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

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ClinicalTrials.gov Identifier: NCT02475655
Recruitment Status : Completed
First Posted : June 19, 2015
Last Update Posted : May 11, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of ruxolitinib in HIV-infected adults who are virologically suppressed and who are on antiretroviral therapy (ART).

Condition or disease Intervention/treatment Phase
HIV Infections Drug: Ruxolitinib Phase 2

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 is to evaluate the safety and tolerability of ruxolitinib in HIV-infected adults who are on ART and who are virologically suppressed. Researchers will evaluate the effect ruxolitinib has on inflammation and immune activation.

This study will enroll HIV-infected adults who are on select ART regimens and who have viral suppression. ART will not be provided by the study; participants will continue to receive ART from their own health care providers. Participants will be randomly assigned to receive either ruxolitinib (Arm A) or no study treatment (Arm B). Participants in Arm A will receive ruxolitinib twice a day for 5 weeks. All participants will attend study visits at entry (Day 0) and Weeks 1, 2, 4, 5, 10, and 12. These visits will include 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 will take part in pharmacokinetic (PK) sampling, which will involve having blood drawn several times over 6 to 8 hours.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Pilot Study of Ruxolitinib in Antiretroviral-Treated HIV-Infected Adults
Study Start Date : February 2016
Actual Primary Completion Date : February 18, 2018
Actual Study Completion Date : April 4, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Arm A: Ruxolitinib
Participants will receive ruxolitinib twice a day for 5 weeks. Participants must remain on ART regimen (not provided by the study) for the duration of the study.
Drug: Ruxolitinib
10 mg orally twice daily for 5 weeks

No Intervention: Arm B: No Study Treatment
Participants will not receive any study treatment. Participants should be encouraged to remain on ART regimen for the duration of the study.



Primary Outcome Measures :
  1. Occurrence of any one of the following safety milestones (from entry to Week 5) [ Time Frame: Measured through Week 5 ]
    • For participants with entry CD4+ T cell count less than 700 cells/mm^3, confirmed CD4+ decline greater than 33% of baseline and to less than 350 cells/mm^3.
    • For participants with entry CD4+ T cell count greater than or equal to 700 cells/mm^3, a confirmed CD4+ T cell decline greater than 50% of baseline.
    • Confirmed HIV-1 RNA level above the lower limit of quantification in the absence of an interruption in ART.
    • New or recurrent Centers for Disease Control and Prevention (CDC) category C AIDS-indicator condition.
    • HIV-1 associated infection including herpes zoster.
    • Lymphoproliferative malignancies.
    • Discontinuation of ruxolitinib due to thrombocytopenia.
    • Grade 4 or recurrence of Grade 3 anemia/neutropenia.
    • Any Grade 4 or recurrence of Grade 3 toxicity related to study drug.
    • New diagnosis of pneumonia, sepsis, or bacteremia.

  2. Occurrence of premature discontinuation of study treatment [ Time Frame: Measured through Week 5 ]
  3. Participant-specific change in the level of plasma interleukin 6 (IL-6) [ Time Frame: Measured through Week 5 ]
    Using geometric means of two enzyme-linked immunosorbent assay (ELISA) measurements at pre-entry and entry, and Weeks 4 and 5


Secondary Outcome Measures :
  1. Proportion of participants who experienced any one of the primary safety milestones during total follow-up [ Time Frame: Measured through Week 12 ]
  2. Change in the level of plasma IL-6 from baseline to Weeks 4, 5, 10, and 12 [ Time Frame: Measured through Week 12 ]
  3. Changes in soluble markers of immune activation and inflammation in the peripheral blood from baseline to Weeks 4, 5, and 12 [ Time Frame: Measured through Week 12 ]
    sCD14, tumor necrosis factor alpha (TNF-α), IL-1α, IL-1-β, macrophage colony stimulating factor (m-CSF), and neopterin

  4. Changes in cellular markers of immune activation and inflammation in the peripheral blood from baseline to Weeks 5 and 12 [ Time Frame: Measured through Week 12 ]
    HLA-DR, CD38, CD69, and CD14+/CD16+ monocyte levels

  5. Changes in plasma HIV-1 RNA and CD4+ T cell counts from baseline to Weeks 2, 5, and 12 [ Time Frame: Measured through Week 12 ]
  6. Changes in HIV-1 reservoir from baseline to Weeks 5 and 12 [ Time Frame: Measured through Week 12 ]
    HIV-1 RNA by single-copy assay (SCA), cellular HIV-1 total RNA and DNA, 2 long terminal repeat sequences (LTRs), integrated DNA

  7. Level of human herpes viruses (HHV) shedding (CMV, EBV, HHV 6, 7, 8) at pre-entry, entry, and Weeks 1, 2, 4, 5, 10, and 12 [ Time Frame: Measured through Week 12 ]
  8. Hematology profile [ Time Frame: Measured through Week 12 ]
    Hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), white blood cells (WBC), differential WBC, absolute neutrophil count (ANC), platelets

  9. Liver function profile [ Time Frame: Measured through Week 12 ]
    AST (SGOT), ALT (SGPT), alkaline phosphatase, indirect bilirubin, direct bilirubin, and total bilirubin

  10. Blood chemistries profile [ Time Frame: Measured through Week 12 ]
    Electrolytes (sodium, potassium, chloride, bicarbonate), glucose, creatinine, blood urea nitrogen (BUN), and CrCl as estimated by the Cockcroft-Gault equation

  11. Fasting lipid panel profile [ Time Frame: Measured through Week 12 ]
    Cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL). If the LDL cannot be calculated due to elevated triglyceride levels, a direct LDL should be measured.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
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, or historical plasma HIV-1 RNA viral load. More information on this criterion is available in the protocol.
  • CD4+ T cell count greater than 350 cells/mm^3 within 45 days prior to study entry at any U.S. laboratory that has a CLIA (Clinical Laboratory Improvement Amendments) certification or its equivalent
  • Documentation of virologic suppression defined as:

    • Have 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 performed by any laboratory that has a CLIA certification or its equivalent. Single determinations that are between the assay quantification limit and 500 copies/mL (ie, "blips") are allowed as long as the preceding and subsequent determinations are below the level of quantification. The screening value may serve as the subsequent undetectable value following a blip.
  • Screening HIV-1 RNA level below the limit of quantification (eg, less than 20, less than 40, less than 50, or less than 75 copies/mL, depending on the assay) using a FDA-approved assay with a quantification limit of 75 copies/mL or lower performed by any laboratory that has a CLIA certification or its equivalent within 45 days prior to study entry.
  • 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 by any U.S. laboratory that has a CLIA certification or its equivalent:

    • 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). NOTE: A calculator for estimating the CrCl can be found under Calculator Utilities at www.fstrf.org/ACTG/ccc.html
    • 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 (defined as women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy) must have 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 are 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. Acceptable forms of contraceptive include:

    • Condoms (male or female) with or without a spermicidal agent
    • Diaphragm or cervical cap with spermicide
    • Intrauterine device (IUD)
    • Hormone-based contraceptive (must contain at least 35 mcg of ethinyl estradiol)
  • Women who are not of reproductive potential (women who have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy and/or bilateral oophorectomy or salpingectomy) or men who have documented azoospermia or undergone vasectomy are eligible to start study drugs without requiring the use of contraceptives. Acceptable documentation of sterilization and menopause is specified in the protocol.
  • Men and women age greater than or equal to 18 and less than 75 years
  • 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. NOTE: Influenza vaccine is permitted. Participants are encouraged to get this vaccine greater than or equal to 7 days prior to the study pre-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 are 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 is 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
    • *NOTE: If a site investigator is unsure of whether a history of a significant medical or psychiatric condition should lead to participant exclusion, the investigator should err on the side of safety if s/he believes that an active or clinically resolved disorder may put the participant at risk from participation in the study, influence the results of the study, or affect the participant's ability to participate. If still uncertain, then the site should contact the protocol team (actg.corea5336@fstrf.org) to assist in a determination.
  • Change in the ART regimen within 12 weeks, inclusive, prior to study entry or intended modification of ART during the study. NOTE: Modifications of ART doses during the 12 weeks prior to study entry are permitted. In addition, the change in formulation (e.g., from standard formulation to fixed-dose combination) is allowed within 12 weeks prior to study entry. A within class single drug substitution (e.g., switch from nevirapine to efavirenz or from atazanavir to darunavir) is allowed within 12 weeks prior to study entry, with the exception of a switch between any other NRTI to/from abacavir. No other changes in ART within the 12 weeks prior to study entry are permitted. However, participants need to be receiving (and tolerating) an allowable (for study purposes) ART regimen for at least 4 weeks prior to study entry.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02475655


Locations
United States, Alabama
Alabama CRS
Birmingham, Alabama, United States, 35294
United States, California
UCLA CARE Center CRS
Los Angeles, California, United States, 90035
UCSD Antiviral Research Center CRS
San Diego, California, United States, 92103
Ucsf Hiv/Aids Crs
San Francisco, California, United States, 94110
United States, Illinois
Northwestern University CRS
Chicago, Illinois, United States, 60611
United States, Missouri
Washington University Therapeutics (WT) CRS
Saint Louis, Missouri, United States, 63110-1010
United States, New York
Weill Cornell Chelsea CRS
New York, New York, United States, 10010
Weill Cornell Uptown CRS
New York, New York, United States, 10065
University of Rochester Adult HIV Therapeutic Strategies Network CRS
Rochester, New York, United States, 14642
United States, Ohio
Cincinnati Clinical Research Site
Cincinnati, Ohio, United States, 45219
Case Clinical Research Site
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
Penn Therapeutics, CRS
Philadelphia, Pennsylvania, United States, 19104
United States, Rhode Island
The Miriam Hospital Clinical Research Site (TMH CRS) CRS
Providence, Rhode Island, United States, 02906
United States, Tennessee
Vanderbilt Therapeutics (VT) CRS
Nashville, Tennessee, United States, 37204
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Vincent Marconi, MD Emory University
Study Chair: Jeffrey Lennox, MD Emory University

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02475655     History of Changes
Other Study ID Numbers: A5336
11977 ( Registry Identifier: DAIDS-ES )
First Posted: June 19, 2015    Key Record Dates
Last Update Posted: May 11, 2018
Last Verified: May 2018

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases