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

Phase 2

Completed

Conditions: Rheumatoid Arthritis

Interventions: Biological: Rituximab
Drug: Atacicept
Drug: Placebo matched to atacicept

Registration Number: NCT00664521

Lead Sponsor: Merck KGaA, Darmstadt, Germany

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 27

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rituximab Plus Atacicept	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.
Rituximab Plus Atacicept	Rituximab	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.
Rituximab Plus Placebo	Rituximab	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.
Rituximab Plus Placebo	Placebo matched to atacicept	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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.
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.
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.