Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

NCT02741323 | Completed Phase 2 Results DMC

• 2 other identifiers: HIVTR-CCR520730
• Study Type: interventional
• Target: 97
• Locations: 1 country
• Sites: 10

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.

Conditions

HIV Infections; Kidney Diseases

Keywords

HIV-infected with end-stage kidney disease

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (27)

• Mean CD45 Gene Expression Count (PTPRC)

  Measured at Week 26 Post-transplant

• Mean CD45 Quantitative Immunohistochemistry (IHC)

  Measured at Week 26 Post-transplant

• Tissue Common Rejection Module (tCRM) Score Using the 11-gene tCRM Module on FFPE Biopsy Shaves

  Measured at Week 26 Post-transplant

• Urine Common Rejection Module (uCRM) Score Using the 11-gene uCRM Module on Urine Cell Pellets

  Measured at Week 26 Post-transplant

• Urine Common Rejection Module (uCRM) Score Using the 11-gene uCRM Module on Urine Cell Pellets

  Measured at Week 52 Post-transplant

Study Arms (2)

Arm 1: Maraviroc (MVC)

EXPERIMENTAL

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

Arm 2: Placebo

PLACEBO COMPARATOR

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

Interventions

Maraviroc DRUG

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.

Also known as: MVC

Arm 1: Maraviroc (MVC)

Placebo DRUG

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.

Arm 2: Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (10)

UAB HIVTR-CCR5 Non-Network CRS

Birmingham, Alabama, 35233-2060, United States

Location

UCLA HIVTR-CCR5 Non-Network CRS

Los Angeles, California, 90024, United States

Location

UCSF HIVTR-CCR5 Non-network CRS

San Francisco, California, 94118, United States

Location

Georgetown HIVTR-CCR5 Non-Network CRS

Washington D.C., District of Columbia, 20007, United States

Location

Emory HIVTR-CCR5 Non-Network CRS

Atlanta, Georgia, 30322, United States

Location

Northwestern HIVTR-CCR5 Non-Network CRS

Chicago, Illinois, 60611-2927, United States

Location

Univ. of Maryland HIVTR-CCR5 Non-Network CRS

Baltimore, Maryland, 21201, United States

Location

JHU HIVTR-CCR5 Non-Network CRS

Baltimore, Maryland, 21287, United States

Location

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

New York, New York, 10029, United States

Location

Univ. of Penn HIVTR-CCR5 Non-network CRS

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

HIV Infections; Kidney Diseases

Interventions

Maraviroc

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

For the primary outcome "measured GFR by iohexol clearance at week 52", only 30 subjects (vs. 130 planned) could complete the on-site iohexol study due to COVID-19 restrictions and contribute data. There were also consistency/reliability issues with the generated data due to varying laboratory controls. Secondary outcome of "Mean eGFR at Week 52 Based on CKD-EPI Creatinine Equation" is a good surrogate for the primary outcome, with better reliability and bigger sample size for group comparison.

Results Point of Contact

• Title: Clinical Research Manager
• Organization: University of California, San Francisco

Rodney.Rogers@ucsf.edu

415-595-1226

Study Officials

• Peter Stock, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 13, 2016
• First Posted: April 18, 2016
• Study Start: January 1, 2017
• Primary Completion: May 10, 2022
• Study Completion: May 10, 2022
• Last Updated: August 21, 2023
• Results First Posted: August 21, 2023

Record last verified: 2023-08

Locations

US (10)