Cardiovascular Disease
Conditions
Keywords
endothelium, inflammation, oxidative stress, HIV-1
Brief summary
The purpose of this study is to compare the cardiovascular profiles of efavirenz and rilpivirine, which are two drugs used to treat HIV infection.
Detailed description
This is a randomized, controlled, open-label, single-center study comparing the effects of efavirenz (EFV) versus rilpivirine (RPV) on endothelial function in a total of 40 HIV-uninfected healthy volunteers (20 in each arm) at the Indiana University Medical Center. Enrolled subjects will have their brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and other cardiovascular, inflammatory, and oxidative stress parameters measured at baseline and again after 4 weeks of study treatment.
Interventions
DRUGEfavirenz
600mg orally every evening
DRUGRilpivirine
25mg orally once daily
Sponsors
Janssen Services, LLC
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. 18 years of age or older 2. Negative ELISA for HIV-1 or HIV-2 at screening 3. Negative hepatitis B surface antigen at screening 4. Negative hepatitis C antibody at screening 5. For women of reproductive potential, a negative urine pregnancy test at screening and willingness to use two forms of birth control during the course of the study 6. For men who are capable of impregnating a female sexual partner, a willingness to use condoms with spermicidal gel for all sexual contacts during the course of the study 7. No documented history of or receipt of medications being used to treat any psychiatric disorder, including (but not limited to) depression, dysthymia, mania, bipolar disease, schizophrenia, or previous suicidal ideation/attempts 8. No anticipated changes or additions to other medical therapies during the course of the study 9. No documented history of seizure disorder
Exclusion criteria
1. Inability to provide written, informed consent 2. Known allergy/intolerance to rilpivirine, efavirenz, or nitroglycerin 3. Absolute neutrophil count \< 750cell/mL at screening 4. Hemoglobin \< 11g/dL at screening 5. Platelet count \< 100,000/mL at screening 6. Estimated creatinine clearance (per Cockcroft-Gault equation) \< 55 mL/min at screening 7. Liver transaminases (AST or ALT) \> 100 IU/mL or total bilirubin \> 1.5mg/dL at screening 8. Serum glucose \> 200mg/dL at screening 9. Serum total cholesterol \> 190mg/dL at screening 10. Breastfeeding at screening or during the course of the study 11. Hypotension, defined as SBP \< 90mmHg at time of each main study visit before brachial artery ultrasound measurements 12. Hypertension, defined as SBP \> 160mmHg at time of screening 13. Receipt of investigational agents within 30 days of each screening visit or anticipated use during the trial 14. Receipt of cytotoxic chemotherapy within 30 days of each screening visit or anticipated use during the trial 15. Receipt of systemic glucocorticoids (\> 10mg/day of prednisone or the equivalent), inhaled/nasal/topical fluticasone, or anabolic steroids within 30 days of each screening visit or anticipated use during the trial 16. Use of sildenafil (Viagra or Silagra), vardenafil (Levitra), or tadalafil (Cialis), within 72 hours (before or after) of brachial artery reactivity testing 17. Indwelling vascular catheters within any upper body vessel at time of brachial artery reactivity testing 18. Active drug or alcohol use or dependence that, in the opinion of the investigator or study personnel, would interfere with adherence to study requirements 19. Acute therapy for serious infection or other serious medical illnesses (in the judgment of the site investigator) requiring systemic treatment and/or hospitalization within 14 days prior to each screening and study visit 20. History of migraine headaches 21. History of Raynaud's phenomenon 22. History of cardiac arrythmias 23. History of hypothyroidism or hyperthyroidism that is untreated (defined as a TSH outside the normal range on most recent testing during normal clinical care) 24. History of carotid bruits 25. History of any tobacco use (cigarette smoking, cigar smoking, chewing tobacco) or nicotine replacement treatments (patch, gum) within 45 days of screening 26. Drugs/therapies with significant CYP 450 induction or inhibition potential at screening 27. Use of antacids, H2-blockers, or proton pump inhibitors within 30 days of screening or anticipated use of these drugs during the trial 28. Any history of injection or illicit drug use 29. Presence of fever, defined as an oral or tympanic temperature \> 100.3F, at either the Entry or Closeout Visits 30. On the PHQ-9 depression questionnaire at screening, a total score of more than 9 or any score over 0 on question 9.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Flow-mediated Dilation of the Brachial Artery | Change from baseline to 4 weeks | This is a measure of in vivo endothelial function |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inflammatory Markers | Change from baseline to 4 weeks | Change in high sensitivity C-reactive protein levels |
| Endothelial Activation Markers | Change from baseline to 4 weeks | Change in soluble vascular cell adhesion molecule-1 levels |
| Oxidative Stress Markers | Change from baseline to 4 weeks | Change in F2-isoprostane levels |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Efavirenz Efavirenz 600mg given nightly without food for 30 days
Efavirenz: 600mg orally every evening | 20 |
| Rilpivirine Rilpivirine 25mg given daily with meals for 30 days
Rilpivirine: 25mg orally once daily | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
Baseline characteristics
| Characteristic | Efavirenz | Total | Rilpivirine |
|---|---|---|---|
| Age, Continuous | 30.4 years | 31.54 years | 34.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 36 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 22 Participants | 10 Participants |
| Region of Enrollment United States | 20 participants | 40 participants | 20 participants |
| Sex: Female, Male Female | 15 Participants | 25 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 15 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 20 | 11 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Change in Flow-mediated Dilation of the Brachial Artery
This is a measure of in vivo endothelial function
Time frame: Change from baseline to 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz | Change in Flow-mediated Dilation of the Brachial Artery | 0.089 absolute percentage change | Standard Deviation 3.65 |
| Rilpivirine | Change in Flow-mediated Dilation of the Brachial Artery | 0.63 absolute percentage change | Standard Deviation 2.42 |
p-value: 0.395% CI: [-1.56, 2.64]t-test, 1 sided
Secondary
Endothelial Activation Markers
Change in soluble vascular cell adhesion molecule-1 levels
Time frame: Change from baseline to 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz | Endothelial Activation Markers | -27.62 pg/mL | Standard Deviation 125.2 |
| Rilpivirine | Endothelial Activation Markers | -20.92 pg/mL | Standard Deviation 68.95 |
p-value: 0.4195% CI: [-62.49, 75.89]t-test, 2 sided
Secondary
Inflammatory Markers
Change in high sensitivity C-reactive protein levels
Time frame: Change from baseline to 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz | Inflammatory Markers | 0.80 mg/L | Standard Deviation 2.47 |
| Rilpivirine | Inflammatory Markers | -0.41 mg/L | Standard Deviation 6.01 |
p-value: 0.3595% CI: [-4.71, 2.3]t-test, 2 sided
Secondary
Oxidative Stress Markers
Change in F2-isoprostane levels
Time frame: Change from baseline to 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efavirenz | Oxidative Stress Markers | 92.7 pg/mL | Standard Deviation 178.6 |
| Rilpivirine | Oxidative Stress Markers | -101.4 pg/mL | Standard Deviation 215.7 |
p-value: 0.0295% CI: [-353.7, -34.6]t-test, 2 sided