Dinesh Khanna1, Cathie Spino1, Sindhu Johnson2, Lorinda Chung3, Michael L Whitfield4, Christopher P Denton5, Veronica Berrocal1, Jennifer Franks4, Bhavan Mehta4, Jerry Molitor6, Virginia D Steen7, Robert Lafyatis8, Robert W Simms9, Anna Gill5, Suzanne Kafaja10, Tracy M Frech11, Vivien Hsu12, Robyn T Domsic13, Janet E Pope14, Jessica K Gordon15, Maureen D Mayes16, Elena Schiopu1, Amber Young1, Nora Sandorfi17, Jane Park18, Faye N Hant19, Elana J Bernstein20, Soumya Chatterjee21, Flavia V Castelino22, Ali Ajam23, Yue Wang4, Tammara Wood4, Yannick Allanore24, Marco Matucci-Cerinic25, Oliver Distler26, Ora Singer1, Erica Bush1, David A Fox1, Daniel E Furst27. 1. University of Michigan, Ann Arbor. 2. Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada. 3. Stanford University School of Medicine, Palo Alto, California. 4. Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. 5. Royal Free Campus, London, UK. 6. University of Minnesota, Minneapolis. 7. MedStar Georgetown University Hospital, Washington, DC. 8. Pittsburgh University Medical Center, Pittsburgh, Pennsylvania. 9. Boston University School of Medicine, Boston, Massachusetts. 10. David Geffen School of Medicine at University of California, Los Angeles. 11. University of Utah, Salt Lake City. 12. Robert Wood Johnson University, New Brunswick, New Jersey. 13. University of Pittsburgh, Pittsburgh, Pennsylvania. 14. University of Western Ontario, London, Ontario, Canada. 15. Hospital for Special Surgery, New York, New York. 16. University of Texas McGovern Medical School, Houston. 17. Perelman School of Medicine at the University of Pennsylvania, Pittsburgh. 18. Seattle Rheumatology Associates, Seattle, Washington. 19. Medical University of South Carolina, Charleston. 20. Columbia University, New York, New York. 21. Cleveland Clinic, Cleveland, Ohio. 22. Harvard Medical School, Boston, Massachusetts. 23. Ohio State University Wexner Medical Center, Columbus. 24. Hôpital Cochin, Paris, France. 25. University of Florence, Florence, Italy. 26. University Hospital Zurich, Zurich, Switzerland. 27. University of California, Los Angeles.
Abstract
OBJECTIVE: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. RESULTS: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. CONCLUSION: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.
RCT Entities:
OBJECTIVE: T cells play a key role in the pathogenesis of early systemic sclerosis. This study was undertaken to assess the safety and efficacy of abatacept in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, participants were randomized 1:1 to receive either subcutaneous abatacept 125 mg or matching placebo, stratified by duration of dcSSc. Escape therapy was allowed at 6 months for worsening disease. The coprimary end points were change in the modified Rodnan skin thickness score (MRSS) compared to baseline and safety over 12 months. Differences in longitudinal outcomes were assessed according to treatment using linear mixed models, with outcomes censored after initiation of escape therapy. Skin tissue obtained from participants at baseline was classified into intrinsic gene expression subsets. RESULTS: Among 88 participants, the adjusted mean change in the MRSS at 12 months was -6.24 units for those receiving abatacept and -4.49 units for those receiving placebo, with an adjusted mean treatment difference of -1.75 units (P = 0.28). Outcomes for 2 secondary measures (Health Assessment Questionnaire disability index and a composite measure) were clinically and statistically significantly better with abatacept. The proportion of subjects in whom escape therapy was needed was higher in the placebo group relative to the abatacept group (36% versus 16%). In the inflammatory and normal-like skin gene expression subsets, decline in the MRSS over 12 months was clinically and significantly greater in the abatacept group versus the placebo group (P < 0.001 and P = 0.03, respectively). In the abatacept group, adverse events occurred in 35 participants versus 40 participants in the placebo group, including 2 deaths and 1 death, respectively. CONCLUSION: In this phase II trial, abatacept was well-tolerated, but change in the MRSS was not statistically significant. Secondary outcome measures, including gene expression subsets, showed evidence in support of abatacept. These data should be confirmed in a phase III trial.
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