Clinical trial NCT02339415: Targeted Anticoagulation Therapy to Reduce Inflammation and Cellular Activation in Long-term HIV Disease
Official title: Targeted Anticoagulation Therapy to Reduce Inflammation and Cellular Activation in Long-term HIV Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Inflammation
Coagulation
HIV Infection
Lead sponsor: Hennepin Healthcare Research Institute
Sponsor class: OTHER
First posted: 2015-01-15
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the effects of pharmacologic FXa inhibition (via edoxaban 30 mg daily) on inflammation, as reflected in plasma Interleukin-6 levels.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Interleukin 6 (IL-6) Plasma Levels From Baseline to 4 Months.
timeFrame: Through study completion, an average of 4 months on each treatment.
Secondary outcomes:
measure: Change in D-Dimer Levels From Baseline to 4 Months
timeFrame: Through study completion, an average of 4 months on each treatment.
Other outcomes:
measure: Safety (Bleeding Events)
timeFrame: 4 months while on Edoxaban or Placebo
Locations:
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
Study officials:
affiliation: Hennepin Healthcare Research Institute
name: Jason Baker, M.D.
role: PRINCIPAL_INVESTIGATOR
References: