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Delay in IRB approval
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Our hypothesis is that budesonide will provide effective hepatic ISP that will replace prednisone and allow lower systemic drug levels of FK, thus reducing the steroid- and calcineurin-associated complications often observed in the OLT population. This study is intended to investigate the therapeutic potential of this ISP combination.
This study will be a randomized, open-label non-inferiority trial to assess the efficacy, safety and tolerability of budesonide in combination with low-dose FK and standard-dose MMF as post-OLT ISP in comparison to standard ISP (S-ISP). Subjects will include OLT patients age 18 years and older receiving their first single-organ living- or deceased-donor liver transplant. Subjects must have post-operative recovery of graft function and be able to take oral medications before beginning treatment according to the study protocol.
Subjects will be randomized to receive either (1) investigational oral ISP including budesonide 9mg by mouth in three daily divided doses, FK with an initial target trough level of no greater than 5-6ng/mL, and MMF (I-ISP); or (2) S-ISP including prednisone, calcineurin antagonist, and MMF. After randomization, subjects will be followed for a total of 52 weeks and assessed for adequacy of graft function, and complications of therapy, particularly ACR
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Budesonide treatment arm | Experimental | Patients treated with budesonide in place of prednisone as part of immunosuppressive regimen |
|
| Standard immunosuppression arm | Active Comparator | Patients treated with standard immunosuppression after liver transplant |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Budesonide | Drug | Oral steroid with high first-pass metabolism in liver |
|
| Measure | Description | Time Frame |
|---|---|---|
| Acute cellular rejection (ACR) | Incidence of ACR in budesonide treatment arm as compared to standard treatment arm | 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Tacrolimus trough levels | Cumulative average trough level of tacrolimus in budesonide and standard treatment arms | 12 months |
| Diabetes | Incidence of diabetes in in budesonide and standard treatment arms |
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Inclusion Criteria: Adult patients age 18 years or older who undergo initial single-organ living- or deceased-donor liver-transplant surgery. Research participants are required to have satisfactory post-operative recovery of graft function and no post-operative renal-replacement therapy prior to starting medication according to protocol. They must also be able to take oral medications.
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Exclusion Criteria: Patients will be excluded from the study if they are: (1) undergoing retransplantation; (2) have fulminant hepatic failure as an indication for liver transplantation; (3) have surgical complication(s) potentially affecting post-operative graft function (i.e., hepatic artery thrombosis); or have delayed initial recovery of graft function (primary non-function) requiring non-standard induction therapy. Furthermore, patients with a contraindication to budesonide (i.e., hypersensitivity) will not be included in the study
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7720517 | Background | Jonsson G, Astrom A, Andersson P. Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver. Drug Metab Dispos. 1995 Jan;23(1):137-42. | |
| 9311706 | Background | Weber T, Kalbhenn T, Herrmann G, Hanisch E. Local immunosuppression with budesonide after liver transplantation in the rat: a preliminary histomorphological analysis. Transplantation. 1997 Sep 15;64(5):705-8. doi: 10.1097/00007890-199709150-00007. |
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Annonymous IPD will be shared in the event that the study protocol is approved at other transplanting institutions who then collaborate in this study. IPD will include standard clinical and laboratory data monitored after liver transplantation
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| ID | Term |
|---|---|
| D051437 | Renal Insufficiency |
| D007239 | Infections |
| D003920 | Diabetes Mellitus |
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D019819 | Budesonide |
| D016559 | Tacrolimus |
| D009173 | Mycophenolic Acid |
| D011241 | Prednisone |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
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Comparison of standard immunosuppression to immunosuppression incorporating budesonide in place of prednisone
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| Tacrolimus（FK506） | Drug | Calcineurin immunosuppressant |
|
|
| Mycophenolate Mofetil | Drug | Immunosupressant |
|
|
| Prednisone | Drug | Immunosuppresant |
|
| 12 months |
| Worsening kidney function | Incidence of worsening kidney function in budesonide and standard treatment arms | 12 months |
| Hyptertension | Incidence of hypertension in in budesonide and standard treatment arms | 12 months |
| Graft survival | Graft survival in budesonide and standard treatment arms | 12 months |
| Patient survival | Patient survival in budesonide and standard treatment arms | 12 months |
| Infection | Incidence of infection in budesonide and standard treatment arms | 12 months |
| 9158013 | Background | Ozcay N, Fryer J, Grant D, Freeman D, Garcia B, Zhong R. Budesonide, a locally acting steroid, prevents graft rejection in a rat model of intestinal transplantation. Transplantation. 1997 May 15;63(9):1220-5. doi: 10.1097/00007890-199705150-00006. |
| 22006869 | Background | Bhat M, Ghali P, Wong P, Marcus V, Michel R, Cantarovich M, Metrakos P, Deschenes M. Immunosuppression with budesonide for liver transplant recipients with severe infections. Liver Transpl. 2012 Feb;18(2):262-3. doi: 10.1002/lt.22453. No abstract available. |
| 26094251 | Background | Lichtenstein GR, Travis S, Danese S, D'Haens G, Moro L, Jones R, Huang M, Ballard ED, Bagin R, Hardiman Y, Collazo R, Sandborn WJ. Budesonide MMX for the Induction of Remission of Mild to Moderate Ulcerative Colitis: A Pooled Safety Analysis. J Crohns Colitis. 2015 Sep;9(9):738-46. doi: 10.1093/ecco-jcc/jjv101. Epub 2015 Jun 20. |
| 20600032 | Result | Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, Bahr MJ, Gunther R, Hultcrantz RW, Spengler U, Lohse AW, Szalay F, Farkkila M, Prols M, Strassburg CP; European AIH-BUC-Study Group. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology. 2010 Oct;139(4):1198-206. doi: 10.1053/j.gastro.2010.06.046. Epub 2010 Jun 22. |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |