<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02990312</url>
  </required_header>
  <id_info>
    <org_study_id>HP-00072807</org_study_id>
    <nct_id>NCT02990312</nct_id>
  </id_info>
  <brief_title>Impact of Sirolimus and Maraviroc on CCR5 Expression and the HIV-1 Reservoir in HIV-infected Kidney Transplant Recipients</brief_title>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Maryland, Baltimore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Maryland, Baltimore</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this proof of concept, pilot study is to determine whether the unique&#xD;
      combination of the human immunodeficiency virus (HIV) co-receptor antagonist, Maraviroc, and&#xD;
      the mammalian target of rapamycin (mTOR) inhibitor, Sirolimus, in HIV-infected kidney&#xD;
      transplant recipients has an impact on chemokine receptor 5 (CCR5) density, the&#xD;
      HIV-reservoir, or rejection of the transplanted kidney. 15 HIV-infected kidney transplant&#xD;
      recipients will be recruited and their immunosuppressant regimen will be changed to include&#xD;
      an mTOR inhibitor (such as Sirolimus) unless they are already on one. In addition, Maraviroc&#xD;
      will be added to their HIV regimen, unless they are already on Maraviroc. Blood will be taken&#xD;
      to measure markers of the HIV reservoir, their CCR5 density and expression, and immune&#xD;
      activation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be a pilot, prospective, single-center, open-label, non-randomized,&#xD;
      non-controlled clinical trial. 15 HIV-infected kidney transplant recipients will be enrolled&#xD;
      in the study. Recruitment will be conducted through the renal transplant and infectious&#xD;
      diseases outpatient clinics at the University of Maryland.&#xD;
&#xD;
      The study will include patients with stable glomerular filtration rates (GFRs) &gt;25 with&#xD;
      suppressed HIV with CD4 counts &gt;200. These patients will be recruited from the University of&#xD;
      Maryland's transplant nephrology and infectious diseases clinics. The transplant nephrology&#xD;
      clinic is a multidisciplinary clinic that incorporates nephrologists, pharmacists to aid in&#xD;
      medication management, and coordinators to assist the patients in coordination of care.&#xD;
&#xD;
      All patients will be screened either at the Institute of Human Virology (IHV) Clinical&#xD;
      Research Unit or in the transplant nephrology or infectious disease clinics. At this visit,&#xD;
      all patients will sign an informed consent as approved by our institutional review board&#xD;
      (IRB), have a history and physical examination, and have screening clinical and research labs&#xD;
      drawn. Additional requirements will be Trofile testing prior to enrollment. Eligibility will&#xD;
      be determined based upon these results.&#xD;
&#xD;
      Study drugs will be prescribed (if the patient is not already taking them) starting on day 0&#xD;
      after an interval history and physical examination is performed and safety labs (and&#xD;
      pregnancy tests for women of childbearing potential) are checked. The medications will be&#xD;
      filled by the patient's pharmacy, using their insurance as these are both Food and Drug&#xD;
      Administration (FDA) approved drugs.&#xD;
&#xD;
      Patients will be initially monitored weekly for sirolimus levels and renal function, until&#xD;
      their sirolimus is at the pre-determined (by their transplant nephrologist) steady state.&#xD;
      They will then be followed at week 4, and then every 12 weeks while they are on the new&#xD;
      medication combination. Safety labs (blood counts, renal and liver function), HIV viral&#xD;
      loads, cluster of differentiation 4 (CD4) counts, and rapamycin levels will be reviewed at&#xD;
      each of these visits and if not checked within the specified time period these labs will be&#xD;
      repeated at the study visit. Patients will also be advised about study adherence and&#xD;
      monitored for adverse events.&#xD;
&#xD;
      Safety and adverse event monitoring will occur each study visit. Research nurses will inquire&#xD;
      about adverse events that may or may not be related to study drugs. Any unfavorable medical&#xD;
      occurrences will be recorded, whether or not considered related to the patient's&#xD;
      participation in the research or temporally associated with the patient's participation in&#xD;
      the research. Any grade 3 or 4 AEs and all serious adverse events (SAEs) will be reviewed as&#xD;
      they occur by the study team. Adverse events (AEs) classified as grade 3 or higher occurring&#xD;
      at a frequency greater than that expected by the study team will be reported to the IRB and&#xD;
      principal investigator.&#xD;
&#xD;
      The end of treatment visit will occur at week 96. Clinical safety labs (blood counts, renal&#xD;
      and liver function), HIV viral load, CD4 counts and rapamycin levels will be performed at&#xD;
      this visit if not done in the pre-specified time period. Patients will be given the option,&#xD;
      in conjunction with their transplant nephrologist and their infectious disease provider, to&#xD;
      discontinue or continue the new medications at this time.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Lack of enrollment&#xD;
  </why_stopped>
  <start_date type="Actual">May 1, 2017</start_date>
  <completion_date type="Actual">July 17, 2019</completion_date>
  <primary_completion_date type="Actual">July 17, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>HIV viral reservoir</measure>
    <time_frame>96 weeks</time_frame>
    <description>total cellular HIV DNA</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary measures of the HIV viral reservoir</measure>
    <time_frame>96 weeks</time_frame>
    <description>Chromosomal HIV DNA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating HIV</measure>
    <time_frame>96 weeks</time_frame>
    <description>Ultrasensitive HIV RNA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CCR5 Receptor Density</measure>
    <time_frame>96 weeks</time_frame>
    <description>CCR5 receptor density</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CCR5 Expression</measure>
    <time_frame>96 weeks</time_frame>
    <description>Percentage of T cells expressing CCR5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute cellular rejection</measure>
    <time_frame>96 weeks</time_frame>
    <description>Incidence of T cell mediated rejection (ACR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antibody mediated rejection</measure>
    <time_frame>96 weeks</time_frame>
    <description>Incidence of antibody mediated rejection (AMR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of immune activation/inflammation measured by Ki67</measure>
    <time_frame>96 weeks</time_frame>
    <description>Measurement of Ki67</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of immune activation/inflammation measured by cluster of differentiation 38 (CD38)</measure>
    <time_frame>96 weeks</time_frame>
    <description>Measurement of CD38</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of immune activation/inflammation measured by human leukocyte antigen-antigen D Related (HLA DR)</measure>
    <time_frame>96 weeks</time_frame>
    <description>Measurement of HLA DR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of immune activation/inflammation measured by programmed death 1 (PD-1)</measure>
    <time_frame>96 weeks</time_frame>
    <description>Measurement of PD-1</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Hiv</condition>
  <condition>Kidney Transplant</condition>
  <condition>HIV Reservoir</condition>
  <condition>CCR5</condition>
  <arm_group>
    <arm_group_label>Sirolimus + Maraviroc</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be placed on the combination of Sirolimus and Maraviroc, unless they are already on one of these medications.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sirolimus + Maraviroc</intervention_name>
    <description>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</description>
    <arm_group_label>Sirolimus + Maraviroc</arm_group_label>
    <other_name>Rapamycin</other_name>
    <other_name>Rapamune</other_name>
    <other_name>Selzentry</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient is able to understand and provide informed consent and comply with the study&#xD;
             protocol&#xD;
&#xD;
          2. Diagnosis of HIV infection based on medical record documentation, ELISA and western&#xD;
             blot testing, or a record of a detectable HIV viral load&#xD;
&#xD;
          3. Participant is &gt; or = 18 years&#xD;
&#xD;
          4. CD4 T cell count &gt; or = 200 cells per microliter within 16 weeks prior to enrollment&#xD;
&#xD;
          5. Most recent HIV-1 RNA &lt; 50 copies per milliliter within 16 weeks prior to enrollment&#xD;
&#xD;
          6. Participant must be &gt; or = 6 months post-renal transplant&#xD;
&#xD;
          7. GFR &gt;25 for a minimum of 6 months prior to enrollment&#xD;
&#xD;
          8. On a maintenance immunosuppressive regimen for a minimum of 6 months prior to&#xD;
             enrollment&#xD;
&#xD;
          9. Female participants of child bearing age must have a negative beta-human chorionic&#xD;
             gonadotropin (HCG) pregnancy test within 30 days of enrollment and agree to use&#xD;
             contraception during the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Proteinuria at screening defined by spot urine protein to creatinine ratio &gt;1000&#xD;
             milligrams per gram&#xD;
&#xD;
          2. The following active opportunistic infections: Ongoing chronic infections such as&#xD;
             progressive multifocal leukoencephalopathy (PML), disseminated cryptococcosis, chronic&#xD;
             cryptosporidiosis&#xD;
&#xD;
          3. Active malignancy other than superficial skin neoplasms, vulvar intraepithelial&#xD;
             neoplasia (VIN), cervical intraepithelial neoplasia (CIN), or anal intraepithelial&#xD;
             neoplasia (AIN)&#xD;
&#xD;
          4. Any history of augmented immunosuppression with induction immunosuppression regimens&#xD;
             for the treatment of rejection in the 6 months prior to enrollment&#xD;
&#xD;
          5. Known allergy or intolerance to maraviroc or sirolimus&#xD;
&#xD;
          6. Pregnancy or breastfeeding&#xD;
&#xD;
          7. Active substance abuse or mental health concerns that are judged to place a&#xD;
             significant limitation on medication adherence by the PI.&#xD;
&#xD;
          8. Triglyceride elevation at screening &gt; 750; or LDL-c &gt; 160 despite medical treatment&#xD;
&#xD;
          9. Use of any investigational drugs within 30 days prior to screening&#xD;
&#xD;
         10. History of serious adverse reactions to macrolide antibiotics, including anaphylaxis&#xD;
             and related symptoms such as hives, respiratory difficulty, angioedema, and abdominal&#xD;
             pain.&#xD;
&#xD;
         11. Past or current medical problems not listed above which, at the discretion of the&#xD;
             investigator, may pose additional risks from participation in the study, interfere&#xD;
             with the participants ability to comply with study requirements or impact the quality&#xD;
             or interpretation of data obtained from the study&#xD;
&#xD;
         12. Known contraindication to the use of maraviroc or sirolimus&#xD;
&#xD;
         13. Current and ongoing need for concomitant use of rifampin, rifabutin, rifapentine, St.&#xD;
             John's wort, phenytoin, phenobarbital, carbamazepine or dofetilide&#xD;
&#xD;
         14. Any current incompletely healed wounds&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jennifer S Husson, MD,MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Maryland, College Park</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institute of human virology</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>November 21, 2016</study_first_submitted>
  <study_first_submitted_qc>December 8, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 13, 2016</study_first_posted>
  <last_update_submitted>December 12, 2019</last_update_submitted>
  <last_update_submitted_qc>December 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Maryland, Baltimore</investigator_affiliation>
    <investigator_full_name>Jennifer Husson</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Maraviroc</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02990312
org study id: HP-00072807
nct id: NCT02990312
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: HIV viral reservoir
time frame: 96 weeks
description: total cellular HIV DNA
measure: Secondary measures of the HIV viral reservoir
time frame: 96 weeks
description: Chromosomal HIV DNA
measure: Circulating HIV
time frame: 96 weeks
description: Ultrasensitive HIV RNA
measure: CCR5 Receptor Density
time frame: 96 weeks
description: CCR5 receptor density
measure: CCR5 Expression
time frame: 96 weeks
description: Percentage of T cells expressing CCR5
measure: Acute cellular rejection
time frame: 96 weeks
description: Incidence of T cell mediated rejection (ACR)
measure: Antibody mediated rejection
time frame: 96 weeks
description: Incidence of antibody mediated rejection (AMR)
measure: Markers of immune activation/inflammation measured by Ki67
time frame: 96 weeks
description: Measurement of Ki67
measure: Markers of immune activation/inflammation measured by cluster of differentiation 38 (CD38)
time frame: 96 weeks
description: Measurement of CD38
measure: Markers of immune activation/inflammation measured by human leukocyte antigen-antigen D Related (HLA DR)
time frame: 96 weeks
description: Measurement of HLA DR
measure: Markers of immune activation/inflammation measured by programmed death 1 (PD-1)
time frame: 96 weeks
description: Measurement of PD-1
arm group label: Sirolimus + Maraviroc
arm group type: Experimental
description: Participants will be placed on the combination of Sirolimus and Maraviroc, unless they are already on one of these medications.
intervention type: Drug
intervention name: Sirolimus + Maraviroc
description: 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
arm group label: Sirolimus + Maraviroc
other name: Rapamycin
other name: Rapamune
other name: Selzentry
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jennifer S Husson, MD,MPH
role: Principal Investigator
affiliation: University of Maryland, College Park
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Maryland, Baltimore
investigator full name: Jennifer Husson
investigator title: Assistant Professor
mesh term: Sirolimus
mesh term: Maraviroc
sharing ipd: No