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Impact of Sirolimus and Maraviroc on CCR5 Expression and the HIV-1 Reservoir in HIV-infected Kidney Transplant Recipients

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by Jennifer Husson, University of Maryland
Sponsor:
Information provided by (Responsible Party):
Jennifer Husson, University of Maryland
ClinicalTrials.gov Identifier:
NCT02990312
First received: November 21, 2016
Last updated: May 13, 2017
Last verified: May 2017
  Purpose
The purpose of this proof of concept, pilot study is to determine whether the unique combination of the human immunodeficiency virus (HIV) co-receptor antagonist, Maraviroc, and the mammalian target of rapamycin (mTOR) inhibitor, Sirolimus, in HIV-infected kidney transplant recipients has an impact on chemokine receptor 5 (CCR5) density, the HIV-reservoir, or rejection of the transplanted kidney. 15 HIV-infected kidney transplant recipients will be recruited and their immunosuppressant regimen will be changed to include an mTOR inhibitor (such as Sirolimus) unless they are already on one. In addition, Maraviroc will be added to their HIV regimen, unless they are already on Maraviroc. Blood will be taken to measure markers of the HIV reservoir, their CCR5 density and expression, and immune activation.

Condition Intervention Phase
Hiv Kidney Transplant HIV Reservoir CCR5 Drug: Sirolimus + Maraviroc Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: The Effect of Sirolimus Plus Maraviroc on the Expression of Chemokine Receptor 5 (CCR5) and the HIV-1 Viral Reservoir in HIV-Infected Renal Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Jennifer Husson, University of Maryland:

Primary Outcome Measures:
  • HIV viral reservoir [ Time Frame: 96 weeks ]
    total cellular HIV DNA


Secondary Outcome Measures:
  • Secondary measures of the HIV viral reservoir [ Time Frame: 96 weeks ]
    Chromosomal HIV DNA

  • Circulating HIV [ Time Frame: 96 weeks ]
    Ultrasensitive HIV RNA

  • CCR5 Receptor Density [ Time Frame: 96 weeks ]
    CCR5 receptor density

  • CCR5 Expression [ Time Frame: 96 weeks ]
    Percentage of T cells expressing CCR5

  • Acute cellular rejection [ Time Frame: 96 weeks ]
    Incidence of T cell mediated rejection (ACR)

  • Antibody mediated rejection [ Time Frame: 96 weeks ]
    Incidence of antibody mediated rejection (AMR)

  • Markers of immune activation/inflammation measured by Ki67 [ Time Frame: 96 weeks ]
    Measurement of Ki67

  • Markers of immune activation/inflammation measured by cluster of differentiation 38 (CD38) [ Time Frame: 96 weeks ]
    Measurement of CD38

  • Markers of immune activation/inflammation measured by human leukocyte antigen-antigen D Related (HLA DR) [ Time Frame: 96 weeks ]
    Measurement of HLA DR

  • Markers of immune activation/inflammation measured by programmed death 1 (PD-1) [ Time Frame: 96 weeks ]
    Measurement of PD-1


Estimated Enrollment: 15
Actual Study Start Date: May 1, 2017
Estimated Study Completion Date: July 2020
Estimated Primary Completion Date: January 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sirolimus + Maraviroc
Participants will be placed on the combination of Sirolimus and Maraviroc, unless they are already on one of these medications.
Drug: Sirolimus + Maraviroc
Patients will be placed on the combination of Sirolimus and Maraviroc starting on Day 0 and followed for 96 weeks during which they will have regular monitoring of both clinical safety labs, Sirolimus levels, and research labs to look at the HIV reservoir, CCR5 density, and immune activation
Other Names:
  • Rapamycin
  • Rapamune
  • Selzentry

Detailed Description:

The study will be a pilot, prospective, single-center, open-label, non-randomized, non-controlled clinical trial. 15 HIV-infected kidney transplant recipients will be enrolled in the study. Recruitment will be conducted through the renal transplant and infectious diseases outpatient clinics at the University of Maryland.

The study will include patients with stable glomerular filtration rates (GFRs) >25 with suppressed HIV with CD4 counts >200. These patients will be recruited from the University of Maryland's transplant nephrology and infectious diseases clinics. The transplant nephrology clinic is a multidisciplinary clinic that incorporates nephrologists, pharmacists to aid in medication management, and coordinators to assist the patients in coordination of care.

All patients will be screened either at the Institute of Human Virology (IHV) Clinical Research Unit or in the transplant nephrology or infectious disease clinics. At this visit, all patients will sign an informed consent as approved by our institutional review board (IRB), have a history and physical examination, and have screening clinical and research labs drawn. Additional requirements will be Trofile testing prior to enrollment. Eligibility will be determined based upon these results.

Study drugs will be prescribed (if the patient is not already taking them) starting on day 0 after an interval history and physical examination is performed and safety labs (and pregnancy tests for women of childbearing potential) are checked. The medications will be filled by the patient's pharmacy, using their insurance as these are both Food and Drug Administration (FDA) approved drugs.

Patients will be initially monitored weekly for sirolimus levels and renal function, until their sirolimus is at the pre-determined (by their transplant nephrologist) steady state. They will then be followed at week 4, and then every 12 weeks while they are on the new medication combination. Safety labs (blood counts, renal and liver function), HIV viral loads, cluster of differentiation 4 (CD4) counts, and rapamycin levels will be reviewed at each of these visits and if not checked within the specified time period these labs will be repeated at the study visit. Patients will also be advised about study adherence and monitored for adverse events.

Safety and adverse event monitoring will occur each study visit. Research nurses will inquire about adverse events that may or may not be related to study drugs. Any unfavorable medical occurrences will be recorded, whether or not considered related to the patient's participation in the research or temporally associated with the patient's participation in the research. Any grade 3 or 4 AEs and all serious adverse events (SAEs) will be reviewed as they occur by the study team. Adverse events (AEs) classified as grade 3 or higher occurring at a frequency greater than that expected by the study team will be reported to the IRB and principal investigator.

The end of treatment visit will occur at week 96. Clinical safety labs (blood counts, renal and liver function), HIV viral load, CD4 counts and rapamycin levels will be performed at this visit if not done in the pre-specified time period. Patients will be given the option, in conjunction with their transplant nephrologist and their infectious disease provider, to discontinue or continue the new medications at this time.

  Eligibility

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

Inclusion Criteria:

  1. Patient is able to understand and provide informed consent and comply with the study protocol
  2. Diagnosis of HIV infection based on medical record documentation, ELISA and western blot testing, or a record of a detectable HIV viral load
  3. Participant is > or = 18 years
  4. CD4 T cell count > or = 200 cells per microliter within 16 weeks prior to enrollment
  5. Most recent HIV-1 RNA < 50 copies per milliliter within 16 weeks prior to enrollment
  6. Participant must be > or = 6 months post-renal transplant
  7. GFR >25 for a minimum of 6 months prior to enrollment
  8. On a maintenance immunosuppressive regimen for a minimum of 6 months prior to enrollment
  9. Female participants of child bearing age must have a negative beta-human chorionic gonadotropin (HCG) pregnancy test within 30 days of enrollment and agree to use contraception during the study

Exclusion Criteria:

  1. Proteinuria at screening defined by spot urine protein to creatinine ratio >1000 milligrams per gram
  2. The following active opportunistic infections: Ongoing chronic infections such as progressive multifocal leukoencephalopathy (PML), disseminated cryptococcosis, chronic cryptosporidiosis
  3. Active malignancy other than superficial skin neoplasms, vulvar intraepithelial neoplasia (VIN), cervical intraepithelial neoplasia (CIN), or anal intraepithelial neoplasia (AIN)
  4. Any history of augmented immunosuppression with induction immunosuppression regimens for the treatment of rejection in the 6 months prior to enrollment
  5. Known allergy or intolerance to maraviroc or sirolimus
  6. Pregnancy or breastfeeding
  7. Active substance abuse or mental health concerns that are judged to place a significant limitation on medication adherence by the PI.
  8. Triglyceride elevation at screening > 750; or LDL-c > 160 despite medical treatment
  9. Use of any investigational drugs within 30 days prior to screening
  10. History of serious adverse reactions to macrolide antibiotics, including anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and abdominal pain.
  11. Past or current medical problems not listed above which, at the discretion of the investigator, may pose additional risks from participation in the study, interfere with the participants ability to comply with study requirements or impact the quality or interpretation of data obtained from the study
  12. Known contraindication to the use of maraviroc or sirolimus
  13. Current and ongoing need for concomitant use of rifampin, rifabutin, rifapentine, St. John's wort, phenytoin, phenobarbital, carbamazepine or dofetilide
  14. Any current incompletely healed wounds
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02990312

Contacts
Contact: Jennifer S Husson, MD,MPH 410-706-6973 jhusson@ihv.umaryland.edu
Contact: Ilise Marrazzo, RN,BSN,CCRP 410-706-2564 IMarrazzo@ihv.umaryland.edu

Locations
United States, Maryland
Institute of human virology Recruiting
Baltimore, Maryland, United States, 21201
Contact: Jennifer Husson, MD    410-706-6973    Jhusson@ihv.umaryland.edu   
Contact: Ilise Marrazzo    4107062564    IMarrazzo@ihv.umaryland.edu   
Sponsors and Collaborators
University of Maryland
Investigators
Principal Investigator: Jennifer S Husson, MD,MPH University of Maryland
  More Information

Responsible Party: Jennifer Husson, Assistant Professor, University of Maryland
ClinicalTrials.gov Identifier: NCT02990312     History of Changes
Other Study ID Numbers: HP-00072807
Study First Received: November 21, 2016
Last Updated: May 13, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Sirolimus
Everolimus
Maraviroc
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
CCR5 Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents

ClinicalTrials.gov processed this record on June 22, 2017