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

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ClinicalTrials.gov Identifier: NCT03864406
Recruitment Status : Recruiting
First Posted : March 6, 2019
Last Update Posted : June 6, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC)

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Tybost (Cobicistat) Drug: Prezcobix (Darunavir/Cobicistat) Drug: Xarelto (Rivaroxaban) Drug: Eliquis (Apixaban) Phase 1

Detailed Description:
Rivaroxaban and apixaban are direct oral anticoagulants (DOACs) used for the prevention and treatment of various thromboembolic disorders. Predictable pharmacokinetic (PK) and pharmacodynamic (PD) properties, coupled with a few drug-drug and food-drug interactions, distinguishes DOACs from traditionally used anticoagulant - warfarin, allowing fixed dosing without routine coagulation monitoring. Patients with human immunodeficiency virus (HIV) are living as long as their HIV negative counterparts due to safe and efficacious antiretroviral therapy (ART). Persons with HIV are at higher risk for thromboembolic events and DOACs are a feasible option for anticoagulation in this population. However, there is a lack of drug interaction and safety data currently on the co-administration cobicistat (COBI)-boosted antiretroviral (ARV) regimens with rivaroxaban and apixaban. Rivaroxaban and apixaban are both metabolized by cytochrome P450 isozyme (CYP) 3A4 and their absorption is modulated by permeability-glycoprotein (P-gp), both of which are inhibited by the PK booster COBI. It is therefore possible that plasma concentrations of rivaroxaban and apixaban may be significantly increased when co-administered together with COBI. This is of clinical concern as increased anticoagulant exposure may result in bleeding without the security of routine clinical monitoring. The purpose of this study is to determine the effects of steady state concentrations of COBI and DRV/COBI on the PK and PD of single oral doses of rivaroxaban and apixaban.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Impact of Steady State Cobicistat and Darunavir/Dobicistat on the Pharmacokinetics and Pharmacodynamics of Oral Anticoagulants (Rivaroxaban, Apixaban) in Healthy Volunteers (CLOTRx)
Actual Study Start Date : June 4, 2019
Estimated Primary Completion Date : August 30, 2021
Estimated Study Completion Date : August 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Arm Intervention/treatment
Experimental: A
Phase 1: a single dose of rivaroxaban on day 1 followed by serial PK/PD blood sampling Phase 2: cobicistat once daily (Days 2 7), followed by single dose of rivaroxaban and serial PK/PD blood sampling on day 7 Phase 3: darunavir /cobicistat once daily (days 8-13) followed by single dose of rivaroxaban and serial PK /PD blood sampling on day 13.
Drug: Tybost (Cobicistat)
Each tablet of Tybost contains 150 mg of cobicistat.

Drug: Prezcobix (Darunavir/Cobicistat)
Each tablet of Prezcobix contains 800 mg of darunavir and 150 mg of cobicistat.

Drug: Xarelto (Rivaroxaban)
Each tablet of Xarelto contains 10 mg of rivaroxaban.

Experimental: B
Phase 1: a single dose of apixaban on day 1 followed by serial PK/PD blood sampling Phase 2: cobicistat once daily (Days 2-7), followed by single dose of apixaban and serial PK /PD blood sampling on day 7 Phase 3: darunavir /cobicistat once daily (days 8-13) followed bysingle dose of apixaban and serial PK/PD blood sampling on day 13.
Drug: Tybost (Cobicistat)
Each tablet of Tybost contains 150 mg of cobicistat.

Drug: Prezcobix (Darunavir/Cobicistat)
Each tablet of Prezcobix contains 800 mg of darunavir and 150 mg of cobicistat.

Drug: Eliquis (Apixaban)
Each tablet of Eliquis contains 5 mg of apixaban.




Primary Outcome Measures :
  1. Plasma area under the curve during the dosing interval of 0 to 24 hours and 0 to infinity (AUC0-24hr, AUC0-inf), maximum total plasma concentration (Cmax), time to maximum plasma concentration (tmax), terminal half-life (t1/2), apparent oral cl... [ Time Frame: Days 1, 7 and 13 at the following times: Arm A (Rivaroxaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10 and 24 hours post-dose. Arm B (Apixaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose. ]
    To characterize the PK of oral anticoagulants (rivaroxaban, apixaban alone and in combination with cobicistat or darunavir/cobicistat in healthy volunteers.


Secondary Outcome Measures :
  1. Area under the effect curve for factor Xa, aPTT and PT from 0 to 24 hours (AUEC0-24), and the maximum effect ratio over baseline (ERmax), [ Time Frame: Days 1, 7 and 13 at the following times: Arm A (Rivaroxaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10 and 24 hours post-dose. Arm B (Apixaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose. ]
    To characterize the PD (anti FXa, aPTT, PT/INR) of oral anticoagulants (rivaroxaban, apixaban) alone and in combination with cobicistat or darunavir/cobicistat in healthy volunteers.

  2. AEs and abnormal laboratory values, as graded according to the DAIDS AE table and Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials AE table (total bilirubin only). [ Time Frame: Days 1, 7 and 13 at the following times: Arm A (Rivaroxaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10 and 24 hours post-dose. Arm B (Apixaban): times 0 (predose), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose ]
    To evaluate the safety of coadministration of oral anticoagulants (rivaroxaban, apixaban) alone and in combination with cobicistat or darunavir/cobicistat in healthy volunteers through documentation of adverse events (AEs) according to the Division of AIDS (DAIDS) AE Table for Grading the Severity of Adult and Pediatric Adverse Events Table and the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials AE table (total bilirubin only).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • 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 18-65 years.
  • Body Mass Index (BMI) between 18-30 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, PLT > 150,000/microL, hemoglobin (Hgb) greater than or equal to 12 g/dL, aPTT less than or equal to ULN, PTT less than or equal to ULN, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03864406


Contacts
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Contact: Cheryl L. Chairez (301) 496-3840 chairezc@mail.nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institutes of Health Clinical Center (CC)
Investigators
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Principal Investigator: Jomy M George, Pharm.D. National Institutes of Health Clinical Center (CC)

Additional Information:
Publications:
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Responsible Party: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT03864406     History of Changes
Other Study ID Numbers: 190063
19-CC-0063
First Posted: March 6, 2019    Key Record Dates
Last Update Posted: June 6, 2019
Last Verified: February 27, 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC):
Antiretroviral Therapy
Human Immunodeficiency Disease
Drug-Drug Interactions
Thrombosis
Bleeding
Additional relevant MeSH terms:
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Darunavir
Cobicistat
Rivaroxaban
Apixaban
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
HIV Protease Inhibitors
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors