We plan an open-label continuation trial of sirolimus for patients who have completed all phases of the study. Open in a separate window Figure 1 Treatment schedule and outcome measures. global assessment (100?mm visual analog scale) at 2, 4, 8, 12, and 16 weeks; change in lymphadenopathy at 16 weeks; and pharmacodynamic assessment, including the measurement of whole blood sirolimus level. Discussion: This clinical trial will provide evidence of efficacy and safety of sirolimus as a potential new therapeutic agent for patients with TCZ-resistant iMCD. Trial Registration: This study was registered with the Japan Registry of Clinical Trials as jRCT2071190029 on October 8, 2019. strong class=”kwd-title” Keywords: double-blind, idiopathic multicentric Castleman disease, mammalian target of rapamycin, sirolimus, tocilizumab-resistant 1.?Introduction Castleman disease (CD) is a rare lymphoproliferative disorder with 2 distinct clinical entities: the localized form, unicentric Castleman disease and the multicentric form, multicentric CD (MCD).[1,2] Individuals with unicentric Castleman disease are generally asymptomatic, whereas MCD is a systemic disease with multiple regions of lymphadenopathy and systemic symptoms that include fever, night sweats, weight loss, and fatigue.[3C5] Some MCD cases are associated with human herpesvirus 8 infection in human immunodeficiency virus-positive patients.[6] However, for patients with unknown etiology and pathophysiology, MCD is referred to as idiopathic MCD (iMCD).[7,8] In clinical practice, therapy for iMCD is introduced to improve systemic symptoms, reduce the size of lymph nodes, normalize levels of acute-phase reactants such as C-reactive protein (CRP), and to prevent organ damage. The anti-interleukin 6 (IL-6) monoclonal antibody including tocilizumab (TCZ) is the preferred first-line therapy for iMCD.[9] However, 40% of iMCD cases are refractory or resistant to TCZ.[10] In addition, plasma proteomics and histological examination of lymph nodes suggest that an IL-6 independent pathway exists for the pathogenesis of iMCD.[11] Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been reported to be effective for iMCD cases that are refractory to IL-6 inhibitors,[12] suggesting activation of the phosphatidylinositol-3?kinase/Akt/mTOR pathway Lurbinectedin in the pathogenesis of iMCD. Inhibition of this pathway suppresses proliferation of T cells and B cells activated by iMCD, as well as vascular endothelial growth factor, and is especially effective for some IL -6 independent iMCD.[13,14] In a recent report of 3 cases, sirolimus treatment significantly attenuated CD8-positive T cell activation and decreased vascular endothelial growth factor-A levels in patients with IL-6 inhibitor-resistant iMCD and achieved clinical remission in all 3 cases.[15] Thus, Lurbinectedin sirolimus may be a candidate for second-line therapy in patients with inadequate response to TCZ. Taken together, these findings prompted us to design the current phase II study to confirm the beneficial effects of sirolimus in patients with iMCD. Herein, we describe the final protocol (version 3.1; April 19, 2019) for this study. The results of this study are expected to provide evidence regarding the usefulness of sirolimus for the treatment of TCZ-resistant iMCD patients. 2.?Methods/design 2.1. Study design The present study has been designed in accordance with the standard protocol items: Recommendations for Interventional Trials and Consolidated Standards of Reporting Trials 2010 guidelines.[16,17] This is an investigator-initiated, multicenter, phase II, double-blind, randomized, parallel-group comparison study of the efficacy and safety of sirolimus compared with placebo in patients with TCZ-resistant iMCD. This study will be conducted at 8 centers in Japan and will be performed in accordance with the principles of the Declaration of Helsinki[18] and the Japan Lurbinectedin Good Clinical Practice. The study was registered on the Japan Registry of Clinical Trials as jRCT2071190029, and was approved by the Institutional Review Board in Nagasaki University Hospital, Keio University Hospital, Jikei University Hospital, Kanazawa Medical University Hospital, Kyoto University Hospital, Sumitomo Hospital, Daini Osaka Police Hospital, and Kyushu University Hospital. 2.2. Participant recruitment Participants will be recruited at Rabbit polyclonal to Caspase 3 Nagasaki University Hospital, Keio University Hospital, Jikei University Hospital, Kanazawa Medical University Hospital, Kyoto University Hospital, Sumitomo Hospital, Daini Osaka Police Hospital, and Kyushu University Hospital. All eligible patients will.