Ignite Creation Date:
2024-05-06 @ 9:05 AM
Last Modification Date:
2024-10-26 @ 12:09 PM
Study NCT ID:
NCT02893176
Status:
WITHDRAWN
Last Update Posted:
2020-12-11
First Post:
2016-03-09
Brief Title:
Macitentan in the Treatment of Organ Rejection After Lung Transplantation
Sponsor:
University of California Los Angeles
Organization:
University of California Los Angeles
Study Overview
Official Title:
Potential Therapy With MACITENTAN in the Treatment of Chronic Lung Allograft Dysfunction CLAD After Lung Transplantation
Status:
WITHDRAWN
Status Verified Date:
2020-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Potential therapy with MACITENTAN in the treatment of Chronic Lung Allograft Dysfunction CLAD after Lung Transplantation Pilot Study Double-blind ADD-ON Therapy with MACITENTAN to usual standard of care immunosuppressive therapies after lung transplantation for established BOS Stages I or II versus a matched control group who receive usual standard of care immunosuppressive therapies alone results in a decrease in the Primary Endpoint rate of decline in Forced Expiratory Volume-1 sec FEV1 versus time while Secondary Endpoints including differences in Six minute walk distance 6MWD BORG Score corrected single-breath diffusing capacity DCO corrected at time intervals of 1 3 6 months on therapy Specific biomarkers for BOS including inflammatory chemokines which are routinely collected in the context of post-transplant surveillance will be analyzed Chemokines which our group has previously described in the pathogenesis of the continuum of acute-to-chronic lung allograft rejection have included both C-C CCL2 CCL5 and CXC CXCL9 CXCL10 CXCL11 chemokines as determined in bronchial-alveolar lavage BAL
Detailed Description:
Preliminary studies employing a rat tracheal allograft transplant model have demonstrated amelioration of the fibrous airway obliteration associated with blockade of the renin-angiotension and the endothelin system implementing the ERA antagonist BOSENTAN 100 mgkg Clinical studies have indeed demonstrated that the mitogenic and profibrotic peptide ET-1 may represent a potential biomarker in clinical BOS Detection of levels of ET-1 mRNA were significantly increased in the lung allografts of those with versus those without BOS at 3 and 12 months post-transplantation while ET-1 concentrations were significantly elevated both in serum and bronchoalveolar lavage fluid BALF from patients with BOS Additional studies have further demonstrated a pronounced inhibitory effect elicited by chronic ETA receptor blockade in the absence of immunosuppressive therapy on both plasma levels and transcriptional regulation of inflammatory chemokines in a rat heterotopic heart transplant model of chronic rejection
MACITENTAN a novel competitive ERA with significantly slower receptor dissociation kinetics than currently approved ERAs may represent a renewed hope for patients suffering from progressive CLAD post-transplantation The efficacy of MACITENTAN was not realized in the exploratory Phase II MUSIC Trial for IPF for the primary endpoint measure of forced vital capacity FVC nevertheless mechanistic disparities in the pathobiology of CLAD versus IPF therefore should not preclude a separate therapeutic trial Further in vitro treatment with MACITENTAN and its major metabolite ACT-132577 decreases alpha smooth muscle actin elaboration by dermal fibroblasts in systemic sclerosis fibrotic skin lesions therefore offering significant promise for potential disease modulation Most importantly the MUSIC Trial has further demonstrated the clinical safety of this pharmacologic therapy in 178 patients with IPF with mean drug exposure of approximately 14 months and without statistical differences in incidence of abnormal liver function studies Recent pharmacokinetic studies of MACITENTAN have suggested no clinically significant drug-drug interaction with respect to Cytochrome P4503A4 for concurrent post-transplant immunosuppressive type therapies such as cyclosporine tacrolimus and mycophenolate mofetil while insignificant interaction with the frequently implemented azole-type antibiotics was also observed
MACITENTAN a novel competitive ERA with significantly slower receptor dissociation kinetics than currently approved ERAs may represent a renewed hope for patients suffering from progressive CLAD post-transplantation The efficacy of MACITENTAN was not realized in the exploratory Phase II MUSIC Trial for IPF for the primary endpoint measure of forced vital capacity FVC nevertheless mechanistic disparities in the pathobiology of CLAD versus IPF therefore should not preclude a separate therapeutic trial Further in vitro treatment with MACITENTAN and its major metabolite ACT-132577 decreases alpha smooth muscle actin elaboration by dermal fibroblasts in systemic sclerosis fibrotic skin lesions therefore offering significant promise for potential disease modulation Most importantly the MUSIC Trial has further demonstrated the clinical safety of this pharmacologic therapy in 178 patients with IPF with mean drug exposure of approximately 14 months and without statistical differences in incidence of abnormal liver function studies Recent pharmacokinetic studies of MACITENTAN have suggested no clinically significant drug-drug interaction with respect to Cytochrome P4503A4 for concurrent post-transplant immunosuppressive type therapies such as cyclosporine tacrolimus and mycophenolate mofetil while insignificant interaction with the frequently implemented azole-type antibiotics was also observed
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None