Background: Primary Sjögren's syndrome (pSS) is a chronic inflammatory and lymphoproliferative disease with autoimmune features. pSS is characterised by a progressive lymphocytic infiltration of the exocrine glands, notably the lacrimal and salivary glands. The main clinical features are a progressive dryness of the eyes, mouth, vagina and skin. Furthermore, various extraglandular manifestations may develop of which restricting fatigue is the most common. Patients may be restricted in their activities and their participation in society, resulting in a reduced health-related quality of life and an impaired socioeconomic status. The latter results in lower employment rates and more disability as compared to the general population. The estimated prevalence of pSS in the general population is between 0.5-2%, which makes pSS, after rheumatoid arthritis (RA), the most common systemic autoimmune disease. Most of the traditional anti-rheumatic drugs used in RA and systemic lupus erythematosus have been tried in pSS with limited results. Currently, biological agents have been introduced in various systemic autoimmune diseases. These biological agents enhance or replace conventional immunosuppressive therapy. In contrast to RA and systemic lupus erythematosus (SLE), no biological agent has yet been approved for the treatment of pSS. Abatacept is a fully human soluble co-stimulation modulator that selectively targets the CD80/CD86:CD28 co-stimulatory signal required for full T-cell activation, and T cell dependent activation of B-cells. We have recently shown in a phase II open label study that Abatacept treatment of pSS patients has promising efficacy results, as reflected by a significant decrease in disease activity indices such as the EULAR Sjögrens Syndrome Disease Activity Index and Patient Reported Index (ESSDAI and ESSPRI) (Meiners et al., 2014). Importantly, we also have shown that Abatacept is safe and side effects are very limited in pSS patients. For these reasons a larger and randomized clinical trial with Abatacept is warranted.

Objective: Primary: to evaluate efficacy of weekly subcutaneous (SC) administration of Abatacept vs placebo on disease activity assessed with ESSDAI at in patients with pSS. Secondary: to assess efficacy of Abatacept on clinical, functional, laboratory, subjective, and histological parameters over 48 weeks in patients with pSS. To evaluate the safety of abatacept, by monitoring serious adverse events (SAE), adverse events (AE) related SAE and AE, treatment discontinuation related to SAE and AE, and lab abnormalities over 48 weeks in patients with pSS. Exploratory: to assess efficacy on laboratory parameters over 48 weeks in patients with pSS.

Study design: The first stage is a 24-week randomized, double-blind, placebo-controlled phase III study to assess the efficacy and safety of Abatacept (weekly SC administration of 125 mg Abatacept or placebo) in patients with pSS. The primary endpoint (ESSDAI) will be evaluated at 24 weeks. The second stage is composed of a 24-week open-label period in which both Abatacept and placebo treated patients will receive Abatacept for 24 weeks. The total study duration will be 48 weeks where after the study will be opened.

Study population: 88 adult pSS patients

Intervention: Weekly subcutaneous administration of 125 mg Abatacept up to 48 weeks.

Main endpoints: The primary endpoint is the difference in ESSDAI score between the Abatacept and the placebo group at 24 weeks. Secondary endpoints are clinical, functional, laboratory, subjective, and histological parameters and the prevalence of adverse events, treatment discontinuation and laboratory abnormalities.

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