Coagulation, HIV Infection, Inflammation
Conditions
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.
Interventions
DRUGEdoxaban 30mg daily
DRUGMatching placebo
Sponsors
Hennepin Healthcare Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Interleukin 6 (IL-6) Plasma Levels From Baseline to 4 Months. | Through study completion, an average of 4 months on each treatment. | Difference between treatment and control ln-transformed IL-6 plasma levels in change from pre-treatment to on-treatment values |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in D-Dimer Levels From Baseline to 4 Months | Through study completion, an average of 4 months on each treatment. | Difference between treatment and control ln-transformed D-Dimer levels in change from pre-treatment to on-treatment values |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety (Bleeding Events) | 4 months while on Edoxaban or Placebo | Number of bleeding events on Edoxaban or Placebo. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo First Then Edoxaban Participants receive placebo during first period, then Edoxaban (30mg daily) in second period after washout. | 22 |
| Edoxaban First Then Placebo Participants receive Edoxaban (30mg daily) in first period, then placebo during second period after washout. | 22 |
| Total | 44 |
Baseline characteristics
| Characteristic | Placebo First Then Edoxaban | Edoxaban First Then Placebo | Total |
|---|---|---|---|
| Age, Continuous | 51 years STANDARD_DEVIATION 8 | 47 years STANDARD_DEVIATION 10 | 49 years STANDARD_DEVIATION 9 |
| D-dimer | 0.18 μg/mL | 0.18 μg/mL | 0.18 μg/mL |
| Diastolic Blood Pressure | 81.4 mmHg STANDARD_DEVIATION 11 | 78.9 mmHg STANDARD_DEVIATION 10.4 | 80.1 mmHg STANDARD_DEVIATION 10.6 |
| Interleukin-6 (IL-6) | 0.695 pg/mL | 0.465 pg/mL | 0.575 pg/mL |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 8 Participants | 2 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White (Non-Hispanic) | 13 Participants | 18 Participants | 31 Participants |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 18 Participants | 22 Participants | 40 Participants |
| Systolic Blood Pressure | 122.4 mmHg STANDARD_DEVIATION 17.3 | 126.1 mmHg STANDARD_DEVIATION 13 | 124.3 mmHg STANDARD_DEVIATION 15.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 44 |
| other Total, other adverse events | 21 / 44 | 21 / 44 |
| serious Total, serious adverse events | 1 / 44 | 1 / 44 |
Outcome results
Primary
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
Time frame: Through study completion, an average of 4 months on each treatment.
Population: 44 participants were randomized to each arm, of those, 41 went on to receive placebo and have follow up data, 40 received study drug (Edoxaban) and had follow up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Interleukin 6 (IL-6) Plasma Levels From Baseline to 4 Months. | -0.02 ln-pg/mL | Standard Deviation 0.39 |
| Edoxaban | Change in Interleukin 6 (IL-6) Plasma Levels From Baseline to 4 Months. | 0.09 ln-pg/mL | Standard Deviation 0.29 |
p-value: 0.2695% CI: [-0.06, 0.21]Mixed Models Analysis
Secondary
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
Time frame: Through study completion, an average of 4 months on each treatment.
Population: 44 participants were randomized to each arm, of those, 41 went on to receive placebo and have follow up data, 40 received study drug (Edoxaban) and had follow up data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in D-Dimer Levels From Baseline to 4 Months | -0.13 ln-μg/mL | Standard Deviation 0.77 |
| Edoxaban | Change in D-Dimer Levels From Baseline to 4 Months | -0.66 ln-μg/mL | Standard Deviation 1.01 |
p-value: 0.00295% CI: [-0.88, -0.2]Mixed Models Analysis
Other Pre-specified
Safety (Bleeding Events)
Number of bleeding events on Edoxaban or Placebo.
Time frame: 4 months while on Edoxaban or Placebo
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Safety (Bleeding Events) | Bloody stool | 3 event |
| Placebo | Safety (Bleeding Events) | Hematuria | 0 event |
| Placebo | Safety (Bleeding Events) | Bleeding gums | 3 event |
| Placebo | Safety (Bleeding Events) | Laceration | 2 event |
| Placebo | Safety (Bleeding Events) | Bruising | 5 event |
| Placebo | Safety (Bleeding Events) | Epistaxis | 2 event |
| Edoxaban | Safety (Bleeding Events) | Bruising | 7 event |
| Edoxaban | Safety (Bleeding Events) | Bloody stool | 4 event |
| Edoxaban | Safety (Bleeding Events) | Laceration | 5 event |
| Edoxaban | Safety (Bleeding Events) | Epistaxis | 8 event |
| Edoxaban | Safety (Bleeding Events) | Bleeding gums | 10 event |
| Edoxaban | Safety (Bleeding Events) | Hematuria | 1 event |