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Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02741323
Recruitment Status : Recruiting
First Posted : April 18, 2016
Last Update Posted : June 6, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE April 13, 2016
First Posted Date  ICMJE April 18, 2016
Last Update Posted Date June 6, 2019
Actual Study Start Date  ICMJE January 1, 2017
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 13, 2016)
  • Measured glomerular filtration rate by iohexol clearance [ Time Frame: Measured at Week 52 ]
  • Number of participants with graft loss, Grade 3 or greater toxicities, and/or permanent treatment discontinuations [ Time Frame: Measured through Week 52 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02741323 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
  • Mean CD45 gene expression count (PTPRC) [ Time Frame: Measured through Week 26 ]
    Based on the formalin-fixed paraffin-embedded (FFPE) kidney biopsy sample
  • Mean CD45 quantitative immunohistochemistry (IHC) [ Time Frame: Measured through Week 26 ]
    Based on FFPE sample
  • Mean tCRM score [ Time Frame: Measured through Week 26 ]
    Using the 11-gene tCRM module on FFPE biopsy shaves
  • Mean uCRM score [ Time Frame: Measured through Week 26 ]
    Using the 11-gene uCRM module on urine cell pellets
  • Mean uCRM score [ Time Frame: Measured through Week 52 ]
    Using the 11-gene uCRM module on urine cell pellets
  • 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
  • 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 ]
  • 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
  • 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
  • HIV reactivation (frequency of CD4+ T cells producing HIV multiply spliced RNAs upon T-cell receptor stimulation [TCR] stimulation) [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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
  • 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
  • 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 ]
  • 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 ]
  • Prevalence of de novo anti-donor human leukocyte antigen (HLA) antibodies [ Time Frame: Measured at Week 52 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 13, 2016)
  • 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
  • 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 ]
  • 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
  • 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
  • HIV reactivation (frequency of CD4+ T cells producing HIV multiply spliced RNAs upon T-cell receptor stimulation [TCR] stimulation) [ Time Frame: Measured through participants' last study visit, which will be during Years 1 to 3, depending on when they enroll in the study ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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
  • 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
  • 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 ]
  • 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 ]
  • Prevalence of de novo anti-donor human leukocyte antigen (HLA) antibodies [ Time Frame: Measured at Week 52 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients
Official Title  ICMJE Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • HIV Infections
  • Kidney Diseases
Intervention  ICMJE
  • 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
  • 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.

Study Arms  ICMJE
  • 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.
    Intervention: Drug: Maraviroc
  • 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.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 13, 2016)
130
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2022
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02741323
Other Study ID Numbers  ICMJE HIVTR-CCR5
20730 ( Registry Identifier: DAIDS-ES Registry Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Peter Stock, MD, PhD University of California, San Francisco
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP