Evaluating the Safety and Tolerability of Ruxolitinib in Antiretroviral-Treated HIV-Infected Adults

NCT02475655 | Completed Phase 2 Results DMC

• 2 other identifiers: A533611977
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 14

Brief Summary

The purpose of this study was to evaluate the safety and tolerability of ruxolitinib in HIV-positive adults who were virologically suppressed and who were on antiretroviral therapy (ART).

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (5)

• Percentage of Participants on the Ruxolitinib Arm Who Experienced Any Safety Milestone Events While On-Treatment

  Events defined as safety milestones are listed below and together makeup the composite endpoint. * Confirmed CD4+ decline \> 33% of entry and to \< 350 cell/mm\^3 (for participants with entry CD4+ T cell count \< 700 cells/mm\^3) * Confirmed CD4+ decline \> 50% of entry (for participants with entry CD4+ T cell count ≥ 700 cells/mm\^3) * Confirmed HIV-1 RNA level above the lower limit of quantification in the absence of an interruption of ART * New or recurrent CDC category C AIDS-indicator condition * HIV-1 associated infection including Herpes zoster * Lymphoproliferative malignancies * Grade 4 or recurrence of Grade 3 anemia/neutropenia * New diagnosis of pneumonia, sepsis, or bacteremia * Discontinuation of Ruxolitinib due to thrombocytopenia * Any Grade 4 or recurrence of Grade 3 toxicity related to study drug Percent experiencing a safety milestone will be reported.

  Entry to Week 5

• Percentage of Participants Who Experienced Any Safety Milestones On-study From Entry to Week 5

  Events defined as safety milestones are listed below and together makeup the composite endpoint. * Confirmed CD4+ decline \> 33% of entry and to \< 350 cell/mm\^3 (for participants with entry CD4+ T cell count \< 700 cells/mm\^3) * Confirmed CD4+ decline \> 50% of entry (for participants with entry CD4+ T cell count ≥ 700 cells/mm\^3) * Confirmed HIV-1 RNA level above the lower limit of quantification in the absence of an interruption of ART * New or recurrent CDC category C AIDS-indicator condition * HIV-1 associated infection including Herpes zoster * Lymphoproliferative malignancies * Grade 4 or recurrence of Grade 3 anemia/neutropenia * New diagnosis of pneumonia, sepsis, or bacteremia * Occurrence of Grade 2 or higher thrombocytopenia * Any Grade 4 or recurrence of Grade 3 toxicity Percent experiencing a safety milestone will be reported.

  Entry to Week 5

• Percentage of Participants Who Experienced Each Safety Milestone That Occurred On-study From Entry to Week 5

  Events defined as safety milestones are listed below. * Confirmed CD4+ decline \> 33% of entry and to \< 350 cell/mm\^3 (for participants with entry CD4+ T cell count \< 700 cells/mm\^3) * Confirmed CD4+ decline \> 50% of entry (for participants with entry CD4+ T cell count ≥ 700 cells/mm\^3) * Confirmed HIV-1 RNA level above the lower limit of quantification in the absence of an interruption of ART * New or recurrent CDC category C AIDS-indicator condition * HIV-1 associated infection including Herpes zoster * Lymphoproliferative malignancies * Grade 4 or recurrence of Grade 3 anemia/neutropenia * New diagnosis of pneumonia, sepsis, or bacteremia * Occurrence of Grade 2 or higher thrombocytopenia * Any Grade 4 or recurrence of Grade 3 toxicity Percent experiencing each safety milestone will be reported. Safety milestone categories are not mutually exclusive.

  Entry to Week 5

• Number of Participants With Premature Discontinuation of Study Treatment in the Ruxolitinib Arm

  Number of participants with premature discontinuation of study treatment are summarized.

  Entry to Week 5

• Fold Change in the Level of Plasma Interleukin 6 (IL-6) From Baseline to Week 4/5

  All values were log10 transformed prior to calculating change and conducting analyses and back transformed for presentation. Baseline is defined as the geometric mean of the Pre-entry and Entry values. Week 4/5 is defined as the geometric mean of the Week 4 and Week 5 values. Fold change was calculated as the value at Week 4/5 divided by the value at Baseline.

  Pre-entry, Entry, Weeks 4 and 5

Secondary Outcomes (68)

• Percentage of Participants on the Ruxolitinib Arm Who Experienced Any Safety Milestone Events During Total Follow-up

  Entry to Week 12

• Percentage of Participants Who Experienced Any Safety Milestones On-study From Entry to Week 12

  Entry to Week 12

• Percentage of Participants Who Experienced Each Safety Milestone That Occurred On-study From Entry to Week 12

  Entry to Week 12

• Number of Participants Who Experienced a Protocol-defined Reportable Adverse Event at Any Post-entry Time Point.

  Entry to Week 12

• Creatinine Clearance

  Entry, Weeks 1, 2, 4, 5, 10, and 12

Other Outcomes (3)

• Change in 2 Long-terminal Repeat Sequences [LTRs]

  Entry, Week 5, and Week 12

• Level of HHV Shedding (EBV, HSV, HHV-6, HHV-7, and HHV-8)

  Pre-entry, Entry, Weeks 1, 2, 4, 5, 10, and 12

• Fold Change in Integrated DNA

  Entry, Weeks 5 and 12

Study Arms (2)

Arm A: Ruxolitinib

EXPERIMENTAL

Participants received ruxolitinib twice a day for 5 weeks. Participants were required to remain on ART regimen (not provided by the study) for the duration of the study.

Drug: Ruxolitinib

Arm B: No Study Treatment

NO INTERVENTION

Participants did not receive any study treatment. Participants were required to remain on ART regimen (not provided by the study) for the duration of the study.

Interventions

Ruxolitinib DRUG

10 mg orally twice daily for 5 weeks

Arm A: Ruxolitinib

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infection
• CD4+ T cell count greater than 350 cells/mm\^3 within 45 days prior to study entry
• Documented virologic suppression defined as HIV-1 RNA level below the limit of quantification (eg, less than 40, less than 50, or less than 75 copies/mL, depending on the assay) using an FDA-approved assay with a quantification limit of 75 copies/mL or lower for at least 48 weeks prior to study entry
• Screening HIV-1 RNA level below the limit of quantification
• Tuberculosis (TB) screening within 365 days of the screening visit diagnosed by tuberculin skin test or interferon gamma release assay
• Currently on continuous ART for at least 730 days prior to study entry, defined as continuous ART for the 730 days period, inclusive, prior to study entry with no ART interruption longer than 7 consecutive days. NOTE: The current regimen must include TDF/FTC, TAF/FTC, TDF+3TC, or ABC/3TC; plus a nonnucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor (NNRTI or INSTI, not containing cobicistat) for at least 60 days, inclusive, prior to study entry.
• The following laboratory values obtained within 45 days prior to entry:
• Absolute neutrophil count (ANC) greater than or equal to 1,000/mm\^3
• Hemoglobin greater than 12.0 g/dL for men and greater than 11.0 g/dL for women
• Platelets greater than or equal to 140,000/mm\^3
• Calculated creatinine clearance (CrCl) greater than or equal to 70 mL/min (by Cockcroft Gault equation)
• Aspartate aminotransferase (AST) (SGOT) less than or equal to 1.5x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) (SGPT) less than or equal to 1.5x ULN
• Alkaline phosphatase less than or equal to 1.5x ULN
• For females of reproductive potential, a negative serum or urine pregnancy test with a sensitivity of 25 mIU/mL within 72 hours, inclusive, prior to study entry

You may not qualify if:

• A current or past history of progressive multifocal leukoencephalopathy
• Breastfeeding or pregnancy
• Use of strong inhibitors or inducers of CYP3A4 including a protease inhibitor, cobicistat or entry inhibitors as part of the current ART regimen or other concomitant therapy
• Known allergy/sensitivity or any hypersensitivity to components of study drug or their formulation
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
• Acute or serious illness or infection requiring systemic treatment and/or hospitalization within 60 days prior to entry
• Vaccinations (other than influenza) less than or equal to 45 days prior to the study entry visit.
• Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), systemic cytotoxic chemotherapy or investigational therapy less than or equal to 60 days prior to study entry
• CDC category C AIDS-indicator conditions
• NOTE A: Except HIV encephalopathy, HIV wasting, esophageal candidiasis, or pneumocystis pneumonia without dissemination.
• NOTE B: List available: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm
• Herpes zoster (dermatomal or non-dermatomal).
• Lymphoproliferative malignancy
• Chronic liver disease of any etiology and any degree of severity
• Chronic hepatitis, except for hepatitis C that has been cured (defined as a Sustained Virologic Response, which is an undetectable HCV-RNA at 12 weeks or more after completing treatment measured by a sensitive, qualitative, or quantitative HCV-RNA assay)

Sponsors & Collaborators

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

Study Sites (14)

Alabama CRS

Birmingham, Alabama, 35294, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90035, United States

Location

UCSD Antiviral Research Center CRS

San Diego, California, 92103, United States

Location

Ucsf Hiv/Aids Crs

San Francisco, California, 94110, United States

Location

Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Washington University Therapeutics (WT) CRS

St Louis, Missouri, 63110-1010, United States

Location

Weill Cornell Chelsea CRS

New York, New York, 10010, United States

Location

Weill Cornell Uptown CRS

New York, New York, 10065, United States

Location

University of Rochester Adult HIV Therapeutic Strategies Network CRS

Rochester, New York, 14642, United States

Location

Cincinnati Clinical Research Site

Cincinnati, Ohio, 45219, United States

Location

Case Clinical Research Site

Cleveland, Ohio, 44106, United States

Location

Penn Therapeutics, CRS

Philadelphia, Pennsylvania, 19104, United States

Location

The Miriam Hospital Clinical Research Site (TMH CRS) CRS

Providence, Rhode Island, 02906, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 37204, United States

Location

Related Publications (1)

• Marconi VC, Moser C, Gavegnano C, Deeks SG, Lederman MM, Overton ET, Tsibris A, Hunt PW, Kantor A, Sekaly RP, Tressler R, Flexner C, Hurwitz SJ, Moisi D, Clagett B, Hardin WR, Del Rio C, Schinazi RF, Lennox JJ. Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus. Clin Infect Dis. 2022 Jan 7;74(1):95-104. doi: 10.1093/cid/ciab212.

  PMID: 33693561 DERIVED

Related Links

• DAIDS AE Grading Table, Version 2.0, November 2014
• Version 2.0 of the DAIDS EAE Manual

MeSH Terms

Conditions

HIV Infections

Interventions

ruxolitinib

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

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

• Vincent Marconi, MD

  Emory University

  STUDY CHAIR

• Jeffrey Lennox, MD

  Emory University

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 16, 2015
• First Posted: June 19, 2015
• Study Start: May 16, 2016
• Primary Completion: February 18, 2018
• Study Completion: April 4, 2018
• Last Updated: November 4, 2021
• Results First Posted: April 18, 2019

Record last verified: 2020-07

Locations

US (14)