Efavirenz Versus Rilpivirine on Vascular Function, Inflammation, and Oxidative Stress

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01585038
• Collaborator: Janssen Services, LLC (Industry)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 28
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Disease	Drug: Efavirenz; Drug: Rilpivirine	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Trial Comparing Efavirenz With Rilpivirine on Changes in Endothelial Function, Inflammatory Markers, and Oxidative Stress in HIV-uninfected Healthy Volunteers
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Efavirenz Efavirenz 600mg given nightly without food for 30 days	Drug: Efavirenz; 600mg orally every evening; Other Names: Sustiva, Stocrin
Active Comparator: Rilpivirine Rilpivirine 25mg given daily with meals for 30 days	Drug: Rilpivirine; 25mg orally once daily; Other Names: Edurant

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Inflammatory Markers [Change from baseline to 4 weeks]

   Change in high sensitivity C-reactive protein levels

2. Endothelial Activation Markers [Change from baseline to 4 weeks]

   Change in soluble vascular cell adhesion molecule-1 levels

3. Oxidative Stress Markers [Change from baseline to 4 weeks]

   Change in F2-isoprostane levels

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana Clinical and Translational Sciences Institute	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Indiana University
• Janssen Services, LLC

Investigators

• Principal Investigator: Samir K Gupta, MD, MS, Indiana University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Samir K Gupta, MD, MS, Associate Professor of Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT01585038
• Other Study ID Numbers: TMC278HIV4002
• First Posted: Apr 25, 2012
• Last Update Posted: Aug 14, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by Samir K Gupta, MD, MS, Associate Professor of Medicine, Indiana University: endothelium; inflammation; oxidative stress; HIV-1
• Additional relevant MeSH terms: Cardiovascular Diseases; Efavirenz; Rilpivirine

Study Results

Participant Flow

Arm/Group Title	Efavirenz	Rilpivirine
Arm/Group Description	Efavirenz 600mg given nightly without food for 30 days Efavirenz: 600mg orally every evening	Rilpivirine 25mg given daily with meals for 30 days Rilpivirine: 25mg orally once daily
Period Title: Overall Study
STARTED	20	20
COMPLETED	18	18
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Efavirenz	Rilpivirine	Total
Arm/Group Description	Efavirenz 600mg given nightly without food for 30 days Efavirenz: 600mg orally every evening	Rilpivirine 25mg given daily with meals for 30 days Rilpivirine: 25mg orally once daily	Total of all reporting groups
Overall Participants	20	20	40
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	30.4	34.5	31.54
Sex: Female, Male (Count of Participants)
Female	15 75%	10 50%	25 62.5%
Male	5 25%	10 50%	15 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 15%	1 5%	4 10%
Not Hispanic or Latino	17 85%	19 95%	36 90%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 30%	9 45%	15 37.5%
White	12 60%	10 50%	22 55%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 10%	1 5%	3 7.5%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	40 100%

Outcome Measures

1. Primary Outcome

Title	Change in Flow-mediated Dilation of the Brachial Artery
Description	This is a measure of in vivo endothelial function
Time Frame	Change from baseline to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Efavirenz	Rilpivirine
Arm/Group Description	Efavirenz 600mg given nightly without food for 30 days Efavirenz: 600mg orally every evening	Rilpivirine 25mg given daily with meals for 30 days Rilpivirine: 25mg orally once daily
Measure Participants	18	18
Mean (Standard Deviation) [absolute percentage change]	0.089 (3.65)	0.63 (2.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efavirenz, Rilpivirine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	t-test, 1 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; -1.56 to 2.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Inflammatory Markers
Description	Change in high sensitivity C-reactive protein levels
Time Frame	Change from baseline to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Efavirenz	Rilpivirine
Arm/Group Description	Efavirenz 600mg given nightly without food for 30 days Efavirenz: 600mg orally every evening	Rilpivirine 25mg given daily with meals for 30 days Rilpivirine: 25mg orally once daily
Measure Participants	18	18
Mean (Standard Deviation) [mg/L]	0.80 (2.47)	-0.41 (6.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efavirenz, Rilpivirine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.21
	Confidence Interval	(2-Sided) 95%; -4.71 to 2.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Endothelial Activation Markers
Description	Change in soluble vascular cell adhesion molecule-1 levels
Time Frame	Change from baseline to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Efavirenz	Rilpivirine
Arm/Group Description	Efavirenz 600mg given nightly without food for 30 days Efavirenz: 600mg orally every evening	Rilpivirine 25mg given daily with meals for 30 days Rilpivirine: 25mg orally once daily
Measure Participants	18	18
Mean (Standard Deviation) [pg/mL]	-27.62 (125.20)	-20.92 (68.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efavirenz, Rilpivirine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.41
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	6.70
	Confidence Interval	(2-Sided) 95%; -62.49 to 75.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Oxidative Stress Markers
Description	Change in F2-isoprostane levels
Time Frame	Change from baseline to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Efavirenz	Rilpivirine
Arm/Group Description	Efavirenz 600mg given nightly without food for 30 days Efavirenz: 600mg orally every evening	Rilpivirine 25mg given daily with meals for 30 days Rilpivirine: 25mg orally once daily
Measure Participants	14	12
Mean (Standard Deviation) [pg/mL]	92.7 (178.6)	-101.4 (215.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Efavirenz, Rilpivirine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-194.1
	Confidence Interval	(2-Sided) 95%; -353.7 to -34.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	One month
Arm/Group Title	Efavirenz		Rilpivirine
Arm/Group Description	Efavirenz 600mg given nightly without food for 30 days Efavirenz: 600mg orally every evening		Rilpivirine 25mg given daily with meals for 30 days Rilpivirine: 25mg orally once daily
All Cause Mortality
	Efavirenz		Rilpivirine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Efavirenz		Rilpivirine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Efavirenz		Rilpivirine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/20 (85%)		11/20 (55%)
Gastrointestinal disorders
Gastrointestinal Abnormalities	4/20 (20%)		3/20 (15%)
Nervous system disorders
CNS Abnormalities	11/20 (55%)		6/20 (30%)
Skin and subcutaneous tissue disorders
Dermatologic Abnormality	2/20 (10%)		2/20 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.