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Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive ART

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by AIDS Clinical Trials Group
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT02440789
First received: April 6, 2015
Last updated: August 23, 2016
Last verified: August 2016
  Purpose
The purpose of this study is to find out about the safety of sirolimus in individuals with HIV infection who are also being treated with ART. The investigators want to learn whether sirolimus will decrease inflammation and immune activation in the body; whether sirolimus will change the level of HIV in the participants' blood; and how sirolimus interacts with ART in the blood. Sirolimus is approved by the Food and Drug Administration (FDA) to prevent organ rejection in patients aged 13 years and older receiving kidney transplants. Sirolimus has also been used for the prevention of complications after stem cell transplants and as a treatment for certain kinds of cancers in HIV-infected patients.

Condition Intervention Phase
HIV-1 Infection
Drug: Sirolimus
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy

Resource links provided by NLM:


Further study details as provided by AIDS Clinical Trials Group:

Primary Outcome Measures:
  • Number of participants who met the study-defined composite safety endpoint [ Time Frame: 44 weeks ]
    The study-defined primary safety endpoint is a composite endpoint. A participant is considered to have met the endpoint if the participant 1) experienced a new Grade ≥3 AE, including signs/symptoms, lab toxicity or clinical event, that is definitely, probably or possibly related to study treatment, as judged by the core team, or 2) had a change in CD4+ cell count ( confirmed >50% decline or to <300 cells/mm3) while on sirolimus

  • Efficacy - Immunologic [ Time Frame: 32 weeks ]
    Frequency of HIV-1 Gag-specific CD8+ T-cells by intracellular staining for IFN-gamma at baseline and at week 32 (20 weeks on sirolimus)

  • Efficacy - Virologic [ Time Frame: 32 weeks ]
    CD4+ T-cell-associated HIV-1 RNA and plasma HIV-1 RNA by SCA at baseline and at week 32 (20 weeks on sirolumus)


Secondary Outcome Measures:
  • Measurement of CD4+ T-cell counts [ Time Frame: Measured through Week 44 ]
    CD4+ T-cell counts at baseline and at weeks 14, 16, 20, 24, 32 (2, 4, 8, 12, 20 weeks on sirolimus) and 44

  • Measurement of HIV-1 RNA levels [ Time Frame: Measured through Week 44 ]
    HIV-1 RNA levels by conventional assay at baseline and at weeks 16, 20, 24, 32 (4, 8, 12, 20 weeks on sirolimus) and 44

  • Measurement of CD4+/CD8+ T-cell responses [ Time Frame: Measured through Week 44 ]
    HIV-1-specific CD4+ T-cell responses and HIV-1-specific CD8+ T-cell responses (other than gag) at baseline and at weeks 13, 16, 24, 32 (1, 4, 12, 20 weeks on sirolimus) and 44

  • T-cell activation and proliferation [ Time Frame: Measured through Week 44 ]
    T-cell activation and proliferation (% CD4+ and CD8+ T cells CD38+/HLA-DR+, CD25+, PD-1+, Ki67+ and PD-L1 expression) at baseline and at weeks 13, 16, 24, 32 (1, 4, 12, 20 weeks on sirolimus) and 44

  • Cell-associated HIV-1 DNA levels in total CD4+ cells [ Time Frame: Measured through Week 44 ]
    HIV-1 DNA levels in CD4+ T-cells at baseline and at weeks 13, 16, 24, 32 (1, 4, 12, 20 weeks on sirolimus) and 44


Estimated Enrollment: 30
Study Start Date: August 2015
Estimated Study Completion Date: August 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sirolimus 0.025 mg/kg/day initial dose for 20 weeks
For subjects on a non-protease inhibitor (PI), non-non-nucleoside reverse transcriptase inhibitor (NNRTI) regimen, and for those on a non-PI, rilpivirine (RPV) based regimen
Drug: Sirolimus
Experimental: Sirolimus 0.05 mg/kg/day initial dose for 20 weeks
For subjects who are on an NNRTI regimen with the exception of RPV
Drug: Sirolimus

  Eligibility

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

Inclusion Criteria:

  • HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all investigational new drug (IND) studies.

WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (eg, indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.

  • Currently on continuous ART for ≥24 months prior to study entry. This is defined as continuous active therapy for the 24-month period prior to study entry with no treatment interruption longer than 5 consecutive days and a total duration off treatment of no more than 7 days in the 90 days prior to study entry.
  • CD4+ cell count ≥400 cells/mm3 obtained within 60 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs.
  • Plasma HIV-1 RNA below the level of quantification (eg, <20, <40, <50, or <75 copies/mL depending on the assay) for ≥24 months by any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with GCLP and participates in appropriate external quality assurance programs. Participants must have at least one documented HIV-1 RNA below the level of quantification obtained 12-24 months prior to screening and one HIV-1 RNA less than the level of quantification obtained within 12 months prior to the screening HIV-1 RNA.

NOTE:

  • One month = 30 days.
  • Plasma HIV-1 RNA measurements above the limit of quantification but <200 copies/mL in the 24 months prior to screening are allowed if directly followed by HIV-1 RNA below assay limit, but none in the 6 months prior to screening.

    • Plasma HIV-1 RNA level of <40 copies/mL obtained by the Abbott real time assay or <20 copies/mL by the Roche COBAS TaqMan HIV-1 Test, Version 2.0 assay within 60 days prior to study entry at any laboratory that has a CLIA certification or its equivalent.
    • For females of reproductive potential (defined as women who have not been postmenopausal for at least 24 consecutive months or documentation that the woman has undergone hysterectomy, bilateral oophorectomy, or salpingectomy), negative serum or urine pregnancy test within 48 hours prior to study entry.

NOTE: Patient-reported history is acceptable documentation of hysterectomy and bilateral oophorectomy, tubal ligation, tubal micro-inserts, vasectomy, and menopause.

  • Females of reproductive potential who are participating in sexual activity that could lead to pregnancy must agree to initiate effective contraceptives before sirolimus therapy, continue use during sirolimus therapy, and maintain use for at least 12 weeks after sirolimus therapy has been stopped.

Female subjects and/or their male partners MUST agree to use appropriately at least one of the following:

  • Condoms (male or female) with or without a spermicidal agent
  • Diaphragm or cervical cap with spermicide
  • Intrauterine device (IUD)
  • Tubal ligation
  • Hormone-based contraceptive

NOTE:

  • Sexual activity with an infertile partner is not sexual activity that can lead to pregnancy.
  • Females on hormone-based contraceptives at study entry must have been on the same method for at least 90 days prior to study entry.

    • Ability and willingness of subject or legal guardian/representative to provide informed consent.
    • Laboratory evaluations obtained within 60 days prior to entry by any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with GCP and participates in appropriate external quality assurance programs.
  • White blood cell (WBC) ≥3000/mm3
  • Platelet count ≥125,000/mm3
  • ANC >1300/mm3
  • Aspartate aminotransferase (AST) <1.25 x ULN
  • Alanine aminotransferase (ALT) <1.25 x ULN
  • Calculated creatinine clearance (CrCl) ≥60 mL/min as estimated by the Cockcroft-Gault equation:

For men, (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72) = CrCl (mL/min)*

  • For women, multiply the result by 0.85 = CrCl (mL/min) NOTE: A program to assist in calculations is available on the DMC website at: http://www.fstrf.org/ACTG/ccc.html

    • Fasting or non-fasting triglyceride level ≤350 mg/dL
    • Fasting or non-fasting LDL <160 mg/dL
    • Urine protein to urine creatinine ratio ≤1 gram from random urine collection

Exclusion Criteria:

  • Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy in the opinion of the site investigator for at least 30 days prior to study entry.
  • Documentation of any CDC Category C AIDS-indicator condition or oropharyngeal candidiasis (thrush) within 90 days prior to study entry. (http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm)
  • Intended modification of ART during the study.
  • Latent tuberculosis (TB) infection defined as a positive PPD ≥5 mm or positive interferon-gamma release assay (IGRA) at any time in the past or evidence of latent TB on the screening chest x-ray without subsequent INH or equivalent antibiotic prophylaxis.

NOTE: Prophylaxis must have been completed at least 48 weeks prior to study entry.

  • TB disease within 48 weeks prior to study entry requiring treatment. Subjects with a history of active TB must have completed treatment at least 48 weeks prior to study entry.
  • History of or current (within 90 days prior to study entry) active hepatitis B (HBV) infection defined as positive HBV surface antigen test or positive HBV DNA in subjects with isolated HBcAb positivity.
  • HCV RNA-positive within 90 days prior to study entry.

NOTE: Subjects who are HCV antibody negative within 90 days prior to study entry are eligible for the study. Those who are not taking HCV therapy and who are HCV antibody-positive but HCV RNA negative within 90 days prior to study entry are eligible for the study.

  • Previously diagnosed myelodysplasia syndrome.
  • History of lymphoproliferative disease prior to study entry.
  • Clinically significant lung disease on the screening chest x-ray that, in the opinion of the site investigator, places the subject at increased risk of lung toxicity (eg, history of pulmonary fibrosis, interstitial lung disease, or pulmonary lymphoproliferative disease).
  • Any prior or current diagnosis of solid tumor or hematologic malignancies, including localized skin cancers with or without evidence of metastasis.
  • History of congestive heart failure as defined by physician documentation in the medical record at any time prior to screening that required medication for heart failure, or that required medical management within 2 years prior to study entry.
  • Detectable Epstein-Barr virus (EBV) in blood by polymerase chain reaction (PCR) within 90 days prior to study entry at any US laboratory that has a CLIA certification or its equivalent.
  • Active infection other than HIV that required receipt of systemic antibiotic therapy by intravenous infusion within 90 days prior to study entry.
  • Life-threatening fungal infection that in the opinion of the site investigator requires treatment within 48 weeks prior to study entry.
  • Herpes-zoster or varicella-zoster viral infection requiring treatment within 90 days prior to study entry or currently on suppressive therapy.
  • History of major hypersensitivity reaction to macrolide drugs including angioedema, anaphylaxis, drug-induced dermatitis, or hypersensitivity vasculitis.
  • Currently pregnant or breastfeeding, or planning to become pregnant prior to or during the study.
  • Use of immunomodulators (eg, interleukins, interferons, and cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 90 days prior to study entry.
  • Active drug or alcohol use or dependence that in the opinion of the site investigator would interfere with adherence to study requirements.
  • Vaccination (eg, pneumococcal polysaccharide/influenza vaccine) within 14 days prior to study entry.

NOTE: If subjects receive influenza vaccination for routine clinical care during or prior to the screening visit, they may be rescreened 14 days after vaccination.

  • On a PI-based ART or cobicistat-boosted regimen within 90 days prior to study entry or plans to change to a PI-based or cobicistat-boosted regimen during the study.

NOTE: Prior PI-based or cobicistat-boosted regimens are allowed.

  • Anal or perianal administration of anti-HPV therapies (eg, imiquimod, 5FU, veregen) for 90 days prior to study entry or plans to initiate anti-HPV therapies during the study.
  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: NCT02440789

Locations
United States, California
Ucsd, Avrc Crs (701) Recruiting
San Diego, California, United States, 92103
Contact: Jill Kunkel    619-543-3094    jkunkel@ucsd.edu   
Principal Investigator: Constance A. Benson, MD         
Ucsf Aids Crs (801) Recruiting
San Francisco, California, United States, 94110
Contact: Jay Dwyer, RN, ACRN    415-476-4082 ext 353    jdwyer@php.ucsf.edu   
Principal Investigator: Diane V. Havlir, MD         
United States, District of Columbia
Whitman Walker Health CRS (31791) Recruiting
Washington, District of Columbia, United States, 20005
Contact: Kristi Kiger, BA, BSN    202-939-7699    kkiger@whitman-walker.org   
Principal Investigator: Sarah Henn, MD, MPH         
United States, Georgia
The Ponce de Leon Center CRS (5802) Recruiting
Atlanta, Georgia, United States, 30308
Contact: Ericka Patrick    404-616-6313    erpatri@emory.edu   
Principal Investigator: Carlos del Rio, MD         
United States, Illinois
Northwestern University CRS (2701) Recruiting
Chicago, Illinois, United States, 60611
Contact: Baiba Berzins, MPH    312-695-5012    baiba@northwestern.edu   
Principal Investigator: Babafemi Taiwo, MBBS, MD         
United States, Maryland
Johns Hopkins Adult AIDS CRS (201) Recruiting
Baltimore, Maryland, United States, 21287
Contact: Ilene Wiggins, RN    410-614-2766    imp@jhmi.edu   
Principal Investigator: Yukari Manabe, MD         
United States, Massachusetts
101 Massachusetts General Hospital (MGH) CRS Recruiting
Boston, Massachusetts, United States, 02114
Contact: Teri Flynn, RN, ANP, MSN    617-724-0072    tflynn@partners.org   
Principal Investigator: Rajesh Gandhi, MD         
Brigham and Women's Hosp. ACTG CRS (107) Recruiting
Boston, Massachusetts, United States, 02115
Contact: Cheryl Keenan, RN, BSN    617-732-5635    ckeenan2@partners.org   
Principal Investigator: Paul E. Sax, MD         
United States, Missouri
Washington University CRS (2101) Recruiting
St. Louis, Missouri, United States, 63110
Contact: Michael Klebert, RNC, PhD, ANP    1-314-747-1098    mklebert@im.wustl.edu   
Principal Investigator: David Clifford, MD         
United States, New Jersey
31786 New Jersey Medical School Clinical Research Center CRS Recruiting
Newark, New Jersey, United States, 07103
Contact: Janet Forcht    973-972-1005    janet.forcht@rutgers.edu   
Principal Investigator: Shobha Swaminathan, MD         
United States, New York
7804 Weill Cornell Chelsea CRS Recruiting
New York, New York, United States, 10010
Contact: Todd Stroberg, R.N., B.S.N.    212-746-4177    tstrober@med.cornell.edu   
Principal Investigator: Timothy Wilkin, MD, MPH         
Cornell CRS (7804) Recruiting
New York, New York, United States, 10011
Contact: Todd Stroberg, R.N., B.S.N.    212-746-7198    tstrober@med.cornell.edu   
Principal Investigator: Timothy Wilkin, MD, MPH         
Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803) Recruiting
New York, New York, United States, 10011
Contact: Valery Hughes, FNP    212-746-4177    vah9001@med.cornell.edu   
Principal Investigator: Marshall J. Glesby, MD         
Columbia Physicians and Surgeons CRS (30329) Recruiting
New York, New York, United States, 10032
Contact: Steven Palmer, PA    212-305-3178    sp500@columbia.edu   
Principal Investigator: Magdalena Sobieszczyk, MD, MPH         
31787 University of Rochester Adult HIV Therapeutic Strategies Network CRS Recruiting
Rochester, New York, United States, 14642
Contact: Emily L. Cosimano, RN    585-276-5903      
Principal Investigator: Amneris Luque, MD         
United States, North Carolina
Unc Aids Crs (3201) Recruiting
Chapel Hill, North Carolina, United States, 27516
Contact: Susan Pedersen, RN, BSN    919-966-6713    spederse@med.unc.edu   
Principal Investigator: David Wohl, MD         
United States, Ohio
Univ. of Cincinnati CRS (2401) Recruiting
Cincinnati, Ohio, United States, 45267
Contact: Sharon Kohrs, RN, BSN    513-584-6383    kohrssd@ucmail.uc.edu   
Principal Investigator: Carl Fichtenbaum, MD         
Case CRS (2501) Recruiting
Cleveland, Ohio, United States, 44106
Contact: Jane Baum, BSN, RN    216-844-2546    baum.jane@clevelandactu.org   
Principal Investigator: Benigno Rodriguez, MD         
United States, Pennsylvania
Hosp. of the Univ. of Pennsylvania CRS (6201) Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Joseph Quinn, RN    215-349-8091    joseph.quinn@uphs.upenn.edu   
Principal Investigator: Pablo Tebas, MD         
United States, Texas
Houston AIDS Research Team CRS (31473) Recruiting
Houston, Texas, United States, 77030
Contact: Maria Martinez, BS    713-500-6718    maria.l.martinez@uth.tmc.edu   
Principal Investigator: Roberto Arduino, MD         
United States, Washington
University of Washington AIDS CRS (1401) Recruiting
Seattle, Washington, United States, 98104
Contact: Christine Jonsson    206-744-8886    cjonsson@uw.edu   
Principal Investigator: Ann C Collier, MD         
Sponsors and Collaborators
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Timothy Henrich, MD Brigham and Women's Hospital
Study Chair: Priscilla Hsue, MD University of California, San Francisco
  More Information

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT02440789     History of Changes
Other Study ID Numbers: ACTG A5337
2UM1AI068636 ( US NIH Grant/Contract Award Number )
Study First Received: April 6, 2015
Last Updated: August 23, 2016

Additional relevant MeSH terms:
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on March 27, 2017