Development of a composite responder index: Sjögren’s syndrome Tool for Assessing Response to treatment (STAR)
The strategy for developing composite responder index (STAR) was both data and expert-driven and was built on the idea that, although the overall outcome of the trial was negative, there may be some patients with similar distinct mechanistic pathways of SjD (subsets) in the population that responded positively to the treatment. The novel endpoint STAR allows for an extensive evaluation of the effectiveness of a drug on all aspects of the disease: systemic activity, patient reported symptoms, salivary gland function, ocular gland function and biological parameters. The consortium completed the development of STAR and published it in The Annals of Rheumatic Diseases in April 2022. Currently, follow-up analysis on the validation of STAR are ongoing on both previously available data sets from previous trials and newly completed indusrial trials for retrospective validation.
Identification of biomarkers for patient stratification and predictive of disease progression
Biomarkers defining different distinct mechanistic pathways of SjD in 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 being analyzed to identify correlation between biomarkers and clinical phenotype (observable expression of the disease), disease progression, damage to the glands. We are also evaluating several stratification algorithms, with the use of novel technologies such as artificial intelligence based algorithms and various clustering approaches (based on symptoms, clinical and biological data). The stratification of methodology using clustering approaches done on French cohort called ASSESS was published in Arthritis and Rheumatology in 2024.
A preliminary list of candidate tissue and blood biomarkers has been identified, with a shortlist of tissue biomarkers being identified and made available for further evaluation by the bigger NECESSITY consortium.
Development of new tools to assess patient reported outcomes
The clinical presentation of SjD 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 called PEPSS was developed for patient self-reporting of pain, dryness and fatigue symptoms on a daily basis from their home (“ecological” environment) and is currently being used in the NECESSITY trial. Physical features have been selected, as proxy for fatigue, and will be assessed with the use of biosensors, data from which will be evaluated during the NECESSITY 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 SjD patients and validating the novel responder index (STAR), the identified biomarkers and various tools the project has developed. The first center opened in February 2022, and in total 31 sites in France, Spain, Italy, The Netherlands, Norway, Sweden, UK and Greece were open by 2024. From the beginning of randomizations in 2022 to end of 2024, 180 patients were randomized in the trial.
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 SjD patients. The EMA has published a Letter for Support for STAR in March 2022. In February of 2023, the consortium participated Critical Path Innovation Meeting with the Food and Drug Administration to discuss STAR. This meeting yielded a summary document from the FDA, describing the strengths of the STAR endpoint and bringing forward some reservations for the consideration of the consortium.
