0%)		1/9 (11.1%)
Conjunctivitis viral	1/18 (5.6%)		0/9 (0%)
Cystitis	1/18 (5.6%)		0/9 (0%)
Fungal skin infection	1/18 (5.6%)		0/9 (0%)
Gastroenteritis	0/18 (0%)		1/9 (11.1%)
Herpes zoster	1/18 (5.6%)		0/9 (0%)
Hordeolum	1/18 (5.6%)		0/9 (0%)
Lower respiratory tract infection	1/18 (5.6%)		0/9 (0%)
Pharyngitis	1/18 (5.6%)		0/9 (0%)
Respiratory tract infection	0/18 (0%)		1/9 (11.1%)
Injury, poisoning and procedural complications
Fall	1/18 (5.6%)		0/9 (0%)
Overdose	1/18 (5.6%)		0/9 (0%)
Wound	1/18 (5.6%)		0/9 (0%)
Investigations
Weight increased	0/18 (0%)		1/9 (11.1%)
Metabolism and nutrition disorders
Gout	1/18 (5.6%)		0/9 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/18 (16.7%)		1/9 (11.1%)
Musculoskeletal pain	2/18 (11.1%)		0/9 (0%)
Rheumatoid arthritis	2/18 (11.1%)		0/9 (0%)
Foot deformity	1/18 (5.6%)		0/9 (0%)
Joint swelling	1/18 (5.6%)		0/9 (0%)
Musculoskeletal stiffness	1/18 (5.6%)		0/9 (0%)
Myopathy	0/18 (0%)		1/9 (11.1%)
Osteoarthritis	0/18 (0%)		1/9 (11.1%)
Osteoporosis	1/18 (5.6%)		0/9 (0%)
Plantar fasciitis	0/18 (0%)		1/9 (11.1%)
Rheumatoid nodule	0/18 (0%)		1/9 (11.1%)
Rotator cuff syndrome	1/18 (5.6%)		0/9 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign bone neoplasm	0/18 (0%)		1/9 (11.1%)
Nervous system disorders
Headache	4/18 (22.2%)		1/9 (11.1%)
Dizziness	2/18 (11.1%)		0/9 (0%)
Brain oedema	0/18 (0%)		1/9 (11.1%)
Hypoaesthesia	0/18 (0%)		1/9 (11.1%)
Migraine	1/18 (5.6%)		0/9 (0%)
Paraesthesia	0/18 (0%)		1/9 (11.1%)
Presyncope	0/18 (0%)		1/9 (11.1%)
Subarachnoid haemorrhage	0/18 (0%)		1/9 (11.1%)
Psychiatric disorders
Insomnia	1/18 (5.6%)		0/9 (0%)
Reproductive system and breast disorders
Breast mass	0/18 (0%)		1/9 (11.1%)
Genital haemorrhage	1/18 (5.6%)		0/9 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/18 (5.6%)		1/9 (11.1%)
Oropharyngeal pain	1/18 (5.6%)		1/9 (11.1%)
Oropharyngeal blistering	1/18 (5.6%)		0/9 (0%)
Dysphonia	1/18 (5.6%)		0/9 (0%)
Dyspnoea	1/18 (5.6%)		0/9 (0%)
Epistaxis	0/18 (0%)		1/9 (11.1%)
Skin and subcutaneous tissue disorders
Pruritus	3/18 (16.7%)		0/9 (0%)
Rash	2/18 (11.1%)		1/9 (11.1%)
Dry skin	2/18 (11.1%)		0/9 (0%)
Eczema	1/18 (5.6%)		1/9 (11.1%)
Rash pruritic	1/18 (5.6%)		0/9 (0%)
Drug eruption	1/18 (5.6%)		0/9 (0%)
Hyperhidrosis	1/18 (5.6%)		0/9 (0%)
Increased tendency to bruise	1/18 (5.6%)		0/9 (0%)
Pruritus generalised	1/18 (5.6%)		0/9 (0%)
Rosacea	1/18 (5.6%)		0/9 (0%)
Skin lesion	0/18 (0%)		1/9 (11.1%)
Skin nodule	1/18 (5.6%)		0/9 (0%)
Vascular disorders
Arteriosclerosis	0/18 (0%)		1/9 (11.1%)
Hot flush	1/18 (5.6%)		0/9 (0%)
Hypertension	1/18 (5.6%)		0/9 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Prior to publishing results, Institution and Principal Investigator (PI) must first provide Sponsor with a copy of proposed publication for review at least 30 days prior to submission. If Institution and PI do not agree to modification, they shall so notify Sponsor and postpone submission for additional 60 days to allow Sponsor to seek legal remedies or file patent applications. There is a need for coordinated approach to any publication of results from sites for any multi-site study.