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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Biological: Rituximab
* Drug: Atacicept
* Drug: Placebo matched to atacicept


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab Plus Atacicept<br>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<br>* Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3.<br>Drug: Atacicept<br>* Atacicept will be administered at a dose of 150 mg subcutaneously once a week from Week 7 to 32.<br>|
| Placebo Comparator: Rituximab Plus Placebo<br>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<br>* Rituximab will be administered as an intravenous infusion at a dose of 1000 mg at Weeks 1 and 3.<br>Drug: Placebo matched to atacicept<br>* Placebo matched to atacicept will be administered subcutaneously once a week from Week 7 to 32.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Baseline up to Week 64 | 
| Percentage of Participants With Immunoglobulin G (IgG) Level Less Than 3 Gram Per Liter (g/L) |  | Week 64 | 
| Percent Change From Baseline in Vital Signs and Routine Safety Lab Parameters at 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. | Baseline, Week 32 | 
| Percent Change From Baseline in Anti-tetanus and Anti-diphteria Immunization Titer at Week 32 | Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value. | Baseline, Week 32 | 
| Percent Change From Baseline in Anti-pneumococcus Titer at Week 32 | Percent change from baseline was calculated as ([Week 32 value minus baseline value] multiplied by 100) divided by baseline value. | Baseline, Week 32 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Week 32 | 
| Change From Baseline in Disease Activity Score in 28 Joints (DAS28) Based on CRP (DAS28-CRP) at 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. | Baseline, Week 32 | 
| Median Percentage Change From Baseline in Levels of Total, Mature and Memory B Cells | 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. | Baseline, Week 3, 7, 12, 16, 26 and 32 |