Plasma cell depletion as an approach to reset autoimmunity in rheumatoid arthritis

INTERVENTION: Trade Name: Orencia Injektionslösung in einer Fertigspritze Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: ABATACEPT CAS Number: 332348‐12‐6 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 125‐ Trade Name: Orencia 125 mg Injektionslösung im Fertigpen Pharmaceutical Form: Solution for injection in pre‐filled pen INN or Proposed INN: ABATACEPT CAS Number: 332348‐12‐6 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 125‐ Product Name: Daratumumab Pharmaceutical Form: Solution for injection INN or Proposed INN: Daratumumab CAS Number: 945721‐28‐8 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1800‐ CONDITION: Rheumatoid arthritis ; MedDRA version: 23.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: •To assess the safety of combined abatacept/daratumumab treatment in ACPA‐positive RA subjects; •To assess the clinical efficacy of combined abatacept/daratumumab treatment in ACPA‐positive RA subjects; Primary end point(s): Safety (Phase I + II):; •Incidence and grading of severity of Injection Related Reactions (IRR) and toxicity after administration of daratumumab until week 12.; •AE and SAE due to IMP (both, daratumumab and abatacept) throughout the whole study.; Clinical efficacy (Phase II):; •Percentage of subjects with anti‐CCP2 antibody seroconversion = CCP2 antibody level <5 RE/ml at week 24.; Secondary Objective: •To achieve drug‐free clinical remission after combined abatacept/daratumumab treatment. Timepoint(s) of evaluation of this end point: week 12/24 SECONDARY OUTCOME: Secondary end point(s): Serological: ; • Change in anti CCP2 antibody levels (RE/ml) ; • Change in anti CCP2 antibody levels (RE/ml) in HLA‐defined subgroups; • Change in total IgG, IgA, IgM subclasses; • Change in glycosylation profile of total IgG and CCP2 antibodies ; • Change in the number of plasmablasts, B cell and T cell numbers; • Change in numbers of CCP2‐specific plasmablasts and B‐cells; • Change in number of CD38+ T cells; ; Clinical: ; • TJC/SJC; • DAS28‐CRP; • SDAI / CDAI; • Percentage of patients in clinical remission (DAS28‐ESR<2.6); • ACR 20, 50, 70 response rates; Timepoint(s) of evaluation of this end point: week 48 vs week 24; week 48 vs week 0 INCLUSION CRITERIA: • Fulfilment of the 2010 ACR‐EULAR criteria of rheumatoid arthritis • CCP antibody positivity (cut off 5 RE/ ml) • Disease activity score DAS28‐ESR > 3.2 • Inadequate treatment response and/ or intolerance to at least one csDMARD (e.g. MTX) and/or bDMARDs (e.g. TNF‐alpha inhibitors or IL‐6 blockers or tsDMARDs) • csDMARD: only simultaneous therapy with MT X(if tolerated) allowed, i.e. Sulfasalazin, Hydroxychloroquine and Leflunomide must be stopped during screening phase and be replaced by MTX • Women of childbearing potential (WOCBP) must use adequate effective methods of contraception during participation in the study and 3 months after the last dose of Daratumumab or 14 weeks after the last dose of Abatacept • Fulfilment of the requirements for the administration of abatacept as stated in the abatacept SmPC Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Num