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Protocol Details

Impact of Steady State Cobicistat and Darunavir/Cobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Healthy Volunteers

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

19-CC-0063

Sponsoring Institute

National Institutes of Health Clinical Center (CC)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 18 Years
Max Age: 65 Years

Referral Letter Required

No

Population Exclusion(s)

Pregnant Women;
Children

Keywords

Antiretroviral Therapy;
Human Immunodeficiency Disease;
Drug-Drug Interactions;
Thrombosis;
Bleeding

Recruitment Keyword(s)

None

Condition(s)

Healthy Volunteers

Investigational Drug(s)

None

Investigational Device(s)

None

Intervention(s)

Drug: Cobicistat
Drug: Darunavir/Cobicistat
Drug: Rivaroxaban

Supporting Site

NIH Clinical Center

Background:

Rivaroxaban and apixaban are blood thinners. People with HIV may need to take them to treat or prevent blood clots. The anti-HIV drug darunavir (DRV) can increase the amount of these blood thinners in the body. This can cause bleeding or other health problems. The drug cobicistat (COBI) is used to help anti-HIV drugs work better. Researchers want to give healthy people DRV combined with COBI to learn how it affects rivaroxaban or apixaban blood levels.

Objective:

To test blood levels of rivaroxaban or apixaban when taken with COBI and DRV/COBI.

Eligibility:

Healthy volunteers ages 18-65

Design:

Participants will be screened with:

Medical history

Physical exam

Fasting blood and urine tests. (Urine tests will be performed in females of child-bearing potential only)

Participants will have 8 visits; 3 are long (about 10-12 hours) and 5 are about 1 hour. They include:

Baseline and final visits:

Fasting blood and urine tests

Day 1 visit (long day):

Fasting blood and urine tests

Catheter placement: A needle will insert a small tube into the participant s arm vein. Blood will be drawn up to 10 times.

Dose of rivaroxaban or apixaban

Day 2 visit (short day):

<TAB>Fasting blood tests

Dose of COBI

Participants will receive a bottle containing COBI tablets to take at home.

Day 7 (long day):

Fasting blood and urine tests

Catheter placement: A needle will insert a small tube into the participant s arm vein. Blood will be drawn up to 10 times.

<TAB>Dose of rivaroxaban or apixaban

<TAB>Dose of COBI

Day 8 (short day):

Fasting blood tests

Dose of DRV/COBI participants will receive a bottle containing DRV/COBI tablets to take at home.

Day 13 (long day):

Fasting blood and urine tests

Catheter placement: A needle will insert a small tube into the participant s arm vein. Blood will be drawn up to 10 times.

<TAB>Dose of rivaroxaban or apixaban

<TAB>Dose of DRV/COBI

Day 14 (short day):

Fasting blood tests

Participants will take COBI tablets daily at home on days 3-6, and DRV/COBI on days 9 -12 during the study. They will record doses and side effects.

During the study, participants cannot:

Take most medications.

Drink alcohol, smoke, or vape

Engage in activities such as contact and extreme sports

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Eligibility

INCLUSION CRITERIA:

A subject will be considered eligible for this study only if all of the following criteria are met:

-Adults between the ages of 18 to 65 years.

-Body mass index between 18 to 30 kg/M(2).

-Judged to be healthy based on medical history, physical examination, vital signs and clinical laboratory tests (liver function tests (LFTs: alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin less than or equal to upper limit of normal (ULN) (with the exception of participants with Gilbert s syndrome), albumin within normal limits (WNL)], eGFR > 90 mL/min/1.73 m(2), PLT>150,000/microL, hemoglobin (Hgb) greater than or equal to 12 g/dL, activated partial thromboplastin time (aPTT) less than or equal to ULN, partial thromboplastin time (PTT) less than or equal to ULN, international normalized ratio (INR) less than or equal to ULN.

-Subject agrees to storage of specimens for future research.

-Negative serum or urine pregnancy test for females of child-bearing potential.

-For female subjects, willing to avoid pregnancy by (a) practicing abstinence or (b) using effective non-hormonal and/or barrier methods of birth control, as well as avoid breast feeding or providing breast milk to infant during the study period. (baseline visit up to end of study day 20 plus minus 3)

-Willing to avoid engaging in activities such as contact sports, including extreme sports, that may increase the risk of bleeding through body injury or bruising, during the study period (baseline visit up to end of study day 20 plus minus 3)

-Willingness to forgo drinking alcohol during the study period (baseline visit up to end of study day 20 plus minus 3)

-Able to provide consent.

EXCLUSION CRITERIA:

A subject will be ineligible for this study if one, or more, of the following criteria are met:

-HIV infection, as determined by standard serologic or virologic assays for HIV infection.

-Laboratory evidence of active or chronic hepatitis A, B or C infection.

-History or presence of any of the following:

--any major medical conditions that requires daily frequent medication or potentially impairs medication absorption, metabolism and elimination

--any other condition that may interfere with the interpretation of the study results, or not be in the best interest of the subject in the opinion of the Investigator.

-Current participation in an ongoing investigational drug protocol or use of any investigational drug within 30 days (based on last dose received) prior to receipt of any study drugs/medications.

-History or presence of the following:

--bleeding/hematologic disorders (e.g., anemia, hemophilia, etc.),

--serious/major bleeding event (intracranial, gastrointestinal (GI), as assessed by subject interview), or

--current increased risk of bleeding

--for female subjects, menorrhagia

-Planned invasive or surgical procedure within (prior to or following) 28 days of study participation.

-Therapy with any prescription, over-the-counter, herbal, or holistic medications, including hormonal contraceptives by any route, within 5 half-lives of the agent prior to receipt of any study medications will not be permitted with the following exception:

Intermittent or short-course therapy (<14 days) with prescription, vaccines or over-the-counter medications will be reviewed by investigators on a case-by-case basis for potential drug interactions.

-Inability to obtain venous access for sample collection.

-Inability to swallow whole capsules and/or tablets.

-Pregnant female.

-Breastfeeding female.

-The presence of persistent diarrhea or malabsorption that could interfere with the subject s ability to absorb drugs.

-Illicit drug or alcohol use

-Use of nicotine-containing tobacco products, including cigarettes, vaping and chewing tobacco.

-Known hypersensitivity to rivaroxaban, apixaban, COBI or DRV.

-History of documented hypersensitivity to sulfa allergy.

-Organ transplant recipient.


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Citations:

Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013 Sep;76(3):455-66. doi: 10.1111/bcp.12075.

Kumar P, Gordon LA, Brooks KM, George JM, Kellogg A, McManus M, Alfaro RM, Nghiem K, Lozier J, Hadigan C, Penzak SR. Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e01201-17. doi: 10.1128/AAC.01201-17. Print 2017 Nov.

Frost C, Nepal S, Wang J, Schuster A, Byon W, Boyd RA, Yu Z, Shenker A, Barrett YC, Mosqueda-Garcia R, Lacreta F. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013 Nov;76(5):776-86. doi: 10.1111/bcp.12106.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Colleen M. Hadigan, M.D.
National Institutes of Health Clinical Center (CC)
NIHBC 10 - CRC BG RM 6-2551
10 CENTER DR
BETHESDA MD 20892
(301) 594-5754
hadiganc@niaid.nih.gov

Cheryl L. Pauls
National Institutes of Health Clinical Center (CC)
National Institutes of Health
Building 10
Room 9N214
10 Center Drive
Bethesda, Maryland 20892
(301) 481-2260
paulsc@nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT03864406

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