Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial

Dinesh Khanna, Cathie Spino, Sindhu Johnson, Lorinda Chung, Michael L. Whitfield, Christopher P. Denton, Veronica Berrocal, Jennifer Franks, Bhavan Mehta, Jerry Molitor, Virginia D. Steen, Robert Lafyatis, Robert W. Simms, Anna Gill, Suzanne Kafaja, Tracy M. Frech, Vivien Hsu, Robyn T. Domsic, Janet E. Pope, Jessica K. GordonMaureen D. Mayes, Elena Schiopu, Amber Young, Nora Sandorfi, Jane Park, Faye N. Hant, Elana J. Bernstein, Soumya Chatterjee, Flavia V. Castelino, Ali Ajam, Yue Wang, Tammara Wood, Yannick Allanore, Marco Matucci-Cerinic, Oliver Distler, Ora Singer, Erica Bush, David A. Fox, Daniel E. Furst

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)125-136
Number of pages12
JournalArthritis and Rheumatology
Volume72
Issue number1
DOIs
StatePublished - Jan 1 2020

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Diffuse Scleroderma
Randomized Controlled Trials
Placebos
Research Personnel
Skin
Gene Expression
Therapeutics
Safety
Abatacept
Systemic Scleroderma
Linear Models
Outcome Assessment (Health Care)
T-Lymphocytes

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Abatacept in Early Diffuse Cutaneous Systemic Sclerosis : Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. / Khanna, Dinesh; Spino, Cathie; Johnson, Sindhu; Chung, Lorinda; Whitfield, Michael L.; Denton, Christopher P.; Berrocal, Veronica; Franks, Jennifer; Mehta, Bhavan; Molitor, Jerry; Steen, Virginia D.; Lafyatis, Robert; Simms, Robert W.; Gill, Anna; Kafaja, Suzanne; Frech, Tracy M.; Hsu, Vivien; Domsic, Robyn T.; Pope, Janet E.; Gordon, Jessica K.; Mayes, Maureen D.; Schiopu, Elena; Young, Amber; Sandorfi, Nora; Park, Jane; Hant, Faye N.; Bernstein, Elana J.; Chatterjee, Soumya; Castelino, Flavia V.; Ajam, Ali; Wang, Yue; Wood, Tammara; Allanore, Yannick; Matucci-Cerinic, Marco; Distler, Oliver; Singer, Ora; Bush, Erica; Fox, David A.; Furst, Daniel E.

In: Arthritis and Rheumatology, Vol. 72, No. 1, 01.01.2020, p. 125-136.

Research output: Contribution to journalArticle

Khanna, D, Spino, C, Johnson, S, Chung, L, Whitfield, ML, Denton, CP, Berrocal, V, Franks, J, Mehta, B, Molitor, J, Steen, VD, Lafyatis, R, Simms, RW, Gill, A, Kafaja, S, Frech, TM, Hsu, V, Domsic, RT, Pope, JE, Gordon, JK, Mayes, MD, Schiopu, E, Young, A, Sandorfi, N, Park, J, Hant, FN, Bernstein, EJ, Chatterjee, S, Castelino, FV, Ajam, A, Wang, Y, Wood, T, Allanore, Y, Matucci-Cerinic, M, Distler, O, Singer, O, Bush, E, Fox, DA & Furst, DE 2020, 'Abatacept in Early Diffuse Cutaneous Systemic Sclerosis: Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial', Arthritis and Rheumatology, vol. 72, no. 1, pp. 125-136. https://doi.org/10.1002/art.41055
Khanna, Dinesh ; Spino, Cathie ; Johnson, Sindhu ; Chung, Lorinda ; Whitfield, Michael L. ; Denton, Christopher P. ; Berrocal, Veronica ; Franks, Jennifer ; Mehta, Bhavan ; Molitor, Jerry ; Steen, Virginia D. ; Lafyatis, Robert ; Simms, Robert W. ; Gill, Anna ; Kafaja, Suzanne ; Frech, Tracy M. ; Hsu, Vivien ; Domsic, Robyn T. ; Pope, Janet E. ; Gordon, Jessica K. ; Mayes, Maureen D. ; Schiopu, Elena ; Young, Amber ; Sandorfi, Nora ; Park, Jane ; Hant, Faye N. ; Bernstein, Elana J. ; Chatterjee, Soumya ; Castelino, Flavia V. ; Ajam, Ali ; Wang, Yue ; Wood, Tammara ; Allanore, Yannick ; Matucci-Cerinic, Marco ; Distler, Oliver ; Singer, Ora ; Bush, Erica ; Fox, David A. ; Furst, Daniel E. / Abatacept in Early Diffuse Cutaneous Systemic Sclerosis : Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. In: Arthritis and Rheumatology. 2020 ; Vol. 72, No. 1. pp. 125-136.
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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.",
author = "Dinesh Khanna and Cathie Spino and Sindhu Johnson and Lorinda Chung and Whitfield, {Michael L.} and Denton, {Christopher P.} and Veronica Berrocal and Jennifer Franks and Bhavan Mehta and Jerry Molitor and Steen, {Virginia D.} and Robert Lafyatis and Simms, {Robert W.} and Anna Gill and Suzanne Kafaja and Frech, {Tracy M.} and Vivien Hsu and Domsic, {Robyn T.} and Pope, {Janet E.} and Gordon, {Jessica K.} and Mayes, {Maureen D.} and Elena Schiopu and Amber Young and Nora Sandorfi and Jane Park and Hant, {Faye N.} and Bernstein, {Elana J.} and Soumya Chatterjee and Castelino, {Flavia V.} and Ali Ajam and Yue Wang and Tammara Wood and Yannick Allanore and Marco Matucci-Cerinic and Oliver Distler and Ora Singer and Erica Bush and Fox, {David A.} and Furst, {Daniel E.}",
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TY - JOUR

T1 - Abatacept in Early Diffuse Cutaneous Systemic Sclerosis

T2 - Results of a Phase II Investigator-Initiated, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial

AU - Khanna, Dinesh

AU - Spino, Cathie

AU - Johnson, Sindhu

AU - Chung, Lorinda

AU - Whitfield, Michael L.

AU - Denton, Christopher P.

AU - Berrocal, Veronica

AU - Franks, Jennifer

AU - Mehta, Bhavan

AU - Molitor, Jerry

AU - Steen, Virginia D.

AU - Lafyatis, Robert

AU - Simms, Robert W.

AU - Gill, Anna

AU - Kafaja, Suzanne

AU - Frech, Tracy M.

AU - Hsu, Vivien

AU - Domsic, Robyn T.

AU - Pope, Janet E.

AU - Gordon, Jessica K.

AU - Mayes, Maureen D.

AU - Schiopu, Elena

AU - Young, Amber

AU - Sandorfi, Nora

AU - Park, Jane

AU - Hant, Faye N.

AU - Bernstein, Elana J.

AU - Chatterjee, Soumya

AU - Castelino, Flavia V.

AU - Ajam, Ali

AU - Wang, Yue

AU - Wood, Tammara

AU - Allanore, Yannick

AU - Matucci-Cerinic, Marco

AU - Distler, Oliver

AU - Singer, Ora

AU - Bush, Erica

AU - Fox, David A.

AU - Furst, Daniel E.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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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DO - 10.1002/art.41055

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