Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

Conditions
-----------------
HIV Infections, Kidney Diseases

Intervention / Treatment
-----------------
* Drug: Maraviroc
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Maraviroc (MVC)<br>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. | Drug: Maraviroc<br>* Initial dose of 300 mg twice daily (150mg twice daily if co-prescribed with a potent CYP3A inhibitor or 600mg twice daily if co-prescribed with a potent CYP3A inducer). Will be modified if GFR < 30, if co-prescribed with a potent CYP3A inhibitor or inducer, or if the calcineurin inhibitor used for maintenance immunosuppression is changed to cyclosporine (which is only allowed for tacrolimus toxicity). Once GFR is greater than or equal to 30, the dose should be returned to the non-renal dosage. If GFR is consistently fluctuating (especially immediately post-transplant), the site investigator may choose when to resume normal dosing of study product based on clinical assessment of stability.<br>* Other names: MVC;|
| Placebo Comparator: Arm 2: Placebo<br>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. | Drug: Placebo<br>* Initial dose of 300 mg twice daily (150mg twice daily if co-prescribed with a potent CYP3A inhibitor or 600mg twice daily if co-prescribed with a potent CYP3A inducer). Will be modified if GFR < 30, if co-prescribed with a potent CYP3A inhibitor or inducer, or if the calcineurin inhibitor used for maintenance immunosuppression is changed to cyclosporine (which is only allowed for tacrolimus toxicity). Once GFR is greater than or equal to 30, the dose should be returned to the non-renal dosage. If GFR is consistently fluctuating (especially immediately post-transplant), the site investigator may choose when to resume normal dosing of study product based on clinical assessment of stability.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Glomerular Filtration Rate by Iohexol Clearance at Week 52 | The primary efficacy endpoint is the 52-week GFR as measured by iohexol clearance | Measured at Week 52 Post-transplant | 
| Cumulative Incidence of Graft Loss, Toxicities ≥ Grade 3 Per the DAIDS Toxicity Table and/or Permanent Treatment Discontinuation | 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 | Measured through Week 52 Post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean CD45 Gene Expression Count (PTPRC) | Based on the formalin-fixed paraffin-embedded (FFPE) kidney biopsy sample. CD45 RNA In Situ Hybridization was performed, and the CD45 gene expression count is calculated by counting the spots (the RNA signal) in QuPath and then dividing the number of spots by biopsy tissue area in mm². | Measured at Week 26 Post-transplant | 
| Mean CD45 Quantitative Immunohistochemistry (IHC) | Mean CD45 quantitative immunohistochemistry (IHC) based on FFPE sample | Measured at Week 26 Post-transplant | 
| Tissue Common Rejection Module (tCRM) Score Using the 11-gene tCRM Module on FFPE Biopsy Shaves | Tissue Common Rejection Module (tCRM) score using the 11-gene tCRM module on FFPE biopsy shaves at 26 weeks. The score measures the average (geometric mean) gene expression level of CRM genes (BASP1, CD6, CXCL10, CXCL9, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, TAP1) in kidney tissue. Possible range (min-max) for the tCRM score is 0.01 - 15.0, with higher values representing worse outcomes. | Measured at Week 26 Post-transplant | 
| Urine Common Rejection Module (uCRM) Score Using the 11-gene uCRM Module on Urine Cell Pellets | Urine Common Rejection Module (uCRM) score using the 11-gene uCRM module on urine cell pellets at week 26. The score measures the average (geometric mean) gene expression level of CRM genes (BASP1, CD6, CXCL10, CXCL9, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, TAP1) in urine sediment. Possible range (min-max) for the uCRM score is 0.01 - 15.0, with higher values representing worse outcomes. | Measured at Week 26 Post-transplant | 
| Urine Common Rejection Module (uCRM) Score Using the 11-gene uCRM Module on Urine Cell Pellets | Urine Common Rejection Module (uCRM) score using the 11-gene uCRM module on urine cell pellets at week 52. The score measures the average (geometric mean) gene expression level of CRM genes (BASP1, CD6, CXCL10, CXCL9, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, TAP1) in urine sediment. Possible range (min-max) for the uCRM score is 0.01 - 15.0, with higher values representing worse outcomes. | 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 by Chronic Kidney Disease Epidemiology collaboration equation (CKD-EPI) Creatinine equation | Measured at Week 52 Post-transplant | 
| Proportion of Participants With Defined CKD Stage 4 or 5 at Year 1 | Proportion of participants with defined CKD stage 4 or 5 at week 52 post-transplant. CKD Stage 4 or 5 is defined as a glomerular filtration rate (GFR) of <30 mL/min. | Year 1 time point | 
| Mean eGFR at Week 52 Based on CKD-EPI Creatinine Equation | Mean eGFR at Week 52 calculated by CKD-EPI creatinine equation | Measured at Week 52 Post-transplant | 
| The Slope of eGFR Over Time in Year 1 | The slope of eGFR over time in Year 1, calculated by CKD-EPI Creatinine equation. Slope is computed via the repeated measures analysis, covering the study time points of weeks 13, 26, 39 and 52. The estimated average slope (and corresponding 95% confidence interval) is provided for incremental progression from one time point to the next (i.e., the displayed slope shows the extent of increase (positive) or decrease (negative) in eGFR level per every time point (13 weeks) elapsed. | Time points in Year 1 (four time points: weeks 13, 26, 39, 52) | 
| HIV DNA in Peripheral Blood CD4+ T Cells at Week 52 | HIV DNA in peripheral blood CD4+ T cells at Week 52. The standard ACTG type extraction protocol was used to extract DNA from PBMC. The readout was copies of cellular HIV-1 DNA per million PBMC. Subsequently, the outcome measure/value was obtained by multiplying the readout by the participant's CD4 percentage level at that time point, to obtain the measure of copies of HIV-1 DNA per million peripheral blood CD4+ T cells | At week 52 post-transplant | 
| HIV RNA in Peripheral Blood CD4+ T Cells at Week 52. | HIV RNA in peripheral blood CD4+ T cells at Week 52. The standard ACTG type extraction protocol was used to extract RNA from PBMC. The readout was copies of cellular HIV-1 RNA per million PBMC. Subsequently, the outcome measure/value was obtained by multiplying the readout by the participant's CD4 percentage level at that time point, to obtain the measure of copies of HIV-1 RNA per million peripheral blood CD4+ T cells | Week 52 Post Transplant | 
| Plasma HIV RNA Levels (Single Copy Assay) at Week 52 | Plasma HIV RNA levels (single copy assay) at Week 52 Post-transplant | Week 52 Post-transplant | 
| Cumulative Incidence/Proportion of Biopsy Proven Acute Rejection Within 1 Year Post Transplant | Defined by histologic evidence of rejection and graft dysfunction as identified on central read of biopsy slides as well as on site biopsies. When a central read of biopsy slide is available, those results will be used; in its absence, site biopsy result will be used. Both acute cellular and humoral rejections were considered for this outcome measure, but borderline results were excluded. | 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 | Measured by the Banff 2007 criteria as identified on central read of biopsy slides; for site biopsy results, grading was not available, all results except for borderline results were assumed to be grade 1A or greater. If available, central read result was used; if not, site biopsy result was used. | Within 3 years post-transplant | 
| Incidence/Proportion of Antibody Mediated Rejection | Incidence of humoral/antibody mediated rejection within 52 weeks of the transplant. Both central reads and site biopsy results were included, and central read result was used if one was available, and if not, the site biopsy result was used. | Within 52 weeks post transplant | 
| Proportion of Participants With de Novo Anti-donor Human Leukocyte Antigen (HLA) Antibodies | Proportion of participants with de novo anti-donor human leukocyte antigen (HLA) antibodies at Week 52 | Measured at Week 52 | 
| Incidence/Proportion of Participants With HIV Infection in the Renal Allograft | Histology/in situ hybridization was used to assess HIV infection in the renal allograft and calculate the proportion of participants with HIV infection | Month 6 Post-transplant | 
| Incidence of Death at Year 1 | Incidence of death within Year 1 post-transplant | Within Year 1 Post-transplant | 
| Incidence of Graft Loss in Year 1 | Incidence of graft loss within Year 1 post-transplant. | Within Year 1 Post-transplant | 
| Incidence of All Adverse Events (AEs) Greater Than or Equal to Grade 3 at Year 1 | Incidence of all adverse events (AEs) greater than or equal to Grade 3 within 1 year post-transplant | Within Year 1 Post-transplant | 
| Incidence of Serious Adverse Events (SAEs) Greater Than or Equal to Grade 3 Within Year 1 | Incidence of serious adverse events (SAEs) greater than or equal to Grade 3 within 1 year post-transplant | Within Year 1 Post-transplant | 
| Incidence of Opportunistic Infections or Neoplasms Within Year 1 | Incidence of opportunistic infections or neoplasms within 1 year post-transplant | Within Year 1 Post-transplant | 
| Incidence of Non-opportunistic Infections Requiring Hospitalization Within Year 1 | Incidence of non-opportunistic infections requiring hospitalization within 1 year post-transplant | Within Year 1 Post-transplant | 
| Calcineurin Inhibitor (Tacrolimus) Trough Levels for Participants on Maraviroc Versus Placebo | Calcineurin inhibitor (tacrolimus) trough levels, from 0-12 hours post-dose at month 3 post-transplant for a subset of participants enrolled at UCSF | Month 3 Post-transplant (0-12 hours post-dose) | 
| Calcineurin Inhibitor (Tacrolimus) AUC for Participants on Maraviroc Versus Placebo | Calcineurin inhibitor (tacrolimus) AUC, 0-12 hours post-dose at month 3 post-transplant for a subset of participants enrolled at UCSF | Month 3 Post-transplant (0-12 hours post-dose) | 
| AUC of CCR5 Blockade (Maraviroc) | AUC of CCR5 blockade (maraviroc), 0-12 hours post-dose at month 3 post-transplant in a subset of participants enrolled at UCSF | Month 3 Post-transplant (0-12 hours post-dose) | 
| Trough Levels of CCR5 Blockade (Maraviroc) | Trough levels of CCR5 blockade (maraviroc) from 0-12 hours post-dose testing at month 3 post-transplant in a subset of participants enrolled at UCSF | Month 3 Post-transplant (0-12 hours post-dose) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV-infected with end-stage kidney disease