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OP0130 (2021)
COMPOSITE OF RELEVANT ENDPOINTS IN SJÖGREN’S SYNDROME (CRESS): A COMPREHENSIVE TOOL FOR CLINICAL TRIALS
S. Arends1, L. de Wolff1, J. F. Van Nimwegen1, G. M. Verstappen1, J. Vehof2, M. Bombardieri3, S. J. Bowman4, E. Pontarini3, A. Baer5, M. Nys6, J. E. Gottenberg7, R. Felten8, N. Ray9, A. Vissink10, F. G. M. Kroese1, H. Bootsma1
1University Medical Centre Groningen and University of Groningen, Rheumatology and Clinical Immunology, Groningen, Netherlands
2University Medical Centre Groningen and University of Groningen, Ophthalmology, Groningen, Netherlands
3Queen Mary University of London, Rheumatology, London, United Kingdom
4Queen Elizabeth Hospital, Rheumatology, Birmingham, United Kingdom
5John Hopkins University School of Medicine, Rheumatology, Baltimore, United States of America
6Bristol Myers Squibb, Brussels, Belgium
7Centre National de Référence des Maladies Auto-immunes et Systémiques rare Est/Sud-Ouest (RESO), Rheumatology, Strasbourgh, France
8Centre National de Référence des Maladies Auto-immunes et Systémiques rare Est/Sud-Ouest (RESO), Rheumatology, Strasbourg, France
9Bristol Myers Squibb, Lawrenceville NJ, United States of America
10University Medical Centre Groningen and University of Groningen, Oral and Maxillofacial Surgery, Groningen, Netherlands

Background: Several large randomised controlled trials (RCTs) in primary Sjögren’s syndrome (pSS) failed to demonstrate drug efficacy. 1-4 Many of these trials used ESSDAI as primary endpoint, showing large but similar response rates in active treatment and placebo groups. 1,3,4 Given the heterogeneous nature of pSS, there is need for a composite endpoint including multiple clinically relevant parameters.


Objectives: To develop and validate the Composite of Relevant Endpoints in Sjögren’s Syndrome (CRESS).


Methods: A multidisciplinary team of pSS experts selected clinically relevant items and measurements to include in the CRESS. Definition of response of CRESS items was based on clinical relevance, previously defined minimal clinically important improvement (MCII) and data of the single-centre ASAP-III (abatacept) trial. 1 CRESS was validated in three independent RCTs: TRACTISS (rituximab) trial 2 , multi-centre abatacept trial 3 and ETAP (tocilizumab) trial 4 . CRESS response rates were assessed at the primary endpoint visit of all four trials.


Results: Five complementary items were selected to form CRESS: systemic disease activity, patient-reported symptoms, tear gland, salivary gland and serological item. Definition of response per item is presented in Table 1 . Total CRESS response was defined as response on ≥3 of 5 items. Since not all trials have ocular staining score or salivary gland ultrasonography (SGUS) available, the concise CRESS (cCRESS) was developed simultaneously, leaving Schirmer’s test and unstimulated whole saliva flow for the tear and salivary gland items, respectively. In the ASAP-III trial, CRESS response rates were 24/40 (60%) for abatacept vs. 7/39 (18%) for placebo at week 24 (p<0.001).

CRESS items and definition of response

Items Measurements Definition of response
Systemic disease activity ClinESSDAI Score<5 (low disease activity)
Patient-reported symptoms ESSPRI Decrease of ≥1 point or ≥15%
Tear gland* Schirmer/OSS** -If abnormal Schirmer (≤5 mm) at baseline: increase of ≥5 mm in Schirmer
-Or if abnormal OSS (≥3 points) at baseline: decrease ≥2 points in OSS
-Or if both Schirmer/OSS normal scores at baseline: no change to abnormal in both
Salivary gland* UWS/SGUS Increase of ≥25% in UWS (or if score is 0 at baseline, any increase)
Or decrease of ≥25% in total Hocevar score (SGUS)
Serological RF/IgG Decrease of ≥25% in RFOr decrease of ≥10% in IgG
CRESS responder Responder on ≥3 of 5 items

Ocular Staining Score (OSS), Unstimulated whole salivary flow (UWS), Salivary gland ultrasonography (SGUS), Rheumatoid factor (RF), Immunoglobuline G (IgG)

*Concise CRESS (cCRESS): CRESS without OSS and SGUS, leaving Schirmer and UWS for tear and salivary gland items, respectively

**Mean of both eyes

In the external validation trials, cCRESS response rates for TRACTISS were: 33/67 (49%) rituximab vs. 20/66 (30%) placebo at week 48 (p=0.026). CRESS response rates (without SGUS) for the multi-centre abatacept trial were: 41/92 (45%) abatacept vs. 30/95 (32%) placebo at week 24 (p=0.067). cCRESS response rates (without rheumatoid factor) for ETAP were: 10/55 (18%) tocilizumab vs. 13/55 (24%) placebo at week 24 (p=0.482) ( Figure 1A -D). Compared to ESSDAI MCII of ≥3 points decrease, CRESS was able to approximately halve placebo response rates in RCTs with high baseline ESSDAI scores (>5) ( Figures 1E -H).


Conclusion: CRESS shows lower placebo response rates compared to ESSDAI MCII, which is crucial for demonstrating treatment efficacy. With the CRESS, higher response rates in abatacept and rituximab treated patients compared to placebo were found in RCTs which previously showed negative primary endpoint results. CRESS confirmed that no differences were found for almost all outcome measures between tocilizumab and placebo, 4 with low response rates. The CRESS is a well-balanced, feasible, composite endpoint for use in clinical trials in pSS patients.


REFERENCES:

[1]Van Nimwegen 2020;9913(19):1–11

[2]Bowman 2017;69(7):1440–50

[3]Baer (doi:218599)

[4]Felten (doi:21846)


Acknowledgements: The authors would like to acknowledge all contributors of the included trials.


Disclosure of Interests: Suzanne Arends: None declared, Liseth de Wolff: None declared, Jolien F. van Nimwegen Speakers bureau: Bristol Myers Squibb, Consultant of: Bristol Myers Squibb, Gwenny M. Verstappen: None declared, Jelle Vehof: None declared, Michele Bombardieri Consultant of: MedImmune, GlaxoSmithKline, Grant/research support from: MedImmune, Simon J. Bowman Consultant of: AstraZenecea/MedImmune, Bristol Myers Squibb, Celgene, Eli Lilly, Glenmark, GlaxoSmithKline, MTPharma, Novartis, Ono, Pfizer, Takeda, UCB, XTLBio, Elena Pontarini: None declared, Alan Baer Consultant of: Bristol Myers Squibb, Sanofi, VielaBio, Novartis, Marleen Nys Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Jacques-Eric Gottenberg Grant/research support from: Bristol Myers Squibb, Pfizer, Renaud FELTEN: None declared, Neelanjana Ray Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Arjan Vissink: None declared, Frans G.M. Kroese Speakers bureau: Bristol Myers Squibb, Roche and Janssen-Cilag, Consultant of: Bristol Myers Squibb, Grant/research support from: Unrestricted grants from Bristol Myers Squibb, Hendrika Bootsma Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Bristol Myers Squibb, Roche, Novartis, Medimmune, Union Chimique Belge, Grant/research support from: Unrestricted grants from Bristol Myers Squibb and Roche

Citation: Ann Rheum Dis, volume 80, supplement 1, year 2021, page 74
Session: SLE, Sjögren’s and APS - treatment and SLE, Sjögren’s and APS - clinical aspects (other than treatment) (Oral Presentations)