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

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT02475655
First received: June 16, 2015
Last updated: May 15, 2017
Last verified: May 2017
  Purpose
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 Intervention Phase
HIV Infections Drug: Ruxolitinib Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Randomized, Pilot Study of Ruxolitinib in Antiretroviral-Treated HIV-Infected Adults

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • 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.

  • Occurrence of premature discontinuation of study treatment [ Time Frame: Measured through Week 5 ]
  • 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:
  • Proportion of participants who experienced any one of the primary safety milestones during total follow-up [ Time Frame: Measured through Week 12 ]
  • Change in the level of plasma IL-6 from baseline to Weeks 4, 5, 10, and 12 [ Time Frame: Measured through Week 12 ]
  • 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

  • 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

  • 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 ]
  • 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

  • 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 ]
  • 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

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

  • 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

  • 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.


Estimated Enrollment: 60
Study Start Date: February 2016
Estimated Primary Completion Date: February 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (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, 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 or equal to 12.0 g/dL
    • Platelets greater than or equal to 200,000/mm^3
    • Calculated creatinine clearance (CrCl) greater than 80 mL/min, or greater than or equal to 70 mL/min for participants on a DTG-containing regimen (by Cockcroft Gault equation). NOTE: A calculator for estimating the CrCl can be found 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 pulmonary, neurologic, cardiac, renal, or hepatic disorder prior to study entry, excluding treated HIV or treated hypertension. 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: A history of prior chickenpox is not exclusionary.
    • Lymphoproliferative malignancy
    • Chronic or severe psychiatric condition
    • Chronic liver disease of any etiology and any degree of severity
    • Chronic hepatitis
    • 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.
  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: NCT02475655

Locations
United States, Alabama
Alabama CRS Recruiting
Birmingham, Alabama, United States, 35294
Contact: Karen Savage, R.N., B.S.N.    205-975-7925    kgsavage@uab.edu   
United States, California
UCLA CARE Center CRS Recruiting
Los Angeles, California, United States, 90035
Contact: Arezou S. Akha, M.D., M.S.    310-557-3798    asadighi@mednet.ucla.edu   
UCSD Antiviral Research Center CRS Recruiting
San Diego, California, United States, 92103
Contact: Jill Kunkel, R.N.    619-543-8080    jkunkel@ucsd.edu   
Ucsf Hiv/Aids Crs Recruiting
San Francisco, California, United States, 94110
Contact: Jay Dwyer    415-476-4082 ext 353    jdwyer@php.ucsf.edu   
United States, Colorado
University of Colorado Hospital CRS Recruiting
Aurora, Colorado, United States, 80045
Contact: Mary Graham Ray, R.N., M.S.N.    303-724-0712    graham.ray@ucdenver.edu   
United States, Florida
The University of Miami AIDS Clinical Research Unit (ACRU) CRS Recruiting
Miami, Florida, United States, 33136
Contact: Hancy Brignol, B.S.N., M.H.S.A.    305-243-3838    hbrignol@med.miami.edu   
United States, Georgia
The Ponce de Leon Center CRS Recruiting
Atlanta, Georgia, United States, 30308-2012
Contact: Ericka Patrick, M.S.N.    404-616-6313    erpatri@emory.edu   
United States, Illinois
Northwestern University CRS Recruiting
Chicago, Illinois, United States, 60611
Contact: Baiba Berzins, M.P.H.    312-695-5012    Baiba@northwestern.edu   
United States, Massachusetts
Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS Recruiting
Boston, Massachusetts, United States, 02115
Contact: Cheryl E. Keenan, R.N.    617-732-5635    ckeenan2@partners.org   
United States, Missouri
Washington University Therapeutics (WT) CRS Recruiting
Saint Louis, Missouri, United States, 63110-1010
Contact: Michael K. Klebert    314-747-1098    mklebert@dom.wustl.edu   
United States, New York
Weill Cornell Chelsea CRS Recruiting
New York, New York, United States, 10010
Contact: Todd Stroberg, R.N., B.S.N.    212-746-7198    tstrober@med.cornell.edu   
Weill Cornell Uptown CRS Recruiting
New York, New York, United States, 10065
Contact: Louise Walshe    212-746-7864    ljw2001@med.cornell.edu   
University of Rochester Adult HIV Therapeutic Strategies Network CRS Recruiting
Rochester, New York, United States, 14642
Contact: Mary Adams    585-275-4768    Maryb_adams@urmc.rochester.edu   
United States, Ohio
Case Clinical Research Site Recruiting
Cleveland, Ohio, United States, 44106
Contact: Jane Baum, R.N.    216-844-2546    jb@clevelandactu.org   
United States, Pennsylvania
Penn Therapeutics, CRS Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Eileen Donaghy    215-349-8092    eileen.donaghy2@uphs.upenn.edu   
United States, Rhode Island
The Miriam Hospital Clinical Research Site (TMH CRS) CRS Recruiting
Providence, Rhode Island, United States, 02906
Contact: Pamela Poethke, R.N.    401-793-4971    ppoethke@lifespan.org   
United States, Tennessee
Vanderbilt Therapeutics (VT) CRS Recruiting
Nashville, Tennessee, United States, 37204
Contact: Beverly O. Woodward, M.S.N., R.N.    615-936-8516    beverly.o.woodward@vanderbilt.edu   
United States, Texas
Houston AIDS Research Team CRS Recruiting
Houston, Texas, United States, 77030
Contact: Maria L. Martinez    713-500-6718    Maria.L.Martinez@uth.tmc.edu   
United States, Washington
University of Washington AIDS CRS Recruiting
Seattle, Washington, United States, 98104-9929
Contact: Christine Jonsson    206-744-8886    cjonsson@u.washington.edu   
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
  More Information

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 )
Study First Received: June 16, 2015
Last Updated: May 15, 2017

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

ClinicalTrials.gov processed this record on July 26, 2017