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Doravirine, Rifapentine and Isoniazid Interaction (DORIIS)

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. Identifier: NCT03886701
Recruitment Status : Completed
First Posted : March 22, 2019
Results First Posted : March 3, 2020
Last Update Posted : March 27, 2020
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Walter K. Kraft, Thomas Jefferson University

Brief Summary:
Drug therapy for persons living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) co-infected with latent tuberculosis infection (LTBI) is complex. Anti-tuberculosis drugs used to treat LTBI often induce drug metabolizing enzymes that share the same metabolic pathway as antiretroviral drugs used for those living with HIV/AIDS. This study evaluates the drug-drug interaction (DDI) potential of an antiretroviral drug when co-administered with a common anti-tuberculosis regimen of drugs.

Condition or disease Intervention/treatment Phase
Latent Tuberculosis Human Immunodeficiency Virus Rifamycins Causing Adverse Effects in Therapeutic Use Drug Interaction Potentiation Drug: Doravirine (DOR) Drug: Rifapentine (RPT) Drug: Isoniazid (INH) Phase 1

Detailed Description:

Rifapentine (RPT) and isoniazid (INH) given once weekly for 12 weeks is commonly used for treating LTBI in adults. For people living with HIV-1, the risks of LTBI is increased. Individuals living with HIV-1 are often on chronic antiretroviral drugs that prevent immunodeficiency and complications associated with infection. Unfortunately, antiretroviral drugs are subject to many DDIs especially with RPT which induces drug clearing enzymes.

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. Because RPT induces the metabolic pathway in which DOR is removed, there is concern that taking both concomitantly will result in an unwanted DDI leading to reduced DOR concentrations in the blood. Reduced levels will result in loss of efficacy for the drug and therefore not provide adequate viral suppression in those living with HIV. This study investigates the DDI potential of the once weekly regimen RPT and INH together with DOR in healthy volunteers.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Fixed-Sequence, Drug Interaction Study to Investigate the Effect of Once-Weekly Rifapentine and Isoniazid on the Pharmacokinetics of Steady-State Doravirine
Actual Study Start Date : April 22, 2019
Actual Primary Completion Date : May 20, 2019
Actual Study Completion Date : May 20, 2019

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Experimental
Period 1: DOR twice-daily alone (Study days 1-4) and Period 2: DOR twice-daily with RPT and INH once-weekly (Study days 7-21)
Drug: Doravirine (DOR)
Non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection in adults in combination with other antiretroviral agents.
Other Name: Pifeltro

Drug: Rifapentine (RPT)
Rifamycin anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.
Other Name: Priftin

Drug: Isoniazid (INH)
Anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.
Other Name: Generic (various)

Primary Outcome Measures :
  1. Doravirine Maximum Concentration (Cmax) [ Time Frame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose ]
    Doravirine maximum observed concentration during the dosing interval

  2. Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12) [ Time Frame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose ]
    Doravirine area under the plasma-concentration time curve derived from plasma sampling during one dosing interval

  3. Doravirine Oral Clearance (CL/F) [ Time Frame: Day 4 and 21 (Period 1 and 2): 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose ]
    Doravirine apparent oral clearance derived from plasma sampling

Secondary Outcome Measures :
  1. Adverse Event [ Time Frame: Days 1-24 post-dose (period 1 and 2) and 31-34 post-dose (post-study) ]
    Safety and tolerability

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  1. Healthy male or female between 18-60 years old at the time of screening.
  2. Have a Body Mass Index (BMI) > 19 and < 33.
  3. Weigh > 45 kg but < 120 kg.
  4. Non-smoker (tobacco or electronic cigarettes).
  5. Negative QuantiFERON-TB Gold at screening.
  6. Subjects who agree to abstain from alcohol consumption throughout the duration of the study.
  7. Female subjects of childbearing potential must demonstrate a urine beta-hCG consistent with non-pregnancy at the time of the screening visit and agree to the use (and/or have their partner use) of an acceptable method of birth-control at initial screening, during the time of the trial and until two weeks after the last dose of drug following the last treatment period.
  8. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.

Exclusion Criteria:

  1. History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, dermatologic, psychiatric abnormalities or neurological (including stroke and chronic seizure) diseases.
  2. >500 mL blood or plasma donation in the 6 weeks prior to study start
  3. Known anaphylactic or severe systemic reactions to any components of doravirine, rifapentine, isoniazid or pyridoxine.
  4. Positive HIV, Hepatitis B or Hepatitis C virus. Evidence of prior Hepatitis B infection and immunity is not exclusionary.
  5. Latent or active tuberculosis infection. Documented prior fully treated latent tuberculosis is not exclusionary.
  6. Females who are postpartum < 12 months.
  7. Current drug or alcohol abuse.
  8. Received study drug in another study within 4 weeks or within 5 half-lives, which ever occurring first, before first anticipated dose of study drug in this study.
  9. Unable to refrain from use of over-the-counter, prescription (unless determined appropriate by the investigator), herbal or natural products, vitamins or supplements, or grapefruit juice/grapefruit products.
  10. Any clinical significant findings on lab, ECG or physical exam at screening.

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 identifier (NCT number): NCT03886701

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United States, Pennsylvania
Thomas Jefferson University Clinical Research Unit
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
Walter K. Kraft
Merck Sharp & Dohme Corp.
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Principal Investigator: Walter K Kraft, MD Sidney Kimmel Medical College at Thomas Jefferson University
  Study Documents (Full-Text)

Documents provided by Walter K. Kraft, Thomas Jefferson University:
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Responsible Party: Walter K. Kraft, Principal Investigator, Thomas Jefferson University Identifier: NCT03886701    
Other Study ID Numbers: 12690
First Posted: March 22, 2019    Key Record Dates
Results First Posted: March 3, 2020
Last Update Posted: March 27, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Walter K. Kraft, Thomas Jefferson University:
Drug-drug interaction
Non-nucleoside reverse transcriptase inhibitor
Additional relevant MeSH terms:
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Acquired Immunodeficiency Syndrome
HIV Infections
Latent Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Immunologic Deficiency Syndromes
Immune System Diseases
Blood-Borne Infections
Communicable Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Slow Virus Diseases
Latent Infection
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents