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NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients

Periodic Reporting for period 2 - NECESSITY (NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients)

Reporting period: 2020-01-01 to 2020-12-31

Primary Sjögren’s syndrome (pSS) is a systemic auto-immune disease caused by the immune system mistakenly attacking and destroying the moisture producing glands. pSS causes extreme dryness in mouth, eyes, lungs, skin and genitals. Patients often experience joint pain and swelling and extreme fatigue (tiredness). In one third of patients, the inflammatory process extends beyond the exocrine glands and patients also experience damage in other organs. About 5 to 10% of patients develop lymphoma, frequently located in salivary glands. The health related quality of life of pSS patients is poor. Extreme fatigue and dryness are debilitating symptoms and the main cause for social and professional isolation leading to anxiety and depression.
Although pSS is the most frequent systemic auto-immune disease after rheumatoid arthritis, no cure is available. Some treatments improve symptoms (such as artificial tears, anti-inflammatory drugs, painkillers), but they are moderately effective. Consequently, there is a high unmet need for new effective treatments in pSS.
The presentation of pSS varies greatly across patients and over time. This raises major challenges when designing studies to assess treatment responses. Treatment outcome measures have recently been developed (ESSDAI and ESSPRI) but their use in clinical trials has yielded mixed results. A composite outcome measure that allows multiple subsets of patients and domains to be tested in a single clinical trial would offer substantial clarity to future clinical trial design.
Consequently, the NECESSITY project aims to develop a composite responder index to evaluate treatment efficacy, to identify biomarkers for patient stratification and disease prognostic and to validate both in a large multicenter multinational clinical trial.
Development of a composite responder index: Sjögren’s syndrome Tool for Assessing Response to treatment (STAR)
The strategy for developing STAR is data and expert-driven and was built on the idea that, although a clinical trial is negative, there may be subsets of patients in the population that responded to the treatment. We used the Virtual Twins methods to enrich the analysis pool of responders to maximize our chances to detect clinical parameters that show differential change between the active and placebo arms. After identifying the items sensitive to change, we built several versions of STAR based on several Delphi rounds and evaluated their sensitivity to change on data from a number of past clinical trials in pSS evaluating biologics with different modes of action. This analysis is almost completed. Based on these results, a final Delphi round will be organised to select the “preliminary” STAR for validation in the NECESSITY clinical trial.
Identification of biomarkers for patient stratification and predictive of disease progression
Biomarkers defining different endotype of patients will allow stratification of patients in clinical trials to evaluate efficacy of a new drug in meaningful populations. Tissue and blood samples from past studies are currently analyzed to identify correlation between biomarkers and clinical phenotype, disease progression, glandular damage. We are also evaluating several stratification algorithms. A preliminary list of candidate tissue biomarkers have been identified for further analyses.

Development of new tools to assess patient reported outcomes
The clinical presentation of pSS varies greatly across patients so there is a high interest in developing innovative tools to capture the potential effect of therapy on the many facets of disease. A web application was developed for patient self-reporting of pain, dryness and fatigue symptoms on a daily basis from their home (“ecological” environment). The utility and feasibility of biosensors for assessing fatigue are also being evaluated in a pilot study. The webapp and the biosensors will both be further validated during the NECESISTY clinical trial.

Implementation of the NECESSITY clinical trial
The objectives of the NECESSITY clinical trial are multiple and include assessing the efficacy of two drug combinations on pSS patients and validating the novel responder index, the identified biomarkers and various tools the project has developed. The study protocol has been revised after a first review by National Competent Authorities and is now in final stage of preparation for a new submission through the Voluntary Harmonization Procedure.

Stakeholder engagement
Reaching consensus with key stakeholders (regulatory agencies, payers, and patients) is critical to ensure that the tools the project is developing will be widely used in future clinical trials and lead to approval of new drugs for pSS patients. We have started the engagement with the European Medicines Agency and are finalizing the preparation of a Qualification request of the responder index STAR. Next steps for engaging with the US Food and Drug Administration and European payers are being discussed. Patients are involved in every step of the project. Several European and American patient associations form the NECESSITY Patient Advisory Board and provide patients’ views on the development of the responder index, biomarkers and clinical trial.
To date, there are no approved disease-modifying therapies for pSS patients. Most clinical trials have been unsuccessful in identifying a drug improving patient symptoms. These negative results can be explained by an inefficient drug or by known limitations in current measures. By developing sensitive and validated tools (responder index, biomarkers) and sharing them with the Sjögren community, the NECESSITY project will contribute to increasing the success rate of clinical trials in pSS and bringing new therapies to patients.
NECESSITY Management structure
NECESSITY Consortium Partners
Organization of NECESSITY work packages
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