Máté Krausz1,2,3, Annette Uhlmann2,4, Ina Caroline Rump1,2, Gabriele Ihorst4, Sigune Goldacker1, Georgios Sogkas5, Sara Posadas-Cantera1, Reinhold Schmidt5, Manuel Feißt6, Laia Alsina7, Ingunn Dybedal8, Mike Recher9, Klaus Warnatz1,2, Bodo Grimbacher1,2,10,11,12. 1. Department of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Hugstetter Straße 55, 79106 Freiburg, Germany. 2. Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Breisacher Straße 115, 79106 Freiburg, Germany. 3. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Schaenzlestraße 1, 79104, Freiburg, Germany. 4. Clinical Trials Unit, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Elsaesser Straße 2, 79110 Freiburg, Germany. 5. Hannover Medical School, Klinik für Rheumatologie und Immunologie, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. 6. Medical Center - University of Heidelberg, Institut für Medizinische Biometrie und Informatik, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany. 7. Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Germany. 8. Oslo University Hospital, Rikshospitalet, Oslo, Norway. 9. Outpatient Internal Medicine Clinic, University Hospital, Basel, Switzerland. 10. DZIF - German Center for Infection Research, Satellite Center Freiburg, Germany. 11. CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Schaenzlestraße 18, 79104, Freiburg, Germany. 12. RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Germany.
Abstract
Background: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) insufficiency and lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency are both complex immune dysregulation syndromes with an underlying regulatory T cell dysfunction due to the lack of CTLA-4 protein. As anticipated, the clinical phenotypes of CTLA-4 insufficiency and LRBA deficiency are similar. Main manifestations include hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, immune-mediated respiratory, gastrointestinal, neurological, and skin involvement, which can be severe and disabling. The rationale of this clinical trial is to improve clinical outcomes of affected patients by substituting the deficient CTLA-4 by administration of CTLA4-Ig (abatacept) as a causative personalized treatment. Objectives: Our objective is to assess the safety and efficacy of abatacept for patients with CTLA-4 insufficiency or LRBA deficiency. The study will also investigate how treatment with abatacept affects the patients' quality of life. Methods: /Design: ABACHAI is a phase IIa prospective, non-randomized, open-label, single arm multi-center trial. Altogether 20 adult patients will be treated with abatacept 125 mg s.c. on a weekly basis for 12 months, including (1) patients already pretreated with abatacept, and (2) patients not pretreated, starting with abatacept therapy at the baseline study visit. For the evaluation of drug safety infection control during the trial, for efficacy, the CHAI-Morbidity Score will be used. Trial registration: The trial is registered in the German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS) with the identity number DRKS00017736, registered: 6 July 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017736.
Background: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) insufficiency and lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency are both complex immune dysregulation syndromes with an underlying regulatory T cell dysfunction due to the lack of CTLA-4 protein. As anticipated, the clinical phenotypes of CTLA-4 insufficiency and LRBA deficiency are similar. Main manifestations include hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, immune-mediated respiratory, gastrointestinal, neurological, and skin involvement, which can be severe and disabling. The rationale of this clinical trial is to improve clinical outcomes of affected patients by substituting the deficient CTLA-4 by administration of CTLA4-Ig (abatacept) as a causative personalized treatment. Objectives: Our objective is to assess the safety and efficacy of abatacept for patients with CTLA-4 insufficiency or LRBA deficiency. The study will also investigate how treatment with abatacept affects the patients' quality of life. Methods: /Design: ABACHAI is a phase IIa prospective, non-randomized, open-label, single arm multi-center trial. Altogether 20 adult patients will be treated with abatacept 125 mg s.c. on a weekly basis for 12 months, including (1) patients already pretreated with abatacept, and (2) patients not pretreated, starting with abatacept therapy at the baseline study visit. For the evaluation of drug safety infection control during the trial, for efficacy, the CHAI-Morbidity Score will be used. Trial registration: The trial is registered in the German Clinical Trials Register (Deutsches Register Klinischer Studien, DRKS) with the identity number DRKS00017736, registered: 6 July 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017736.
Authors: K-H Janke; U Steder-Neukamm; M Bauer; A Raible; C Meisner; J C Hoffmann; M Gregor; B Klump; W Häuser Journal: Gesundheitswesen Date: 2005 Aug-Sep
Authors: Karen I Mead; Yong Zheng; Claire N Manzotti; Laura C A Perry; Michael K P Liu; Fiona Burke; Dale J Powner; Michael J O Wakelam; David M Sansom Journal: J Immunol Date: 2005-04-15 Impact factor: 5.422
Authors: 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 Gordon; Maureen 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 Journal: Arthritis Rheumatol Date: 2019-12-10 Impact factor: 10.995
Authors: Patrick Maffucci; Charles A Filion; Bertrand Boisson; Yuval Itan; Lei Shang; Jean-Laurent Casanova; Charlotte Cunningham-Rundles Journal: Front Immunol Date: 2016-06-13 Impact factor: 7.561
Authors: David Egg; Charlotte Schwab; Annemarie Gabrysch; Peter D Arkwright; Edmund Cheesman; Lisa Giulino-Roth; Olaf Neth; Scott Snapper; Satoshi Okada; Michel Moutschen; Philippe Delvenne; Ann-Christin Pecher; Daniel Wolff; Yae-Jean Kim; Suranjith Seneviratne; Kyoung-Mee Kim; Ji-Man Kang; Samar Ojaimi; Catriona McLean; Klaus Warnatz; Maximilian Seidl; Bodo Grimbacher Journal: Front Immunol Date: 2018-09-10 Impact factor: 7.561