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
調査の概要
詳細な説明
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.
研究の種類
段階
- フェーズ 4
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
アクティブコンパレータ：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
他の名前：
|
|
アクティブコンパレータ：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
他の名前：
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|
アクティブコンパレータ：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
他の名前：
|
|
アクティブコンパレータ：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
他の名前：
|
|
アクティブコンパレータ：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
他の名前：
|
|
アクティブコンパレータ：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
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Number of participants reaching the composite endpoint
時間枠：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
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Proportion of subjects experiencing nephrotoxicity during the study
時間枠：6 months
|
Increase in serum creatinine of ≥0.3mg/dL
|
6 months
|
|
Proportion of subjects experiencing neurotoxicity during the study
時間枠：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
時間枠：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
時間枠：6 months
|
Assessed as the Chronic Kidney Disease - Epidemiology Collaboration equation
|
6 months
|
|
Difference in immunosuppressant side effects between enrolled subjects
時間枠：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
時間枠：6 months
|
Freedom from death and from graft loss at 6 months
|
6 months
|
協力者と研究者
出版物と役立つリンク
一般刊行物
- 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.
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研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (予想される)
研究の完了 (予想される)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
その他の研究ID番号
- Pro00018836
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
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Envarsus XRの臨床試験
-
Beth Israel Deaconess Medical CenterVeloxis Pharmaceuticalsまだ募集していません服薬アドヒアランス | 腎移植
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Roy D. Bloom, MDVeloxis Pharmaceuticals募集