ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 900

Abatacept Vs. Placebo in Early Diffuse Cutaneous Systemic Sclerosis— Results of a Phase 2 Investigator Initiated, Double-Blind, Placebo-Controlled, Multicenter, Randomized Controlled Trial Study

Dinesh Khanna1, Cathie Spino2, Erica Bush3, Sindhu Johnson4, Lorinda Chung5, Jerry Molitor6, Virginia D. Steen7, Robert Lafyatis8, Robert W. Simms9, Christopher P. Denton10, Suzanne Kafaja11, Tracy M. Frech12, Vivien Hsu13, Robyn T. Domsic14, Janet E. Pope15, Jessica K. Gordon16, Maureen D. Mayes17, Elena Schiopu3, Amber Young1, Nora Sandorfi18, Jane Park19, Faye N. Hant20, Elana J. Bernstein21, Soumya Chatterjee22, Flavia V. Castelino23, Ali Ajam24, Yannick Allanore25, Marco Matucci-Cerinic26, Oliver Distler27, Ora Singer28, Haoyan Zhong2, David Fox29 and Daniel E. Furst30, 1Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, University of Michigan, Ann Arbor, MI, 2Biostatistics, University of Michigan, Ann Arbor, MI, 3University of Michigan, Ann Arbor, MI, 4Rheumatology, Mount Sinai Hospital and University Health Network, Toronto, ON, Canada, 5Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, 6Rheumatic & Autoimmune Diseases, University of Minnesota, Minneapolis, MN, 7Rheumatology, MedStar Georgetown University Hospital, Washington, DC, 8Medicine/Division of Rheumatology, Pittsburgh University Medical Center, Pittsburgh, PA, 9Rheumatology, Boston University School of Medicine, Boston, MA, 10UCL Division of Medicine, Royal Free Campus, London, United Kingdom, 11Department of Internal Medicine, University of California Los Angeles, David Geffen School of Medicine, Division of Rheumatology, Los Angeles, CA, 12Division of Rheumatology, University of Utah, Salt Lake City, UT, 13Rheumatology, Robert Wood Johnson University Scleroderma Program, New Brunswick, NJ, 14Medicine - Rheumatology, University of Pittsburgh, Pittsburgh, PA, 15Department of Medicine, University of Western Ontario, London, ON, Canada, 16Rheumatology, Hospital for Special Surgery, New York, NY, 17Rheumatology, University of Texas McGovern Medical School, Houston, TX, 18Perelman School of Medicine, University of Pennsylvania, Pittsburgh, PA, 19Seattle Rheumatology Associates, Seattle, WA, 20Medicine/Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, 21Rheumatology, Columbia University, New York, NY, 22Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, 23Rheumatology, Harvard Medical School, Boston, MA, 24Division of Rheumatology-Immunology, The Ohio State University Wexner Medical Center, Columbus, OH, 25Service de Rhumatologie A, Hôpital Cochin, Paris, France, 26Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy, 27Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland, 28Medicine, University of Michigan, Ann Arbor, MI, 29Internal Medicine, University of Michigan, Ann Arbor, MI, 30UCLA, Los Angeles, CA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Date: Sunday, October 21, 2018

Title: 3S089 ACR Abstract: Systemic Sclerosis & Rel D/O–Clinical I: Clinical Trials I (898–903)

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Abatacept (ABA) is a recombinant fusion protein including extracellular domain of human CTLA4 and hinge‑ CH2‑CH3 of the Fc domain of human IgG. This phase 2 trial assessed the safety and efficacy of ABA 125 mg subcutaneous (SC) versus placebo SC given every week on skin fibrosis using the modified Rodnan skin score (mRSS) in diffuse cutaneous SSc (dcSSc; clinicaltrials.gov NCT02161406).

Methods: A 12-month, investigator-initiated, double-blind, randomized placebo-controlled trial was conducted between 2014 to 2018 at 27 US, Canadian and UK sites. Eligible subjects were randomized in a 1:1 ratio to either ABA or matching placebo, stratified by duration of dcSSc (≤18 vs >18 to ≤36 months). Key inclusion criteria included dcSSc with disease duration of ≤ 36 months (defined as first non−Raynaud phenomenon) and mRSS ≥ 10 and ≤ 35 units for disease duration of ≤ 18 months and mRSS ≥ 15 and ≤ 45 units with evidence of active disease for disease duration of >18-36 months. Escape therapy was allowed at 6 months for worsening SSc. Primary outcomes included safety and change in mRSS over 12 months (ΔmRSS). Secondary endpoints included ΔFVC%, ΔHAQ-DI, Δpatient and Δphysician global assessment, and ACR CRISS (composite measure in dcSSc). The primary endpoint of ΔmRSS was assessed using a linear mixed model with primary end point data censored after initiation of escape therapy.

Results: 88 subjects were randomized (44/group) and formed the mITT group; 34 (77%) and 35 (80%) completed the 12-month double-blind treatment period in ABA and placebo groups, respectively. At baseline, the mean age was 49 years, 75% were female, mean disease duration was 1.59 years, 60% had disease duration ≤ 18 months, mRSS was 22.4, mean FVC% was 85.3%, and mean HAQ-DI was 1.0. Compliance with both drugs was >98%. ABA was well tolerated with comparable adverse events (AEs), serious AEs, and AEs of special interest (e.g., infections and malignancies) between treatments. There were 3 deaths during the treatment— 2 in ABA (both scleroderma renal crisis-days 11 and 46) and 1 in placebo (sudden cardiac arrest- day 310). The primary endpoint showed an adjusted mean decrease of mRSS of -6.24 in ABA vs. -4.49 in placebo, p= 0.28 (Table). The secondary outcome measures were statistically significant (HAQ-DI, physician global assessment, and ACR CRISS) or showed numerical results favoring ABA (Table). A larger proportion of placebo subjects required escape immunosuppressive therapy vs. ABA (36% vs. 16%, p=0.03).

Conclusion: In patients with early dcSSc, ABA was well tolerated, but ΔmRSS was not statistically significant. Secondary outcome measures showed evidence in favor of ABA, including greater requirement of escape therapy in the placebo group. mRSS showed large variability, despite recruiting an early dcSSc population.

Outcome

at Month 12

Abatacept

N=44

Placebo

N=44

Difference

(ABA – Placebo)

P-value

ΔmRSS

-6.24

-4.49

-1.75

0.28

ΔPatient Global Assessment

-0.31

-0.09

-0.22

0.73

ΔPhysician Global Assessment

-1.30

-0.35

-0.95

0.03

ΔFVC% predicted

-1.34

-4.13

2.79

0.11

ΔHAQ-DI

-0.17

0.11

-0.28

0.005

ACR CRISS index, Median (IQR)

0.68 (1.00)

0.01 (0.86)

0.03

Estimates are from a linear mixed model with treatment group, month (3, 6, and 12), treatment x month interaction, duration of dcSSc (≤18 vs >18 to ≤36 months), and baseline outcome measure as fixed effects and participant as a random effect (except for ACR CRISS). For ACR CRISS, the treatment differences, adjusted for duration of dcSSc, were assessed by the non-parametric Van Elteren test. Multiple imputation was used for CRISS analysis.

Acknowledgment: This project was supported by NIH/NIAID Clinical ACE grant (5UM1AI110557-05) and an investigator-initiated grant by Bristol-Myers Squibb.

Disclosure: D. Khanna, Eicos Sciences, 1,Pfizer, Inc., 2,Horizon, 2,BMS, 2,Actelion, 5,Bayer, 5,Bayer, 2,Corbus, 5,Cytori, 5,EMD Serono, 5,Genentech, Inc., 5,Sanofi-Aventis, 5,GSK, 5,Boehringer Ingelheim, 5,Civi BioPharma, 3; C. Spino, None; E. Bush, None; S. Johnson, Roche, Bayer, Boehringer, BMS, NIH, Merck, 9; L. Chung, Third Rock Ventures; Incyte, 5; J. Molitor, Bohringer Ingelheim, Shire, Human Genetics, 2, 5; V. D. Steen, Bayer, 2, 5,Reata, 2; R. Lafyatis, None; R. W. Simms, None; C. P. Denton, Roche, Actelion, GlaxoSmithKline, Sanofi-Aventis, Inventiva, SCL Behring, Boehringer-Ingelheim, Bayer., 5; S. Kafaja, None; T. M. Frech, None; V. Hsu, None; R. T. Domsic, None; J. E. Pope, AbbVie Inc., 5,Amgen Inc., 5,Bristol-Myers Squibb, 5,Lilly, 5,Merck & Co., 5,Novartis, 5,Pfizer, Inc., 5,Roche, 5,Sanofi, 5,Sandoz, 5,Celltrion, 5,United Chemicals Belgium, 2; J. K. Gordon, None; M. D. Mayes, Boehringer-Ingelheim, 2, 5,Corbus, 2,Reata, 2,Sanofi, 2,Mitsubishi-Tanabe, 5,Roche-Genentech, 2; E. Schiopu, BMS, 2; A. Young, T32-AR007080-38, 2; N. Sandorfi, None; J. Park, None; F. N. Hant, None; E. J. Bernstein, Genentech, Inc., 5; S. Chatterjee, None; F. V. Castelino, Genentech, Inc.; Boehringer Ingelheim, 5; A. Ajam, None; Y. Allanore, None; M. Matucci-Cerinic, None; O. Distler, None; O. Singer, None; H. Zhong, None; D. Fox, None; D. E. Furst, no stocks, 2, 5, 6, 7.

To cite this abstract in AMA style:

Khanna D, Spino C, Bush E, Johnson S, Chung L, Molitor J, Steen VD, Lafyatis R, Simms RW, Denton CP, 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, Allanore Y, Matucci-Cerinic M, Distler O, Singer O, Zhong H, Fox D, Furst DE. Abatacept Vs. Placebo in Early Diffuse Cutaneous Systemic Sclerosis— Results of a Phase 2 Investigator Initiated, Double-Blind, Placebo-Controlled, Multicenter, Randomized Controlled Trial Study [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/abatacept-vs-placebo-in-early-diffuse-cutaneous-systemic-sclerosis-results-of-a-phase-2-investigator-initiated-double-blind-placebo-controlled-multicenter-randomized-controlled-trial-stu/. Accessed .

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