Evaluation of Abatacept and Daratumumab Combination Therapy in ACPA-Positive Rheumatoid Arthritis Patients

The primary objective of this study is to assess the **safety** and clinical efficacy of combined abatacept/daratumumab treatment in ACPA-positive rheumatoid arthritis (RA) subjects. Evaluating the safety profile is crucial to ensure that the therapeutic regimen does not pose undue risk to patients, while assessing clinical efficacy is essential to determine the potential benefits of this combination therapy in managing RA symptoms and progression. The study focuses on the impact of plasma cell depletion as a strategy to reset autoimmunity in individuals with RA, which could offer a novel therapeutic approach for this chronic inflammatory condition.

The clinical trial involves participants diagnosed with **rheumatoid arthritis**, specifically those who are ACPA-positive. The study population includes both male and female subjects, with an age range that corresponds to categories 3 and 4, indicating adult participants. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their fulfillment of the 2010 ACR-EULAR criteria for rheumatoid arthritis, CCP antibody positivity, and a disease activity score (DAS28-ESR) greater than 3.2. Additionally, participants must have had an inadequate response or intolerance to at least one conventional synthetic DMARD (csDMARD) or biologic DMARDs (bDMARDs). The trial includes individuals who are part of a vulnerable population, and lifestyle considerations such as the use of effective contraception are required for women of childbearing potential. The trial aims to assess the safety and clinical efficacy of combined abatacept/daratumumab treatment in this specific patient group.

The clinical trial is designed to evaluate the safety and clinical efficacy of combined **abatacept** and **daratumumab** treatment in subjects with ACPA-positive rheumatoid arthritis. This is a Phase I/II trial, characterized by a randomized, double-blind, and controlled design. The trial is expected to commence recruitment on December 1, 2024, and conclude by August 31, 2027. Participants will be involved in the study for a duration that includes multiple visits, starting with an inclusion (screening) visit, followed by regular follow-up visits, and concluding with an end-of-study visit.

The inclusion visit will assess eligibility based on criteria such as fulfillment of the 2010 ACR-EULAR criteria for rheumatoid arthritis, CCP antibody positivity, and a disease activity score (DAS28-ESR) greater than 3.2. Participants must have an inadequate response or intolerance to at least one csDMARD or bDMARD. Women of childbearing potential are required to use effective contraception during the study and for a specified period after the last dose of the investigational medicinal products (IMPs).

Follow-up visits will monitor the incidence and severity of injection-related reactions and any adverse events (AEs) or serious adverse events (SAEs) associated with the IMPs. The primary endpoints include the incidence and grading of injection-related reactions and toxicity after administration of **daratumumab** until week 12, as well as the percentage of subjects achieving anti-CCP2 antibody seroconversion by week 24. The end-of-study visit will finalize data collection and assess the overall outcomes of the trial.

Participants may be subject to early termination from the study if they experience significant adverse reactions, fail to comply with study protocols, or withdraw consent. The trial aims to provide valuable insights into the potential of combined **abatacept**/**daratumumab** therapy in managing rheumatoid arthritis, with a focus on safety and efficacy outcomes.

The clinical trial involves the administration of **ORENCIA** 125 mg solution for injection, which is available in two pharmaceutical forms: a pre-filled pen and a pre-filled syringe. The active substance in both forms is **abatacept**, a protein-based therapeutic agent. The solution is administered via the **subcutaneous** route. The frequency of administration is determined by the study protocol, and participant compliance is monitored through regular assessments. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and holds the marketing authorization number EU/1/07/389/011 for the pre-filled pen and EU/1/07/389/004 for the pre-filled syringe. Both forms are not pediatric formulations and are classified under the ATC code L04AA24.

Additionally, the trial includes the administration of **DARZALEX** 1800 mg solution for injection, with **daratumumab** as the active substance. This solution is also administered via the **subcutaneous** route. The pharmaceutical form is a solution for injection, and the product is manufactured by Janssen-Cilag International NV. The marketing authorization number for DARZALEX is EU/1/16/1101/004, and it is classified under the ATC code L01FC01. The administration schedule and participant compliance are similarly monitored as per the study protocol.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. The focus of the trial is to assess the safety and clinical efficacy of the combined treatment of abatacept and daratumumab in subjects with ACPA-positive rheumatoid arthritis. The trial does not include any orphan drug designations or pediatric formulations for the investigational products.

The clinical trial aims to assess the efficacy of combined treatment with **abatacept** and **daratumumab** in patients with ACPA-positive rheumatoid arthritis. Efficacy will be evaluated using several primary endpoints. These include the incidence and grading of severity of Injection Related Reactions (IRR) and toxicity following the administration of **daratumumab** until week 12, as well as adverse events (AE) and serious adverse events (SAE) due to the investigational medicinal products (IMP), both **daratumumab** and **abatacept**, throughout the entire study duration. Additionally, the percentage of subjects achieving anti-CCP2 antibody seroconversion, defined as a CCP2 antibody level of less than 5 RE/ml or less than 20 U/ml, will be measured at week 24.