Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive Antiretroviral Therapy (ART)

NCT02440789 | Completed Phase 1 Results DMC

• 2 other identifiers: ACTG A53372UM1AI068636
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 10

Brief Summary

The purpose of this study was to find out about the safety of sirolimus in individuals with HIV infection who were also being treated with ART. The investigators wanted to learn whether sirolimus decreases inflammation and immune activation in the body; whether sirolimus changes 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 had 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.

Conditions

HIV-1 Infection

Outcome Measures

Primary Outcomes (7)

• Number of Participants Who Met the Study-defined Composite Safety Endpoint

  The study-defined primary safety endpoint was a composite endpoint. A participant was considered to have met the endpoint if the participant 1) experienced a new Grade ≥3 Adverse Event (AE), including signs/symptoms, lab toxicity or clinical event, that was 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. The screening visit occurred within 60 days of study entry.

  Screening to study week 32 (week 20 of Sirolimus)

• Efficacy - Immunologic: Frequency of HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma

  Frequency of HIV-1 Gag-specific CD8+ T-cells by intracellular staining for IFN-gamma. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

• Efficacy - Immunologic: Change in HIV-1 Gag-specific CD8+ T-cells by Intracellular Staining for IFN-gamma

  Change in HIV-1 Gag-specific CD8+ T-cells by intracellular staining for IFN-gamma (week 32 measurement minus baseline measurement)

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

• Efficacy - Virologic: CD4+ T-cell-associated HIV-1 RNA

  CD4+ T-cell-associated HIV-1 RNA. Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

• Efficacy - Virologic: Change in CD4+ T-cell-associated HIV-1 RNA

  Change in CD4+ T-cell-associated HIV-1 RNA (week 32 measurement minus baseline measurement)

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

• Efficacy - Virologic: Plasma HIV-1 RNA by SCA

  Plasma HIV-1 RNA by SCA

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

• Efficacy - Virologic: Change in Plasma HIV-1 RNA by SCA

  Change in plasma HIV-1 RNA by SCA (week 32 measurement minus baseline measurement). Baseline is the mean of the two pre-Sirolimus measurements (study entry and study week 12).

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

Secondary Outcomes (39)

• Measurement of CD4+ T-cell Counts

  At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44

• Change in CD4+ T-cell Counts

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

• Measurement of HIV-1 RNA Levels

  weeks 0, 12, (pre-Sirolimus) 16, 24, 32 (4, 12, 20 weeks on Sirolimus) and 44

• Cell-associated HIV-1 DNA Levels in Total CD4+ Cells

  At study weeks 0, 12, 16, 24, 32 (4, 12, 20 weeks on sirolimus) and 44

• Change in Cell-associated HIV-1 DNA Levels in Total CD4+ Cells

  At study weeks 0, 12 and 32 (week 20 on Sirolimus)

Study Arms (1)

Sirolimus

EXPERIMENTAL

Drug: Sirolimus

Interventions

Sirolimus DRUG

Participants 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 received 0.025 mg/kg/day initial dose for 20 weeks. Participants on an NNRTI regimen with the exception of RPV received 0.05 mg/kg/day initial dose for 20 weeks.

Sirolimus

Eligibility Criteria

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

You may qualify if:

• HIV-1 infection
• On continuous ART for ≥24 months prior to study entry.
• CD4+ cell count ≥350 cells/mm\^3
• Plasma HIV-1 RNA below the level of quantification for ≥24 months.
• White blood cell (WBC) ≥3000/mm\^3
• Platelet count ≥125,000/mm\^3
• Absolute neutrophil count (ANC) \>1300/mm\^3
• Aspartate aminotransferase (AST) \<1.25 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) \<1.25 x ULN
• Calculated creatinine clearance (CrCl) ≥60 mL/min
• Fasting or non-fasting triglyceride level ≤350 mg/dL
• Fasting or non-fasting LDL \<160 mg/dL
• Urine protein to urine creatinine ratio ≤1 g/g from random urine collection

You may not qualify if:

• Serious illness requiring systemic treatment and/or hospitalization
• Documentation of any CDC Category C AIDS-indicator condition or oropharyngeal candidiasis (thrush)
• Intended modification of ART during the study.
• Latent tuberculosis (TB) infection
• TB disease within 48 weeks prior to study entry requiring treatment.
• History of active hepatitis B (HBV) infection.
• Hepatitis C virus (HCV) RNA-positive
• Previous myelodysplasia syndrome, lymphoproliferative disease, lung disease, malignancies, congestive heart failure, life-threatening fungal infection or herpes-zoster/varicella-zoster viral infection requiring treatment.
• Detectable Epstein-Barr virus (EBV) in blood
• Active infection other than HIV that required receipt of systemic antibiotic therapy by intravenous infusion
• 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.
• Active drug or alcohol use or dependence
• Vaccination within 14 days prior to study entry.

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (10)

801 University of California, San Francisco HIV/AIDS CRS

San Francisco, California, 94110, United States

Location

Whitman Walker Health CRS (31791)

Washington D.C., District of Columbia, 20005, United States

Location

Univ. of Miami AIDS CRS (901)

Miami, Florida, 33136, United States

Location

The Ponce de Leon Center CRS (5802)

Atlanta, Georgia, 30308, United States

Location

Washington University CRS (2101)

St Louis, Missouri, 63110, United States

Location

Weill Cornell Uptown CRS (7803)

New York, New York, 10011, United States

Location

31787 University of Rochester Adult HIV Therapeutic Strategies Network CRS

Rochester, New York, 14642, United States

Location

Univ. of Cincinnati CRS (2401)

Cincinnati, Ohio, 45267, United States

Location

Houston AIDS Research Team CRS (31473)

Houston, Texas, 77030, United States

Location

University of Washington AIDS CRS (1401)

Seattle, Washington, 98104, United States

Location

Related Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) Version 2.0 January 2010

MeSH Terms

Interventions

Sirolimus

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Timothy Henrich, MD

  University of California, San Francisco

  STUDY CHAIR

• Priscilla Hsue, MD

  University of California, San Francisco

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 6, 2015
• First Posted: May 12, 2015
• Study Start: December 21, 2015
• Primary Completion: November 2, 2017
• Study Completion: February 1, 2018
• Last Updated: August 3, 2021
• Results First Posted: December 30, 2019

Record last verified: 2019-12

Locations

US (10)