Clinical trial NCT02475655: Evaluating the Safety and Tolerability of Ruxolitinib in Antiretroviral-Treated HIV-Infected Adults
Official title: A Randomized, Pilot Study of Ruxolitinib in Antiretroviral-Treated HIV-Infected Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2015-06-19
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed description: Ruxolitinib is a medication approved by the U.S. Food and Drug Administration (FDA) to treat myelofibrosis, a disorder in which bone marrow is replaced by scar (fibrosis) tissue. Many of the cytokines affected by myelofibrosis are also affected by HIV. Because of this, ruxolitinib may also be a possible treatment for HIV. The purpose of this study was to evaluate the safety and tolerability of ruxolitinib in HIV-positive adults who were on ART and who were virologically suppressed. Researchers evaluated the effect ruxolitinib had on inflammation and immune activation.

This study enrolled HIV-positive adults who were on select ART regimens and who had viral suppression. ART was not provided by the study; participants continued to receive ART from their own health care providers. Participants were randomly assigned to receive either ruxolitinib (Arm A) or no study treatment (Arm B) in 2:1 ratio. Participants in Arm A received ruxolitinib twice a day for 5 weeks. All participants attended study visits at entry (Day 0) and Weeks 1, 2, 4, 5, 10, and 12. These visits included physical examinations, clinical assessments, blood collection, adherence assessments, oral swab collection, and pregnancy testing for female participants. At Weeks 1 and 4, participants in Arm A took part in pharmacokinetic (PK) sampling, which involved having blood drawn several times over 6 to 8 hours.

Eligibility criteria: Inclusion Criteria:

* 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
* All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization)
* All participants of reproductive potential, who were participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception while receiving the study drugs and for 7 weeks after stopping the medications
* Ability and willingness of participant or legal representative to provide written informed consent and attend study visits as scheduled at a participating site

Exclusion Criteria:

* 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
* Any current diagnosis or past history of a significant cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, neuropsychiatric, psychiatric, or other serious illness that, in the opinion of the investigator, could constitute a risk when taking investigational product or could interfere with the interpretation of data or affect the participant's ability to participate in the study. Diagnoses that would lead to exclusion include, but were not limited to the following:

  * 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).
  * NOTE C: A history of prior chickenpox was not exclusionary.
  * 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)
  * Disseminated fungal infection of any type or duration that is not limited to cutaneous or mucocutaneous surfaces
  * A medical disorder that predisposes to bleeding
* Change in the ART regimen within 12 weeks, inclusive, prior to study entry or intended modification of ART during the study.
* History of untreated latent tuberculosis infection (LTBI) diagnosed by tuberculin skin test or interferon gamma release assay. LTBI treatment would consist of 9 months of isoniazid or an equivalent therapy completed at least 4 weeks prior to study entry.

Primary outcomes:
measure: Percentage of Participants on the Ruxolitinib Arm Who Experienced Any Safety Milestone Events While On-Treatment
timeFrame: Entry to Week 5
measure: Percentage of Participants Who Experienced Any Safety Milestones On-study From Entry to Week 5
timeFrame: Entry to Week 5
measure: Percentage of Participants Who Experienced Each Safety Milestone That Occurred On-study From Entry to Week 5
timeFrame: Entry to Week 5
measure: Number of Participants With Premature Discontinuation of Study Treatment in the Ruxolitinib Arm
timeFrame: Entry to Week 5
measure: Fold Change in the Level of Plasma Interleukin 6 (IL-6) From Baseline to Week 4/5
timeFrame: Pre-entry, Entry, Weeks 4 and 5
Secondary outcomes:
measure: Percentage of Participants on the Ruxolitinib Arm Who Experienced Any Safety Milestone Events During Total Follow-up
timeFrame: Entry to Week 12
measure: Percentage of Participants Who Experienced Any Safety Milestones On-study From Entry to Week 12
timeFrame: Entry to Week 12
measure: Percentage of Participants Who Experienced Each Safety Milestone That Occurred On-study From Entry to Week 12
timeFrame: Entry to Week 12
measure: Number of Participants Who Experienced a Protocol-defined Reportable Adverse Event at Any Post-entry Time Point.
timeFrame: Entry to Week 12
measure: Creatinine Clearance
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Change in Creatinine Clearance Values From Entry
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Creatinine
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Change in Creatinine Values From Entry
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Absolute Neutrophil Count (ANC)
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Change in Absolute Neutrophil Count (ANC) Values From Entry
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Hemoglobin
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Change in Hemoglobin Values From Entry
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Platelet Count
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Change in Platelet Counts From Entry
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Aspartate Aminotransferase (AST) (SGOT)
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Change in Aspartate Aminotransferase (AST) (SGOT) Values From Entry
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Alanine Aminotransferase (ALT) (SGPT)
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Change in Alanine Aminotransferase (ALT) (SGPT) Values From Entry
timeFrame: Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Fold Change in the Level of Plasma Interleukin 6 (IL-6)
timeFrame: Pre-entry, Entry, Weeks 4, 5, 10 and 12
measure: Fold Change in the Level of Soluble CD14 (sCD14)
timeFrame: Pre-entry, Entry, Weeks 4, 5, and 12
measure: Change in CD4+ T Cell Count
timeFrame: Pre-entry, Entry, Weeks 2, 5, and 12
measure: Number of Participants With Plasma HIV-1 RNA Level Above the Limit of Quantification
timeFrame: Entry, Weeks 2, 5, and 12
measure: Relative Risks of HIV-1 RNA by Single Copy Assay (SCA) < 0.4 Copies/mL
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Tumor Necrosis Factor Alpha (TNF Alpha)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Interleukin 1 Beta (IL-1 Beta)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Interleukin 7 (IL-7)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Interleukin 1 Alpha (IL-1 Alpha)
timeFrame: Pre-entry, Entry, Weeks 4, 5, and 12
measure: Fold Change in the Level of Interferon Gamma-induced Protein 10 (IP-10)
timeFrame: Pre-entry, Entry, Weeks 4, 5, and 12
measure: Fold Change in the Level of Macrophage Colony-stimulating Factor
timeFrame: Pre-entry, Entry, Weeks 4, 5, and 12
measure: Fold Change in the Level of Neopterin
timeFrame: Pre-entry, Entry, Weeks 4, 5, and 12
measure: Fold Change in the Level of Plasma Interleukin 10 (IL-10)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Interleukin 15 (IL-15)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Interleukin 18 (IL-18)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Transforming Growth Factor Beta 1 (TGF Beta-1)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Transforming Growth Factor Beta 2 (TGF Beta-2)
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in the Level of Plasma Transforming Growth Factor Beta 3 (TGF Beta-3)
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD4+) CD38+HLADR+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD8+) CD38+HLADR+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD4+) CD25hi+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD8+) CD25+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD4+) CD127+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD8+) CD127+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD4+) Ki67+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD8+) Ki67+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD4+) Bcl2+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD8+) Bcl2+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD4+) a4b7+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD8+) a4b7+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD4+) CX3CR1+
timeFrame: Entry, Weeks 5 and 12
measure: Change in (CD3+CD8+) CX3CR1+
timeFrame: Entry, Weeks 5 and 12
measure: Change in CD69
timeFrame: Entry, Weeks 5 and 12
measure: Change in PAR-1
timeFrame: Entry, Weeks 5 and 12
measure: Change in Classical Monocytes (CD14+CD16-)
timeFrame: Entry, Weeks 5 and 12
measure: Change in Classical Monocytes (CD14+CD16-) Expressing CD163+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Classical Monocytes (CD14+CD16-) Expressing CCR2+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Classical Monocytes (CD14+CD16-) Expressing CX3CR1+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Inflammatory Monocytes (CD14+CD16+)
timeFrame: Entry, Weeks 5 and 12
measure: Change in Inflammatory Monocytes (CD14+CD16+) Expressing CD163+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Inflammatory Monocytes (CD14+CD16+) Expressing CCR2+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Inflammatory Monocytes (CD14+CD16+) Expressing CX3CR1+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Patrolling Monocytes (CD14dimCD16+)
timeFrame: Entry, Weeks 5 and 12
measure: Change in Patrolling Monocytes (CD14dimCD16+) Expressing CD163+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Patrolling Monocytes (CD14dimCD16+) Expressing CCR2+
timeFrame: Entry, Weeks 5 and 12
measure: Change in Patrolling Monocytes (CD14dimCD16+) Expressing CX3CR1+
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in Cellular HIV-1 DNA
timeFrame: Entry, Weeks 5 and 12
measure: Fold Change in Cellular HIV-1 Total RNA
timeFrame: Entry, Weeks 5 and 12
measure: Percentage of Participants With Detectable CMV Shedding
timeFrame: Pre-entry, Entry, and Weeks 1, 2, 4, 5, 10, and 12
measure: Ruxolitinib Systemic Clearance (CL/F) From 2-compartment Pharmacokinetic (PK)
timeFrame: Week 1 and, Week 4/5; blood samples were drawn pre-dose and at 1-1.5, 2.5-4, 4-6, and 6-8 hours post-dosing
Other outcomes:
measure: Change in 2 Long-terminal Repeat Sequences [LTRs]
timeFrame: Entry, Week 5, and Week 12
measure: Level of HHV Shedding (EBV, HSV, HHV-6, HHV-7, and HHV-8)
timeFrame: Pre-entry, Entry, Weeks 1, 2, 4, 5, 10, and 12
measure: Fold Change in Integrated DNA
timeFrame: Entry, Weeks 5 and 12
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Cleveland
country: United States
facility: Case Clinical Research Site
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital Clinical Research Site (TMH CRS) CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics (VT) CRS
state: Tennessee
Study officials:
affiliation: Emory University
name: Vincent Marconi, MD
role: STUDY_CHAIR
affiliation: Emory University
name: Jeffrey Lennox, MD
role: STUDY_CHAIR
References:
citation: 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.