Evaluation of Anti-rejection Drug, Tacrolimus, in African-Americans With Kidney Transplant
Evaluation of Early Dose Escalation Using Extended-Release Tacrolimus (Envarsus XR®) to Reduce Acute Rejection and Donor Specific Antibodies in African American Renal Transplant Recipients
Обзор исследования
Статус
Условия
Вмешательство/лечение
Подробное описание
Phase 4 (post-marketing) De novo African American living or deceased donor renal transplant recipients 18 to 65 years of age Number of subjects to be enrolled: 60
All patients will receive standard induction immunosuppression according to institution protocol. Within one week of transplantation, all patients will be converted from immediate-release tacrolimus (TAC) to extended-release tacrolimus (ENV) at 20% reduction in total daily dosage. Patients will be randomized to low-, moderate-, or high-intensity ENV groups, stratified by peak panel reactive antibody (pPRA) greater than or equal to 75%. Target tacrolimus trough concentrations for the first month post-transplant will be 8-10 ng/mL in low-intensity group, 10-12 ng/mL in moderate-intensity group, and 12-14 ng/mL in high-intensity group; likewise from month 1-3 post-transplant, target trough concentrations will be 6-8 ng/mL, 8-10 ng/mL, and 10-12 ng/mL, respectively. Subjects experiencing dose-limiting adverse events (AEs) will be de-escalated as warranted. Following month 3, all patients will be maintained on ENV at target tacrolimus trough concentrations according to institution protocol. Additional maintenance immunosuppression will consist of mycophenolate mofetil (MMF) at a goal dose of 2000 mg daily along with an oral prednisone taper to 5-10 mg daily by the end of month 1. All patients will be followed for 6 months post-transplant.
Тип исследования
Фаза
- Фаза 4
Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
Принимает здоровых добровольцев
Полы, имеющие право на обучение
Описание
Inclusion Criteria:
• Primary live donor or deceased donor renal allograft
- African American patients aged 18 to 65 years
- Ability to take oral medications
Not currently on medications known to significantly interfere with tacrolimus metabolism, e.g. strong CYP3A4 inducers or inhibitors including but not limited to rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, protease inhibitors, azole antifungal (voriconazole, itraconazole, posaconazole, ketoconazole)
o Note: All patients will be discharged on clotrimazole 10 mg three times daily for one month for thrush prophylaxis, a known mild-to-moderate CYP3A4 inhibitor
Female subjects of childbearing potential:
- Not current pregnant
- Agree not to try to become pregnant during the study period
- Agree to consistently use two forms of highly effective birth control throughout the study period
- Provision of signed and dated informed consent form
- Stated willingness to comply with all study procedures and availability for the duration of the study
Exclusion Criteria:
• Presence of a positive T- or B-cell flow cytometry allogeneic crossmatch
- Presence of pre-formed anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs)
- Recipient of an ABO-incompatible organ
- Receipt of a multi-organ or dual kidney transplant
- Receipt of pediatric en bloc deceased donor kidneys
- Receipt of deceased donor kidney with a kidney donor profile index (KDPI) greater than or equal to 85%
- Has undergone desensitization, or received antibody removal, anti-B-cell, or anti-plasma cell therapy in the 90 days preceding the transplant
- Planned initiation of antibody removal (i.e. plasmapheresis) within 7 days of the transplant procedure
- Positive test for latent tuberculosis (TB) and has not previously received adequate anti-microbial therapy or would require TB prophylaxis after transplant
- Uncontrolled concomitant infection that would not allow for targeting escalated tacrolimus trough concentrations, as deemed by prescriber
- Known infection or seropositivity for hepatitis B virus (HBV, defined by positive HBsAg, anti-HBcAg, or positive viral load) or hepatitis C virus (HCV) with active viral load
- Current malignancy
- Use of an investigational study in the 30 days prior to the transplant procedure
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Рандомизированный
- Интервенционная модель: Параллельное назначение
- Маскировка: Нет (открытая этикетка)
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
|---|---|
|
Активный компаратор: Group 1 - Low-Intensity
All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol. TAC dosing will be 2 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily. Target Tacrolimus Trough Concentrations: Week 0 to Week 4: 8-10 mg/mL Month 1 to Month 3: 6-8 mg/mL |
tacrolimus, extended-release tablets, a calcineurin inhibitor
Другие имена:
|
|
Активный компаратор: Group 1 - Moderate-Intensity
All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol. TAC dosing will be 3 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily. Target Tacrolimus Trough Concentrations: Week 0 to Week 4: 10-12 mg/mL Month 1 to Month 3: 8-10 mg/mL |
tacrolimus, extended-release tablets, a calcineurin inhibitor
Другие имена:
|
|
Активный компаратор: Group 1 - High-Intensity
All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol. TAC dosing will be 4 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily. Target Tacrolimus Trough Concentrations: Week 0 to Week 4: 12-14 mg/mL Month 1 to Month 3: 10-12 mg/mL |
tacrolimus, extended-release tablets, a calcineurin inhibitor
Другие имена:
|
|
Активный компаратор: Group 2 - Low-Intensity
All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol. TAC dosing will be 2 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily. Target Tacrolimus Trough Concentrations: Week 0 to Week 4: 8-10 mg/mL Month 1 to Month 3: 6-8 mg/mL |
tacrolimus, extended-release tablets, a calcineurin inhibitor
Другие имена:
|
|
Активный компаратор: Group 2 - Moderate-Intensity
All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol. TAC dosing will be 3 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily. Target Tacrolimus Trough Concentrations: Week 0 to Week 4: 10-12 mg/mL Month 1 to Month 3: 8-10 mg/mL |
tacrolimus, extended-release tablets, a calcineurin inhibitor
Другие имена:
|
|
Активный компаратор: Group 2 - High-Intensity
All patients will receive standard induction immunosuppression according to institution protocol. TAC will be started when clinically appropriate according to institution protocol. TAC dosing will be 4 mg twice daily to be reduced by 20% after week 1 and start Envarsus XR once daily. Target Tacrolimus Trough Concentrations: Week 0 to Week 4: 12-14 mg/mL Month 1 to Month 3: 10-12 mg/mL |
tacrolimus, extended-release tablets, a calcineurin inhibitor
Другие имена:
|
Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Number of participants reaching the composite endpoint
Временное ограничение: 6 months
|
Composite endpoint of freedom from all of the following: i) biopsy-proven T-cell mediated rejection Banff Grade ≥1A, ii) antibody-mediated rejection, iii) de novo DSA, or iv) immune-mediated graft loss.
The endpoint is a binary endpoint (Yes or No) of the composite of all 4 potential outcomes.
The presence of any one of the four possible outcomes will be counted as a No for the binary endpoint (no freedom from the composite endpoint).
The absence of all 4 possible outcomes will be counted as Yes for freedom from all of the possible outcomes.
|
6 months
|
Вторичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
Proportion of subjects experiencing nephrotoxicity during the study
Временное ограничение: 6 months
|
Increase in serum creatinine of ≥0.3mg/dL
|
6 months
|
|
Proportion of subjects experiencing neurotoxicity during the study
Временное ограничение: 6 months
|
Clinical intolerability including headache or significant tremors that resolve with reduction of the dose of Envarsus
|
6 months
|
|
Proportion of subjects experiencing infectious complications during the study
Временное ограничение: 6 months
|
Participants requiring extended (>2 weeks) reduction in dose of Envarsus due to BK-polyomavirus or cytomegalovirus viral loads at 1, 3, and 6 months post-transplant
|
6 months
|
|
Difference in estimated glomerular filtration rate at 1, 3, and 6 months between groups of enrolled subjects
Временное ограничение: 6 months
|
Assessed as the Chronic Kidney Disease - Epidemiology Collaboration equation
|
6 months
|
|
Difference in immunosuppressant side effects between enrolled subjects
Временное ограничение: 6 months
|
Assessed using the "Immunosuppressant Side Effects Instrument - The Memphis Survey" questionnaire
|
6 months
|
|
Enrolled subject overall survival and Graft survival at 6 months
Временное ограничение: 6 months
|
Freedom from death and from graft loss at 6 months
|
6 months
|
Соавторы и исследователи
Соавторы
Публикации и полезные ссылки
Общие публикации
- Langone A, Steinberg SM, Gedaly R, Chan LK, Shah T, Sethi KD, Nigro V, Morgan JC; STRATO Investigators. Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. Clin Transplant. 2015 Sep;29(9):796-805. doi: 10.1111/ctr.12581. Epub 2015 Aug 6.
- Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011 Mar;11(3):450-62. doi: 10.1111/j.1600-6143.2010.03283.x. Epub 2010 Oct 25.
- Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
- Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation. 2013 Jul 27;96(2):191-7. doi: 10.1097/TP.0b013e3182962cc1.
- Bunnapradist S, Ciechanowski K, West-Thielke P, Mulgaonkar S, Rostaing L, Vasudev B, Budde K; MELT investigators. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant. 2013 Mar;13(3):760-9. doi: 10.1111/ajt.12035. Epub 2012 Dec 21.
- Budde K, Bunnapradist S, Grinyo JM, Ciechanowski K, Denny JE, Silva HT, Rostaing L; Envarsus study group. Novel once-daily extended-release tacrolimus (LCPT) versus twice-daily tacrolimus in de novo kidney transplants: one-year results of Phase III, double-blind, randomized trial. Am J Transplant. 2014 Dec;14(12):2796-806. doi: 10.1111/ajt.12955. Epub 2014 Oct 2.
- Kuypers DR, Claes K, Evenepoel P, Maes B, Vanrenterghem Y. Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients. Clin Pharmacol Ther. 2004 May;75(5):434-47. doi: 10.1016/j.clpt.2003.12.009.
- Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10):623-53. doi: 10.2165/00003088-200443100-00001.
- Young CJ, Gaston RS. Renal transplantation in black Americans. N Engl J Med. 2000 Nov 23;343(21):1545-52. doi: 10.1056/NEJM200011233432107. No abstract available.
- Narayanan M, Pankewycz O, Shihab F, Wiland A, McCague K, Chan L. Long-term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four-yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study. Clin Transplant. 2014 Feb;28(2):184-91. doi: 10.1111/ctr.12294. Epub 2013 Dec 24.
- Patel SJ, Suki WN, Loucks-DeVos J, Graviss EA, Nguyen DT, Knight RJ, Kuten SA, Moore LW, Teeter LD, Gaber LW, Gaber AO. Disparate rates of acute rejection and donor-specific antibodies among high-immunologic risk renal transplant subgroups receiving antithymocyte globulin induction. Transpl Int. 2016 Aug;29(8):897-908. doi: 10.1111/tri.12791. Epub 2016 Jul 7.
- Bunnapradist S, Rostaing L, Alloway RR, West-Thielke P, Denny J, Mulgaonkar S, Budde K. LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. Transpl Int. 2016 May;29(5):603-11. doi: 10.1111/tri.12770. Epub 2016 Apr 3.
- Trofe-Clark J, Brennan DC, West-Thielke P, Milone MC, Lim MA, Neubauer R, Nigro V, Bloom RD. Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients. Am J Kidney Dis. 2018 Mar;71(3):315-326. doi: 10.1053/j.ajkd.2017.07.018. Epub 2017 Nov 20.
- Winsett RP, Arheart K, Stratta RJ, Alloway R, Wicks MN, Gaber AO, Hathaway DK. Evaluation of an immunosuppressant side effect instrument. Prog Transplant. 2004 Sep;14(3):210-6, 240. doi: 10.1177/152692480401400306.
- Kuypers DR, Peeters PC, Sennesael JJ, Kianda MN, Vrijens B, Kristanto P, Dobbels F, Vanrenterghem Y, Kanaan N; ADMIRAD Study Team. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013 Jan 27;95(2):333-40. doi: 10.1097/TP.0b013e3182725532.
- Ho ET, Wong G, Craig JC, Chapman JR. Once-daily extended-release versus twice-daily standard-release tacrolimus in kidney transplant recipients: a systematic review. Transplantation. 2013 May 15;95(9):1120-8. doi: 10.1097/TP.0b013e318284c15b.
- Beckebaum S, Iacob S, Sweid D, Sotiropoulos GC, Saner F, Kaiser G, Radtke A, Klein CG, Erim Y, de Geest S, Paul A, Gerken G, Cicinnati VR. Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation. Transpl Int. 2011 Jul;24(7):666-75. doi: 10.1111/j.1432-2277.2011.01254.x. Epub 2011 Apr 5.
- Doesch AO, Mueller S, Konstandin M, Celik S, Erbel C, Kristen A, Frankenstein L, Koch A, Dengler TJ, Ehlermann P, Zugck C, De Geest S, Katus HA. Increased adherence after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation: a pre-experimental study. Transplant Proc. 2010 Dec;42(10):4238-42. doi: 10.1016/j.transproceed.2010.09.074.
- Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol. 1993 Dec 1;138(11):923-36. doi: 10.1093/oxfordjournals.aje.a116813.
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Даты записи исследования
Изучение основных дат
Начало исследования (Действительный)
Первичное завершение (Ожидаемый)
Завершение исследования (Ожидаемый)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Действительный)
Обновления учебных записей
Последнее опубликованное обновление (Действительный)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Ключевые слова
Дополнительные соответствующие термины MeSH
- Урологические заболевания
- Почечная недостаточность
- Почечная недостаточность, хроническая
- Заболевания почек
- Почечная недостаточность, хроническая
- Физиологические эффекты лекарств
- Молекулярные механизмы фармакологического действия
- Ингибиторы ферментов
- Иммунодепрессанты
- Иммунологические факторы
- Ингибиторы кальциневрина
- Такролимус
Другие идентификационные номера исследования
- Pro00018836
Планирование данных отдельных участников (IPD)
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Информация о лекарствах и устройствах, исследовательские документы
Изучает лекарственный продукт, регулируемый FDA США.
Изучает продукт устройства, регулируемый Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США.
Эта информация была получена непосредственно с веб-сайта clinicaltrials.gov без каких-либо изменений. Если у вас есть запросы на изменение, удаление или обновление сведений об исследовании, обращайтесь по адресу register@clinicaltrials.gov. Как только изменение будет реализовано на clinicaltrials.gov, оно будет автоматически обновлено и на нашем веб-сайте. .
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