Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

• ClinicalTrials.gov Identifier: NCT02741323
• Recruitment Status: Completed
• First Posted: April 18, 2016
• Last Update Posted: July 27, 2022
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HIV Infections; Kidney Diseases	Drug: Maraviroc; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients
• Actual Study Start Date: January 1, 2017
• Actual Primary Completion Date: May 10, 2022
• Actual Study Completion Date: May 10, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Maraviroc; 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.; Other Name: MVC
Placebo Comparator: 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.	Drug: Placebo; 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.

Outcome Measures

Primary Outcome Measures :

1. Measured glomerular filtration rate by iohexol clearance [ Time Frame: Measured at Week 52 ]
2. Number of participants with graft loss, Grade 3 or greater toxicities, and/or permanent treatment discontinuations [ Time Frame: Measured through Week 52 ]

Secondary Outcome Measures :

1. Mean CD45 gene expression count (PTPRC) [ Time Frame: Measured through Week 26 ]
   Based on the formalin-fixed paraffin-embedded (FFPE) kidney biopsy sample
2. Mean CD45 quantitative immunohistochemistry (IHC) [ Time Frame: Measured through Week 26 ]
   Based on FFPE sample
3. Mean tCRM score [ Time Frame: Measured through Week 26 ]
   Using the 11-gene tCRM module on FFPE biopsy shaves
4. Mean uCRM score [ Time Frame: Measured through Week 26 ]
   Using the 11-gene uCRM module on urine cell pellets
5. Mean uCRM score [ Time Frame: Measured through Week 52 ]
   Using the 11-gene uCRM module on urine cell pellets
6. Proportion of participants with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m^2 [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
   Measured by chronic kidney disease epidemiology collaboration equation (CKD-EPI), cystatin C, and chronic kidney disease (CKD)-cystatin C
7. Proportion of participants with defined CKD stage 4 or 5 [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
8. Mean eGFR [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
   Calculated by CKD-EPI, cystatin C, and CKD-cystatin C
9. Measurement of the slope of eGFR [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
   Calculated by CKD-EPI, cystatin C, and CKD-cystatin C variable models over time based on serum creatinine
10. HIV DNA in peripheral blood CD4+ T cells [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
11. HIV RNA in peripheral blood CD4+ T cells [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
12. Plasma HIV RNA levels (single copy assay) [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
13. Incidence of clinically suspected and biopsy proven acute rejection [ Time Frame: Measured through Week 156 ]
    Defined by histologic evidence of rejection and graft dysfunction as identified on central read of biopsy slides
14. Incidence of acute cellular rejection grade equal to or greater than IA [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
    Measured by the Banff 2007 criteria as identified on central read of biopsy slides
15. The severity of first and highest grade of acute cellular rejection [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
16. Incidence of antibody mediated rejection [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
17. Prevalence of de novo anti-donor human leukocyte antigen (HLA) antibodies [ Time Frame: Measured at Week 52 ]
18. Histology/in situ hybridization to assess HIV infection in the renal allograft [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
19. Incidence of death [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
20. Incidence of graft loss [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
21. Incidence of all adverse events (AEs) greater than or equal to Grade 3 [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
22. Incidence of serious adverse events (SAEs) greater than or equal to Grade 3 [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
23. Incidence of opportunistic infections or neoplasms [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
24. Incidence of non-opportunistic infections requiring hospitalization or systemic therapy [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
25. Calcineurin inhibitor trough levels for participants on maraviroc versus placebo [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
26. Calcineurin inhibitor AUC for participants on maraviroc versus placebo [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
27. AUC of CCR5 blockade (maraviroc) [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
28. Trough levels of CCR5 blockade (maraviroc) [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 coccidiodomycosis 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.

Contacts and Locations

Locations

United States, Alabama

UAB HIVTR-CCR5 Non-Network CRS

Birmingham, Alabama, United States, 35233-2060

United States, California

UCLA HIVTR-CCR5 Non-Network CRS

Los Angeles, California, United States, 90024

UCSF HIVTR-CCR5 Non-network CRS

San Francisco, California, United States, 94118

United States, District of Columbia

Georgetown HIVTR-CCR5 Non-Network CRS

Washington, District of Columbia, United States, 20007

United States, Georgia

Emory HIVTR-CCR5 Non-Network CRS

Atlanta, Georgia, United States, 30322

United States, Illinois

Northwestern HIVTR-CCR5 Non-Network CRS

Chicago, Illinois, United States, 60611-2927

United States, Maryland

Univ. of Maryland HIVTR-CCR5 Non-Network CRS

Baltimore, Maryland, United States, 21201

JHU HIVTR-CCR5 Non-Network CRS

Baltimore, Maryland, United States, 21287

United States, New York

Mt. Sinai Med. Ctr. HIVTR-CCR5 Non-Network CRS

New York, New York, United States, 10029

United States, Pennsylvania

Univ. of Penn HIVTR-CCR5 Non-network CRS

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Peter Stock, MD, PhD; University of California, San Francisco

More Information

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02741323
• Other Study ID Numbers: HIVTR-CCR5; 20730 ( Registry Identifier: DAIDS-ES Registry Number )
• First Posted: April 18, 2016
• Last Update Posted: July 27, 2022
• Last Verified: July 2022

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

HIV-infected with end-stage kidney disease

Additional relevant MeSH terms:

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Maraviroc; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; CCR5 Receptor Antagonists