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Doravirine, Rifapentine and Isoniazid Interaction (DORIIS)

Primary Purpose

Latent Tuberculosis, Human Immunodeficiency Virus, Rifamycins Causing Adverse Effects in Therapeutic Use

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Doravirine (DOR)

Rifapentine (RPT)

Isoniazid (INH)

About this trial

This is an interventional treatment trial for Latent Tuberculosis focused on measuring Drug-drug interaction, Pharmacokinetics, Non-nucleoside reverse transcriptase inhibitor, NNRTI, LTBI, Antimycobacterial

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Healthy male or female between 18-60 years old at the time of screening.
Have a Body Mass Index (BMI) > 19 and < 33.
Weigh > 45 kg but < 120 kg.
Non-smoker (tobacco or electronic cigarettes).
Negative QuantiFERON-TB Gold at screening.
Subjects who agree to abstain from alcohol consumption throughout the duration of the study.
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.
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:

History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, dermatologic, psychiatric abnormalities or neurological (including stroke and chronic seizure) diseases.
>500 mL blood or plasma donation in the 6 weeks prior to study start
Known anaphylactic or severe systemic reactions to any components of doravirine, rifapentine, isoniazid or pyridoxine.
Positive HIV, Hepatitis B or Hepatitis C virus. Evidence of prior Hepatitis B infection and immunity is not exclusionary.
Latent or active tuberculosis infection. Documented prior fully treated latent tuberculosis is not exclusionary.
Females who are postpartum < 12 months.
Current drug or alcohol abuse.
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.
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.
Any clinical significant findings on lab, ECG or physical exam at screening.

Sites / Locations

Thomas Jefferson University Clinical Research Unit

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental

Arm Description

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)

Outcomes

Primary Outcome Measures

Doravirine Maximum Concentration (Cmax)

Doravirine maximum observed concentration during the dosing interval

Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12)

Doravirine area under the plasma-concentration time curve derived from plasma sampling during one dosing interval

Doravirine Oral Clearance (CL/F)

Doravirine apparent oral clearance derived from plasma sampling

Secondary Outcome Measures

Adverse Event

Safety and tolerability

Full Information

NCT ID

NCT03886701

First Posted

March 12, 2019

Last Updated

March 16, 2020

Sponsor

Walter K. Kraft

Collaborators

Merck Sharp & Dohme LLC

1. Study Identification

Unique Protocol Identification Number

NCT03886701

Brief Title

Doravirine, Rifapentine and Isoniazid Interaction

Acronym

DORIIS

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2020

Overall Recruitment Status

Completed

Study Start Date

April 22, 2019 (Actual)

Primary Completion Date

May 20, 2019 (Actual)

Study Completion Date

May 20, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Walter K. Kraft

Collaborators

Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Latent Tuberculosis, Human Immunodeficiency Virus, Rifamycins Causing Adverse Effects in Therapeutic Use, Drug Interaction Potentiation

Keywords

Drug-drug interaction, Pharmacokinetics, Non-nucleoside reverse transcriptase inhibitor, NNRTI, LTBI, Antimycobacterial

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Experimental

Arm Type

Experimental

Arm Description

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)

Intervention Type

Drug

Intervention Name(s)

Doravirine (DOR)

Other Intervention Name(s)

Pifeltro

Intervention Description

Non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection in adults in combination with other antiretroviral agents.

Intervention Type

Drug

Intervention Name(s)

Rifapentine (RPT)

Other Intervention Name(s)

Priftin

Intervention Description

Rifamycin anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.

Intervention Type

Drug

Intervention Name(s)

Isoniazid (INH)

Other Intervention Name(s)

Generic (various)

Intervention Description

Anti-tuberculosis agent indicated for the treatment of latent and active tuberculosis infection.

Primary Outcome Measure Information:

Title

Doravirine Maximum Concentration (Cmax)

Description

Doravirine maximum observed concentration during the dosing interval

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

Title

Doravirine Area Under the Plasma Concentration Versus Time Curve From 0 to 12 Hours (AUC0-12)

Description

Doravirine area under the plasma-concentration time curve derived from plasma sampling during one dosing interval

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

Title

Doravirine Oral Clearance (CL/F)

Description

Doravirine apparent oral clearance derived from plasma sampling

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

Secondary Outcome Measure Information:

Title

Adverse Event

Description

Safety and tolerability

Time Frame

Days 1-24 post-dose (period 1 and 2) and 31-34 post-dose (post-study)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Healthy male or female between 18-60 years old at the time of screening. Have a Body Mass Index (BMI) > 19 and < 33. Weigh > 45 kg but < 120 kg. Non-smoker (tobacco or electronic cigarettes). Negative QuantiFERON-TB Gold at screening. Subjects who agree to abstain from alcohol consumption throughout the duration of the study. 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. 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: History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, dermatologic, psychiatric abnormalities or neurological (including stroke and chronic seizure) diseases. >500 mL blood or plasma donation in the 6 weeks prior to study start Known anaphylactic or severe systemic reactions to any components of doravirine, rifapentine, isoniazid or pyridoxine. Positive HIV, Hepatitis B or Hepatitis C virus. Evidence of prior Hepatitis B infection and immunity is not exclusionary. Latent or active tuberculosis infection. Documented prior fully treated latent tuberculosis is not exclusionary. Females who are postpartum < 12 months. Current drug or alcohol abuse. 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. 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. Any clinical significant findings on lab, ECG or physical exam at screening.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Walter K Kraft, MD

Organizational Affiliation

Sidney Kimmel Medical College at Thomas Jefferson University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Thomas Jefferson University Clinical Research Unit

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19107

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Doravirine, Rifapentine and Isoniazid Interaction

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