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Impact of Once-Weekly Rifapentine and Isoniazid on the Steady State Pharmacokinetics of Dolutegravir and Darunavir Boosted With Cobicistat in Healthy Volunteers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02771249
Recruitment Status : Completed
First Posted : May 13, 2016
Last Update Posted : December 30, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC)

Brief Summary:

People with human immunodeficiency virus (HIV) often take several medicines to control HIV. Dolutegravir and darunavir boosted with cobicistat are HIV medicines that people may take. They may also need to take medicines for an infection called latent tuberculosis (TB). Researchers think a once-weekly treatment for latent TB would be easier for people with HIV to take. This once weekly treatment consists of two drugs: rifapentine and isoniazid. However, they need to see how TB drugs and HIV drugs interact.

Objective:

To learn how anti-HIV and anti-TB drugs affect each other so that people taking these drugs together can be treated safely.

Eligibility:

Healthy adults ages 18 65.

Design:

Participants will be screened with a medical history and physical exam. They will have vital signs taken and give a blood sample. Women will have a pregnancy test.

Participants cannot take any other medicines during the study, including vitamins. Only occasional, infrequent use of acetaminophen (Tylenol , max 2000 mg/day), ibuprofen (Motrin or Advil ), naproxen (Aleve ), loperamide (Imodium ), and/or antihistamines (such as Benadryl , Zyrtec , Claritin , etc.) will be allowed.

Participants will be assigned to one of three groups. Each group will take a different study drug, once or twice a day, for 19 23 days. At the baseline study visit, they will get a supply of the study drug tablets and instructions for taking them. Participants will keep a medicine diary to serve as a memory aid for taking medicine and reporting any side effects that they may experience.

Participants will have 8 or 9 study visits over about 40 days. The number of visits depends on which group the person is assigned to. All visits will take place at the NIH Clinical Center. Participants will fast before study visits.

The baseline visit will last about 2 3 hours. There will be 3-4 long visits that will last for about 12 hours. The other 4-5 visits will last about 1 hour.

During all study visits, screening procedures will be repeated. During long visits, an intravenous (IV) line will be inserted into an arm vein with a needle. It will be used to take blood.


Condition or disease Intervention/treatment Phase
HIV Infected Population With Latent Tuberculosis Drug: rifapentene (RPT) Drug: darunavir/cobicistat (DRV/c) Drug: Isoniazid (INH) Dietary Supplement: Pyridoxine Phase 1

Detailed Description:

Rifapentine (RPT) is a long-acting rifamycin that can be used weekly with isoniazid (INH) as a first-line regimen in the treatment of latent tuberculosis infection (LTBI). Although this regimen offers several potential benefits, the use of weekly RPT plus INH is not currently recommended in adults infected with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) due to limited evidence on drug interactions with antiretrovirals (ARVs).1Darunavir boosted with cobicistat (DRV/c) comprises part of alternative treatment regimens recommended for the treatment of HIV.2However, drug interactions between these ARV agents and RPT are of concern. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state PK of DRV/c.

This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of DRV/c with coadministration of once weekly RPT and INH given at doses used to treat LTBI. Arm B will be comprised of two phases: (1) DRV/c once daily alone (days 1-4) and (2) DRV/c once daily + (RPT and INH) once weekly (days 5-19). Participants in Arm B will undergo periodic serial ARV PK blood draws on days 4, 14, and 19.

DRV/c PK parameters will be determined using non-compartmental methods. Cobicistat levels will only be assessed if DRV concentrations are significantly decreased. The following PK parameters will be compared between phases: area under the curve over the dosing interval, maximum plasma concentration, time to maximum plasma concentration, terminal half-life, apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and recorded.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Impact of Once-Weekly Rifapentine and Isoniazid on the Steady State Pharmacokinetics of Dolutegravir and Darunavir Boosted With Cobicistat in Healthy Volunteers
Actual Study Start Date : June 3, 2016
Actual Primary Completion Date : August 17, 2021
Actual Study Completion Date : August 17, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm B
Arm B will be comprised of two phases: (1) DRV/c once daily alone (days 1-4) and (2) DRV/c once daily + RPT and INH once weekly (days 5-19).
Drug: rifapentene (RPT)
RPT is a long-acting rifamycin used in combination with INH in the treatment of LTBI.

Drug: darunavir/cobicistat (DRV/c)
DRV is a protease inhibitor (PI) indicated in the treatment of HIV infection.33 DRV requires coadministration with RTV (100 mg once or twice daily) or COBI (150 mg daily), the latter of which has been coformulated into a fixed-dose tablet with DRV (DRV/c 800/150 mg).

Drug: Isoniazid (INH)
INH is an antimycobacterial agent that can be used alone or in combination with RPT for the treatment of LTBI. Given with Pyridoxine (vitamin B6)

Dietary Supplement: Pyridoxine



Primary Outcome Measures :
  1. Area-under-the-curve during the dosing interval of 0 to t (AUC0-t), maximum total plasma concentration (Cmax), time to maximum plasma concentration (t-max), terminal halflife (t1/2), apparent oral clearance (CL/F) [ Time Frame: Days 4 14, and 19 ]
    To assess the effects of once weekly administration of RPT and INH given at doses used for treating LTBI on the steady state PK of DRV/c


Secondary Outcome Measures :
  1. AEs and abnormal laboratory values graded according to the Division of AIDS AE Table, laboratory measures: hepatic & renal function, lipids, complete blood count, creatine kinase & lipase [ Time Frame: Day 34 ]
    To assess the safety of coadministration of DRV/c with once weekly RPT and INH through documentation of adverse events (AE) according to the Division of AIDS AE table



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

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

  1. Ages 18 - 65 years
  2. Weight greater than or equal to 45 kg and less than or equal to 120; BMI greater than or equal to 18.0 and <30
  3. Judged to be healthy based on medical history, physical examination, vital signs, and clinical laboratory tests (liver function tests (AST, ALT, Tbili) greater than or equal to upper limit of normal [ULN], serum creatinine (SCr) less than or equal to ULN, CK less than or equal to 2X ULN, platelets (PLT) >150,0000/mm3, hemoglobin (Hgb) >11 g/dL), C-reactive protein (CRP) less than or equal to ULN)
  4. Negative QuantiFERON-TB Gold test at screening
  5. HIV-negative, as determined by standard serologic assays for HIV infection.
  6. No laboratory evidence of active Hepatitis A, B, or C infection
  7. Willing to abstain from alcohol consumption throughout the study period
  8. Subject agrees to genetic testing and storage of specimens for future research
  9. Negative serum or urine pregnancy test for females of child-bearing potential
  10. For female subjects able to become pregnant (i.e., have not undergone surgical sterilization or are not postmenopausal), willingness to prevent pregnancy during the study period by:

    1. Practicing absolute abstinence from sexual contact or
    2. Committing to use of effective non-hormonal and/or barrier methods of birth control during any and all sexual encounters. Acceptable methods are as follows:

      • Condom, diaphragm, or cervical cap with a spermicide
      • Intrauterine device (IUD) without hormones
      • Male partner with a vasectomy

EXCLUSION CRITERIA:

A subject will be ineligible for this study if 1, or more, of the following criteria are met:

  1. Known hypersensitivity to dolutegravir, darunavir, cobicistat, rifapentine and other rifamycin analogues, or isoniazid
  2. History of type 1 hypersensitivity reaction to sulfonamides
  3. History or presence of any of the following:

    1. Latent or active TB infection
    2. Gastrointestinal disease that is uncontrolled, requires daily treatment with medication, or would interfere with a subject s ability to absorb drugs (diarrhea, pancreatitis, peptic ulcer disease, etc.),
    3. Renal impairment (chronic renal insufficiency of any CKD stage, or acute renal failure not induced by drug therapy defined as GFR < 90 ml/min)
    4. Respiratory disease that is uncontrolled or requires daily treatment with medication (asthma, chronic obstructive pulmonary disease, etc.)
    5. Cardiovascular disease (hypertension [systolic blood pressure >140 mmHg or diastolic blood pressure > 90 mmHg], heart failure, arrhythmia, etc.)
    6. Metabolic disorders (diabetes mellitus, etc.)
    7. Hematologic or bleeding disorders (anemia, hemophilia, serious/major bleeding events, menorrhagia (female subjects), etc.)
    8. Immunologic disorders
    9. Hormonal or endocrine disorders
    10. Psychiatric illness that would interfere with his or her ability to comply with study procedures or that requires daily treatment with medication
    11. Seizure disorder, with the exception of childhood febrile seizures
    12. Malignancy, or
    13. 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
  4. Fasting total cholesterol >240 mg/dL or fasting triglycerides >240 mg/dL on 2 consecutive visits
  5. Fasting glucose >125 mg/dL on 2 consecutive visits
  6. Current participation in an onging 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.
  7. 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 or over-the-counter medications, herbals, or holistic medications within the screening period prior to starting study drug may be permitted, and will be reviewed by investigators on a case-by-case basis for potential drug interactions. Receipt of influenza vaccination will be allowed prior to, during, and/or after the study
  8. Inability to obtain venous access for sample collection
  9. Inability to swallow whole capsules and/or tablets
  10. Current breastfeeding
  11. Drug or alcohol use that may impair safety or adherence
  12. Use of nicotine-containing products, including cigarettes and chewing tobacco, nicotine patches, gum, electronic cigarettes, etc.
  13. Organ or stem cell transplant recipient
  14. Uncorrected and persistent electrolyte abnormalities (e.g., potassium, magnesium, and calcium)
  15. Current alcohol abuse or alcohol dependence disorders (DSM-5 criteria)

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): NCT02771249


Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institutes of Health Clinical Center (CC)
Investigators
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Principal Investigator: Joseph A Kovacs, M.D. National Institutes of Health Clinical Center (CC)
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT02771249    
Other Study ID Numbers: 160112
16-CC-0112
First Posted: May 13, 2016    Key Record Dates
Last Update Posted: December 30, 2021
Last Verified: December 28, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC):
Fixed Sequence
Intrasubject Drug-Drug Interaction
Open-Label
Additional relevant MeSH terms:
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Tuberculosis
Latent Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Latent Infection
Pyridoxine
Darunavir
Cobicistat
Isoniazid
HIV Protease Inhibitors
Viral Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Antitubercular Agents
Anti-Bacterial Agents
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors