Targeted Anticoagulation Therapy to Reduce Inflammation and Cellular Activation in Long-term HIV Disease

We hypothesize that increased generation of activated factor X (FXa) contributes to a
systemic elevation in pro-inflammatory cytokine levels (e.g. IL-6) among HIV positive
patients. This occurs, in part, via FXa activation of protease activated receptor 2 (PAR-2)
on monocytes and tissue macrophages, which perpetuates innate inflammation. We will test our
hypothesis with an oral antagonist to FXa (edoxaban), and quantify the immunologic effects of
PAR-2 inhibition on systemic inflammation and monocyte activation.

The potential benefits of pharmacologic inhibition of FXa will be studied among HIV positive
participants receiving ART with suppressed HIV viral load and a D-dimer >100 ng/mL. The study
design is a cross-over placebo controlled randomized trial of edoxaban 30mg daily versus
matched placebo (n=40 total participants). After screening and baseline visits, participants
will be randomized to the sequence of drug administration (i.e., edoxaban vs. placebo). After
randomization, participants will start study medication #1 and follow-up for visits at months
1, 2, 3 and 4. They will then stop study medication for 3 months, return for visits at months
7 and 8 (analogous to screening and baseline, respectively), then start study medication #2
and follow-up for visits at months 9, 10, 11, and 12.

The treatment effect (i.e., changes from pre-treatment levels) over 4 months will be assessed
in measures of inflammation, immune activation, and coagulation. For comparisons with
placebo, each participant will then serve as his or her own control in this cross-over
design.

Inclusion Criteria

- HIV infection (verified by previous positive antibody or detectable HIV RNA level)

- Age ≥18 years

- Receiving continuous ART for ≥2 years (regimen changes >3 months prior to enrollment
are acceptable)

- HIV RNA level ≤200 copies/mL for ≥1 year (1 measure ≥200 allowed if also <500 and
preceded and followed by one or more values ≤200 copies/mL)

- D-dimer level ≥100 mg/L (or ng/mL) at screening (or within the prior month)

- Estimated creatinine clearance ≥50 mL/min

- Body weight ≥60kg

- Do not anticipate starting (or stopping) statin or aspirin therapy during the study

- For women of child bearing potential, agrees to use a reliable form of birth control

Exclusion Criteria

- Pregnancy or breast feeding

- A contra-indication to taking edoxaban

- A clinical indication for anticoagulation therapy (e.g., atrial fibrillation or Deep
Vein Thrombosis/PE)

- Treatment with anti-platelet, anti-coagulation, or immune-modulatory drugs currently
or within the past 6 months; prior self-limited treatment with aspirin (i.e., not
daily use) is not itself an exclusion.

- Grade ≥1 hematology lab abnormality for INR (>1.1 x ULN), hemoglobin (<10.0 g/L),
platelets (<100,000 cells/μL), and WBC (2,500 cells/mm3)

- Grade ≥2 lab abnormality for chemistries (BMP) or liver panel

- Alcohol or illicit drug abuse/dependency within the prior year

- History of prior myocardial infarction or unstable atherosclerotic disease

- History of prior stroke or transient ischemic attack (TIA)

- History of active gastrointestinal ulcer or bleeding disorder within the prior year

- Intent to have surgery during the study period (12 months)

- Hepatitis C treatments (e.g., interferon, ribavirin, protease inhibitors) within the
past 6 months

- Cirrhosis or hepatic impairment (e.g., Child-Pugh class B or C).

- Seizure disorder

- Previous/current CNS space occupying lesion (e.g., Toxoplasmosis, mTB) with persistent
abnormalities on CNS imaging after completion of treatment.

- Surgical or invasive procedure anticipated during study period.

- Invasive cancer in the prior year or receiving cancer treatment (not including
carcinoma-in-situ or basal cell cancer of the skin)

- Rheumatologic or inflammatory disease, systemic in nature (e.g., systemic lupus
erythematosus, rheumatoid arthritis, vasculitis, sarcoidosis, Crohn's disease)

- Assessment by the clinical investigator that enrollment into the study could entail
excess risk to the participant, beyond what is intended or expected.