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

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.

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.