Evaluating the Pharmacokinetics, Safety, and Tolerability of Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A) in HIV-1-Infected Children and Adolescents

NCT ID: NCT03332095

Last Updated: 2023-02-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-02
• Study Completion Date: 2022-05-25

Brief Summary

The purpose of this study was to evaluate the pharmacokinetics, safety, and tolerability of doravirine (also called MK-1439 or DOR) and doravirine/lamivudine/tenofovir disoproxil fumarate (also called MK-1439A or DOR/3TC/TDF) in HIV-1-infected children and adolescents.

Detailed Description

This study evaluated the pharmacokinetics (PK), safety, and tolerability of DOR and DOR/3TC/TDF in HIV-1-infected children and adolescents.

This study was conducted in two cohorts: Cohort 1 and Cohort 2. At study entry (Day 0), participants in Cohort 1 received a single dose of DOR added to their current HIV regimens. (The antiretroviral drugs in their current HIV regimens were not be provided by the study.) Participants in Cohort 1 underwent intensive PK evaluations, and had an additional study visit at Week 2.

The study team in consultation with a Study Monitoring Committee evaluated data from Cohort 1 before enrolling participants in Cohort 2. Participants in Cohort 2 received DOR/3TC/TDF once daily from Day 0 through Week 96. They had study visits at Weeks 1, 2, 4, 8, 12, 16, 24, 36, 48, 64, 80, and 96. Study visits included physical examinations, PK evaluations, and blood and urine collection.

Conditions

HIV Infections

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1: DOR

Participants received a single dose of DOR at study entry (Day 0).

Group Type: EXPERIMENTAL

Doravirine (DOR)

Intervention Type: DRUG

100 mg of DOR administered orally

Antiretroviral (ARV) medications

Intervention Type: DRUG

Participants in Cohort 1 received a combination of dolutegravir (DTG) or raltegravir (RAL) plus two nucleoside reverse transcriptase inhibitors (NRTIs). The ARV drugs were prescribed by participants' own health care providers and were not provided by the study.

Cohort 2: DOR/3TC/TDF

Participants received DOR/3TC/TDF from Day 0 through Week 96.

Group Type: EXPERIMENTAL

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)

Intervention Type: DRUG

DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily

Interventions

Doravirine (DOR)

100 mg of DOR administered orally

Intervention Type: DRUG

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)

DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily

Intervention Type: DRUG

Antiretroviral (ARV) medications

Participants in Cohort 1 received a combination of dolutegravir (DTG) or raltegravir (RAL) plus two nucleoside reverse transcriptase inhibitors (NRTIs). The ARV drugs were prescribed by participants' own health care providers and were not provided by the study.

Intervention Type: DRUG

Other Intervention Names

MK-1439; MK-1439A; ARVs

Eligibility Criteria

Inclusion Criteria

• Weight greater than or equal 35 kg at entry
• If not of legal age to provide independent informed consent: Parent or guardian was willing and able to provide written informed consent for study participation; in addition, when applicable per local Institutional Review Board / Ethics Committee (IRB/EC) policies and procedures, potential participant was willing and able to provide written informed assent for study participation. If of legal age to provide independent informed consent as determined by site Standard Operating Procedures (SOPs) and consistent with site IRB/EC policies and procedures: Potential participant was willing and able to provide written informed consent for study participation
• Confirmed HIV-1-infection based on documented testing of two samples collected at different time points. More information on this criterion can be found in the protocol.
• Antiretroviral therapy (ART) exposure, virologic suppression, and resistance requirements, as follows:

Cohort 1

• ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records:
• At entry, receiving combination ART with raltegravir (RAL) or dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs); AND
• At entry, had not received non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitor (PIs), or cobicistat within the previous 30 days; AND
• Virologic suppression, as documented in medical records and as defined by:
• One or more HIV RNA polymerase chain reaction (PCR) result below the level of quantification (BLLQ) within 15 months prior to enrollment, AND
• If any HIV RNA PCR tests had been done within 3 months prior to enrollment, all results were below the level of quantification, AND
• HIV RNA PCR result less than 40 copies/mL at screening, performed as per the protocol.

Cohort 2 ART-naive

• ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records:
• At entry, received no antiretrovirals (ARVs) for treatment of HIV infection including investigational agents (prior receipt of ARVs for prevention of perinatal transmission was permitted); AND
• Screening genotypic resistance test results indicated susceptibility to doravirine (DOR), tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) (see the protocol for more information; result must be available prior to enrollment), performed as per the protocol; AND
• If available, as documented in medical records, any prior genotypic resistance test result indicated susceptibility to DOR, TDF, and 3TC (see the protocol for more information).

Note: For individuals that were re-screened, the genotypic resistance test did not need to be repeated.

Cohort 2 ART-experienced

• ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records:
• No previous history of change in ARVs due to clinical or virologic failure, in the opinion of the site investigator or designee; AND
• Virologic suppression, as documented in medical record and as defined by:
• One or more HIV RNA PCR result BLLQ within 15 months prior to enrollment, AND
• If any HIV RNA PCR tests had been done within 3 months prior to enrollment, all results were below the level of quantification, AND
• HIV RNA PCR result less than 40 copies/mL at screening (see the protocol for more information); AND
• If available, as documented in medical records, any prior genotypic resistance test result indicated susceptibility to DOR, TDF, and 3TC (see the protocol for more information).

Note: This group of ARV-experienced, virologically suppressed participants were only enrolled once there was data from the adult switch studies indicating virologic efficacy and safety (see the protocol for more information). Sites were informed via a Clarification Memorandum when ART-experienced participants could be enrolled. A single, unconfirmed HIV-1 RNA result greater than or equal to the level of quantification but less than 500 copies/mL, between 3 and 15 months, prior to enrollment was not exclusionary as long as the other criteria for documentation of virologic suppression were met.

• Grade 2 or lower hemoglobin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase, and lipase on specimens obtained at screening
• For Cohort 2 only, grade 2 or lower creatinine, proteinuria, and glycosuria on specimens obtained at screening
• Estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m^2, on specimens obtained at screening, based on the Schwartz equation. More information on this criterion can be found in the protocol.
• For females who had reached menarche or who were engaging in sexual activity (self-reported), negative pregnancy test at entry
• For females engaging in sexual activity that could lead to pregnancy (self-reported), agreed to use two effective, medically accepted birth control methods while on study and for two weeks after permanently discontinuing study drug
• For males engaging in sexual activity that could lead to pregnancy (self-reported), agreed to use condoms while on study and for two weeks after permanently discontinuing study drug
• Able and willing to swallow available formulation(s) (tablet or, as available, oral granules).

Exclusion Criteria

• Evidence of decompensated liver disease manifested by the presence of or a history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy, or other signs or symptoms of advanced liver diseases.

Note: Individuals with chronic hepatitis B who had grade 2 or lower ALT and AST and had no significant impairment of hepatic synthetic function (significant impairment of hepatic synthetic function was defined as a serum albumin less than 2.8 mg/dL or an international normalized ratio (INR) greater than 1.7 in the absence of another explanation for the abnormal laboratory value) were eligible.

• For Cohort 2 only, detectable hepatitis C virus (HCV) by RNA PCR or current or planned treatment with direct antiviral agent for HCV.

Note: HCV antibody positivity but undetectable by HCV RNA PCR results were permitted.

• Presence of any active AIDS-defining opportunistic infection
• History of malignancy (ever), with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin
• Clinical evidence of pancreatitis, as determined by the clinician (at entry)
• Use of nafcillin, dicloxacillin, or any of the prohibited medications, within 30 days prior to study entry (see the protocol for a complete list of prohibited medications)
• For females, currently breastfeeding an infant at entry
• Enrolled in another clinical trial of an investigational agent, device, or vaccine
• Unlikely to adhere to the study procedures or keep appointments, in the opinion of the site investigator or designee
• Used, or anticipates using, chronic systemic immunosuppressive agents or systemic interferon (e.g., for treatment of HCV infection) within 30 days prior to study entry.

Note: Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (less than or equal to 30 days) were permitted. See the protocol for a complete list of prohibited medications.

• Diagnosed with current active tuberculosis and/or was currently being treated with a rifampicin-containing regimen
• Individual had any other condition, that in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ann Melvin, MD, MPH

Role: STUDY_CHAIR

University of Washington, Seattle Children's Research Institute

Locations

Univ. of Colorado Denver NICHD CRS

Aurora, Colorado, United States

Boston Medical Center Ped. HIV Program NICHD CRS

Boston, Massachusetts, United States

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, United States

Seattle Children's Research Institute CRS

Seattle, Washington, United States

Soweto IMPAACT CRS

Johannesburg, Gauteng, South Africa

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, Thailand

Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Mai, , Thailand

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, , Thailand

Countries

United States; South Africa; Thailand

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Related Links

http://impaactnetwork.org/studies/IMPAACT2014

Link to the IMPAACT 2014 study web page

https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables

The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017

http://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-daids

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Other Identifiers

34150

Identifier Type: REGISTRY

Identifier Source: secondary_id

IMPAACT 2014

Identifier Type: -

Identifier Source: org_study_id