Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 97
- 试验地点
- 10
- 主要终点
- Mean Glomerular Filtration Rate by Iohexol Clearance at Week 52
研究概览
简要总结
Maraviroc (MVC) is a type of HIV medicine called a CCR5 inhibitor. This study will evaluate the safety and tolerability of MVC in HIV-infected adults receiving a kidney transplant.
详细描述
MVC is a CCR5 inhibitor that may have a positive role in modulating the immune response following transplantation. The purpose of this study is to evaluate the safety and tolerability of MVC in HIV-infected adults in need of a kidney transplant. The study will also evaluate whether using both immunosuppressant drugs and MVC will improve kidney function after a kidney transplant.
This study will enroll HIV-infected adults on combination antiretroviral therapy (cART) who need a kidney transplant. At the time of their kidney transplant, study participants will be randomly assigned to receive either MVC or placebo as an addition to their cART regimen. (MVC or placebo will be provided by the study. However, the HIV medicines in their cART regimens will not be provided by the study.) Participants will receive MVC or placebo throughout their participation in the study, which will be 1 to 3 years depending on when they enroll in the study.
Study visits will occur at enrollment (Day 0) and post-transplant Weeks 1, 2, 4, 8, 13, 26, 39, 52, 78, 104, 130, and 156. Study visits may include a physical examination, blood collection, lymph node collection, urine sample collection, and a kidney biopsy. During the study, participants will also be monitored closely for evidence of drug toxicities, HIV treatment failure and rejection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant is able to understand and provide informed consent.
- •Documented HIV infection (by any licensed enzyme-linked immunosorbent assay [ELISA] and confirmation by Western Blot, positive HIV antibody (ab) indirect fluorescent antibody (IFA), or documented history of detectable HIV-1 RNA).
- •Participant is 18 years of age or older.
- •CD4+ T-cell count greater than or equal to 200/µL at any time in the 26 weeks prior to enrollment.
- •Most recent HIV-1 RNA less than 50 copies RNA/mL. Eligibility at the time of enrollment will be determined based on the most recent HIV-1 RNA, not more than 26 weeks prior to enrollment. Subjects who require a switch in combination antiretroviral therapy (cART) regimen to become study eligible must also have an eligible HIV-1 RNA result post change in cART.
- •Participant meets standard listing criteria for placement on transplant waiting list.
- •For participants with an HIV+ deceased donor:
- •No active opportunistic infections.
- •Concurrence by the study team that based on medical history and ART, viral suppression can be achieved in the recipient post-transplant.
- •Must be enrolled in an Institutional Review Board (IRB) approved research protocol that fulfills the requirements of the DHHA Hope Act Policy (see the protocol for more information).
- •HIV+ deceased donor must have no evidence of invasive opportunistic complications of HIV infection, and must have a pre-implant biopsy.
- •Antiretroviral (ARV) Use: Participant is on a stable cART regimen for at least 3 months prior to enrollment (unless changes are made due to toxicity, drug interactions, convenience or to an eligible non-protease inhibitor-based regimen). Switch should not be due to virologic failure. A regimen consisting of 2 NTRTIs and an integrase inhibitor is preferred due to minimal drug interaction but any non-protease inhibitor regimen may be used.
- •If on a protease inhibitor based regimen, participant must be switched to a non-protease inhibitor-based regimen based on lack of any prior drug resistance or antiretroviral-treatment failure, and be willing to remain on indefinitely unless a change is medically necessary. Participants who need to be switched must have been on a stable cART regimen for at least 3 months prior, and must have an eligible HIV-1 RNA result post change in cART.
- •If already on a stable non-protease inhibitor-based regimen, participant is willing to remain on this regimen indefinitely unless a change in regimen is medically indicated.
- •If untreated, must initiate and be willing to remain on indefinitely a non-protease inhibitor-based antiretroviral regimen unless a change is medically necessary.
- •No known allergy or intolerance to components of maraviroc (MVC) or its formulation.
- •No known contraindication to MVC.
- •Female participants of child-bearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test within 30 days of randomization.
排除标准
- •Participant is currently on MVC.
- •Participant needs multi-organ transplant.
- •Participant has a live donor who is HIV+.
- •Participant is unable to switch to a non-protease inhibitor-based cART regimen.
- •Participant has received immunosuppressant medication in the 6 months prior to enrollment. Note: Low dose maintenance steroids (less than or equal to 10 mg per day of prednisone, or equivalent strength steroid) will not be considered immunosuppression.
- •Opportunistic Complication History: Any history of progressive multifocal leukoencephalopathy (PML), chronic intestinal cryptosporidiosis of greater than 1 month duration, or primary central nervous system (CNS) lymphoma. Note: History of pulmonary coccidioidomycosis will be treated per local site policy regarding this infection in HIV negative transplant candidates, generally requiring a 5-year disease-free interval.
- •Participant has a history of any neoplasm except for the following: resolved kaposi's sarcoma, in situ anogenital carcinoma, adequately treated basal or squamous cell carcinoma of the skin, solid tumors (except primary CNS lymphoma) treated with curative therapy and disease free for more than 5 years. History of renal cell carcinoma requires disease-free state for 2 years. History of leukemia and disease-free duration will be per site policy.
- •Substance use that in the opinion of the investigator would interfere with compliance with the study requirements.
- •Participant is pregnant or breastfeeding. Note: Participants who become pregnant post-transplant will continue to be followed in the study and will be managed per local site practice. Women that become pregnant should not breastfeed.
- •Participant has used interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in the prior six months.
- •Participant has received interferon-alpha therapy in the prior 12 weeks.
- •Use of investigational drugs within 4 weeks of enrollment.
- •Past or current medical problems or findings from medical history, physical examination, or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study.
研究组 & 干预措施
Arm 1: Maraviroc (MVC)
Participants will receive MVC at the time of admission for transplantation and prior to transplant. Participants will receive MVC throughout their participation in the study, which will be 1 to 3 years depending on when they enroll.
干预措施: Maraviroc (Drug)
Arm 2: Placebo
Participants will receive placebo at the time of admission for transplantation and prior to transplant. Participants will receive placebo throughout their participation in the study, which will be 1 to 3 years depending on when they enroll.
干预措施: Placebo (Drug)
结局指标
主要结局
Mean Glomerular Filtration Rate by Iohexol Clearance at Week 52
时间窗: Measured at Week 52 Post-transplant
The primary efficacy endpoint is the 52-week GFR as measured by iohexol clearance
Cumulative Incidence of Graft Loss, Toxicities ≥ Grade 3 Per the DAIDS Toxicity Table and/or Permanent Treatment Discontinuation
时间窗: Measured through Week 52 Post-transplant
The primary safety endpoint will be the incidence of graft loss and toxicities ≥ Grade 3 and/or permanent treatment discontinuation within the first 52 weeks post-transplant
次要结局
- Mean CD45 Gene Expression Count (PTPRC)(Measured at Week 26 Post-transplant)
- Mean CD45 Quantitative Immunohistochemistry (IHC)(Measured at Week 26 Post-transplant)
- Mean eGFR at Week 52 Based on CKD-EPI Creatinine Equation(Measured at Week 52 Post-transplant)
- The Slope of eGFR Over Time in Year 1(Time points in Year 1 (four time points: weeks 13, 26, 39, 52))
- HIV DNA in Peripheral Blood CD4+ T Cells at Week 52(At week 52 post-transplant)
- Urine Common Rejection Module (uCRM) Score Using the 11-gene uCRM Module on Urine Cell Pellets(Measured at Week 52 Post-transplant)
- Proportion of Participants With Estimated Glomerular Filtration Rate (eGFR) Less Than 60 mL/Min/1.73 m² at Week 52(Measured at Week 52 Post-transplant)
- Tissue Common Rejection Module (tCRM) Score Using the 11-gene tCRM Module on FFPE Biopsy Shaves(Measured at Week 26 Post-transplant)
- Proportion of Participants With Defined CKD Stage 4 or 5 at Year 1(Year 1 time point)
- HIV RNA in Peripheral Blood CD4+ T Cells at Week 52.(Week 52 Post Transplant)
- Plasma HIV RNA Levels (Single Copy Assay) at Week 52(Week 52 Post-transplant)
- Cumulative Incidence/Proportion of Biopsy Proven Acute Rejection Within 1 Year Post Transplant(Within Year 1 Post-transplant)
- Cumulative Incidence/Proportion of Acute Cellular Rejection Grade Equal to or Greater Than 1A During the Entire Study Follow-up(Within 3 years post-transplant)
- Incidence/Proportion of Antibody Mediated Rejection(Within 52 weeks post transplant)
- Proportion of Participants With de Novo Anti-donor Human Leukocyte Antigen (HLA) Antibodies(Measured at Week 52)
- Incidence/Proportion of Participants With HIV Infection in the Renal Allograft(Month 6 Post-transplant)
- Incidence of Death at Year 1(Within Year 1 Post-transplant)
- Incidence of Graft Loss in Year 1(Within Year 1 Post-transplant)
- Incidence of All Adverse Events (AEs) Greater Than or Equal to Grade 3 at Year 1(Within Year 1 Post-transplant)
- Incidence of Serious Adverse Events (SAEs) Greater Than or Equal to Grade 3 Within Year 1(Within Year 1 Post-transplant)
- Incidence of Opportunistic Infections or Neoplasms Within Year 1(Within Year 1 Post-transplant)
- Incidence of Non-opportunistic Infections Requiring Hospitalization Within Year 1(Within Year 1 Post-transplant)
- Calcineurin Inhibitor (Tacrolimus) Trough Levels for Participants on Maraviroc Versus Placebo(Month 3 Post-transplant (0-12 hours post-dose))
- Calcineurin Inhibitor (Tacrolimus) AUC for Participants on Maraviroc Versus Placebo(Month 3 Post-transplant (0-12 hours post-dose))
- AUC of CCR5 Blockade (Maraviroc)(Month 3 Post-transplant (0-12 hours post-dose))
- Trough Levels of CCR5 Blockade (Maraviroc)(Month 3 Post-transplant (0-12 hours post-dose))