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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Inflammation; Coagulation
• Intervention / Treatment: Drug: Matching placebo; Drug: Edoxaban 30mg daily

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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
    • Minneapolis, Minnesota, United States, 55417
      • Hennepin County Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching Placebo	Drug: Matching placebo
Active Comparator: Treatment; Edoxaban 30mg daily	Drug: Edoxaban 30mg daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Interleukin 6 (IL-6) Plasma Levels From Baseline to 4 Months.	Difference between treatment and control ln-transformed IL-6 plasma levels in change from pre-treatment to on-treatment values	Through study completion, an average of 4 months on each treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in D-Dimer Levels From Baseline to 4 Months	Difference between treatment and control ln-transformed D-Dimer levels in change from pre-treatment to on-treatment values	Through study completion, an average of 4 months on each treatment.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (Bleeding Events)	Number of bleeding events on Edoxaban or Placebo.	4 months while on Edoxaban or Placebo

Collaborators and Investigators

• Sponsor: Hennepin Healthcare Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 1, 2018

Study Registration Dates

• First Submitted: January 12, 2015
• First Submitted That Met QC Criteria: January 14, 2015
• First Posted (Estimate): January 15, 2015

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: August 15, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban
• Other Study ID Numbers: PCC-008