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

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

Sponsors

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Source National Institute of Allergy and Infectious Diseases (NIAID)
Brief Summary

The purpose of this study is 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 will evaluate the pharmacokinetics (PK), safety, and tolerability of DOR and DOR/3TC/TDF in HIV-1-infected children and adolescents. This study will be conducted in two cohorts: Cohort 1 and Cohort 2. At study entry (Day 0), participants in Cohort 1 will receive a single dose of DOR added to their current HIV regimens. (The antiretroviral drugs in their current HIV regimens will not be provided by the study.) Participants in Cohort 1 will undergo intensive PK evaluations, and they will have an additional study visit at Week 2. The study team in consultation with a Study Monitoring Committee will evaluate data from Cohort 1 before enrolling participants in Cohort 2. Participants in Cohort 2 will receive DOR/3TC/TDF once daily from Day 0 through Week 96. They will attend study visits at Weeks 1, 2, 4, 8, 12, 16, 24, 36, 48, 64, 80, and 96. Study visits will include physical examinations, PK evaluations, and blood and urine collection.

Overall Status Active, not recruiting
Start Date 2018-03-21
Completion Date 2021-12-29
Primary Completion Date 2020-08-19
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Single-dose AUC0-∞ of doravirine (DOR) (Cohort 1) Measured through 72-hours post-dose
Single-dose Cmax of DOR (Cohort 1) Measured through 72-hours post-dose
Single-dose C24hr of DOR (Cohort 1) Measured through 72-hours post-dose
Frequency of all adverse events, regardless of severity grade (Cohort 1) Measured through Week 2
Frequency of Grade 3 or higher adverse events assessed as related to study drug (Cohort 1) Measured through Week 2
Frequency of serious adverse events assessed as related to study drug (Cohort 1) Measured through Week 2
Frequency of permanent discontinuation of study drug due to adverse events assessed as related to study drug (Cohort 1) Measured through Week 2
Frequency of Grade 5 adverse events (death) regardless of relationship to study drug (Cohort 1) Measured through Week 2
Frequency of all adverse events, regardless of severity grade (Cohort 2) Measured through Week 24
Frequency of Grade 3 or higher adverse events assessed as related to study drug (Cohort 2) Measured through Week 24
Frequency of serious adverse events assessed as related to study drug (Cohort 2) Measured through Week 24
Frequency of permanent discontinuation of study drug due to adverse events assessed as related to study drug (Cohort 2) Measured through Week 24
Frequency of Grade 5 adverse events (death) regardless of relationship to study drug (Cohort 2) Measured through Week 24
Secondary Outcome
Measure Time Frame
AUC0-24hr of DOR, 3TC, tenofovir (Cohort 2) Measured at Week 1
Cmax of DOR, 3TC, tenofovir (Cohort 2) Measured at Week 1
C24hr of DOR, 3TC, tenofovir (Cohort 2) Measured at Week 1
Frequency of plasma HIV-1 RNA less than 200 copies/mL (Cohort 2) Measured through Week 96
Frequency of plasma HIV-1 RNA less than 50 copies/mL (Cohort 2) Measured through Week 96
Frequency of plasma HIV-1 RNA less than 40 copies/mL (Cohort 2) Measured through Week 96
Summary of log10 drop from baseline in plasma HIV-1 RNA (ART-naive participants) (Cohort 2) Measured through Week 96
Summary of changes in CD4 count from baseline (Cohort 2) Measured through Week 96
Summary of changes in CD4 percent from baseline (Cohort 2) Measured through Week 96
Frequency of all adverse events, regardless of severity grade (Cohort 2) Measured through Week 96
Frequency of Grade 3 or higher adverse events assessed as related to study drug (Cohort 2) Measured through Week 96
Frequency of serious adverse events assessed as related to study drug (Cohort 2) Measured through Week 96
Frequency of permanent discontinuation of study drug due to adverse events assessed as related to study drug (Cohort 2) Measured through Week 96
Frequency of Grade 5 adverse events (death) regardless of relationship to study drug (Cohort 2) Measured through Week 96
Enrollment 55
Condition
Intervention

Intervention Type: Drug

Intervention Name: Doravirine (DOR)

Description: 100 mg of DOR administered orally

Arm Group Label: Cohort 1: DOR

Other Name: MK-1439

Intervention Type: Drug

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

Description: DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg, or as oral granules provided in three capsules that each contain 33.6 mg/100 mg/100 mg) once daily

Arm Group Label: Cohort 2: DOR/3TC/TDF

Other Name: MK-1439A

Intervention Type: Drug

Intervention Name: Antiretroviral (ARV) medications

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

Arm Group Label: Cohort 1: DOR

Eligibility

Criteria:

Inclusion Criteria: - Age 12 years to less than 18 years at entry - Weight greater than or equal 35 kg at entry - If not of legal age to provide independent informed consent: Parent or guardian is 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 is 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 is 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, has 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 have been done within 3 months prior to enrollment, all results are below the level of quantification, AND - HIV RNA PCR result less than 40 copies/mL at screening, performed as per the protocol. Note: 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 is not exclusionary as long as the other criteria for documentation of virologic suppression are met. - 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 is permitted); - AND - Screening genotypic resistance test results indicate 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 indicates susceptibility to DOR, TDF, and 3TC (see the protocol for more information). Note: For individuals that are re-screened, the genotypic resistance test does 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 have been done within 3 months prior to enrollment, all results are 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 indicates susceptibility to DOR, TDF, and 3TC (see the protocol for more information). Note: This group of ARV-experienced, virologically suppressed participants will only enroll once there are data from the adult switch studies indicating virologic efficacy and safety (see the protocol for more information). Sites will be informed via a Clarification Memorandum when ART-experienced participants can be enrolled. Note: 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 is not exclusionary as long as the other criteria for documentation of virologic suppression are 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 have reached menarche or who are engaging in sexual activity (self-reported), negative pregnancy test at entry - For females engaging in sexual activity that could lead to pregnancy (self-reported), agrees 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), agrees 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). Note: The study is expected open to accrual with only the tablet formulation available. Sites will be informed when the oral granule formulation is available for participant use. Once the granule formulation is available, participants in Cohort 2 will be asked to choose which formulation they would like to take at Entry. Formulation switches during the study may be allowed, as described in the protocol. 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 have grade 2 or lower ALT and AST and have no significant impairment of hepatic synthetic function (significant impairment of hepatic synthetic function is 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) are 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 are 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) are permitted. See the protocol for a complete list of prohibited medications. - Diagnosed with current active tuberculosis and/or is currently being treated with a rifampicin-containing regimen - Individual has 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

Gender:

All

Minimum Age:

12 Years

Maximum Age:

17 Years

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Ann Melvin, MD, MPH Study Chair University of Washington, Seattle Children's Research Institute
Location
Facility:
Univ. of Colorado Denver NICHD CRS | Aurora, Colorado, 80045, United States
Boston Medical Center Ped. HIV Program NICHD CRS | Boston, Massachusetts, 02118, United States
St. Jude Children's Research Hospital CRS | Memphis, Tennessee, 38105-3678, United States
Seattle Children's Research Institute CRS | Seattle, Washington, 98101, United States
Soweto IMPAACT CRS | Johannesburg, Gauteng, 1862, South Africa
Siriraj Hospital ,Mahidol University NICHD CRS | Bangkok, Bangkoknoi, 10700, Thailand
Chiangrai Prachanukroh Hospital NICHD CRS | Chiang Mai, 50100, Thailand
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS | Chiang Mai, 50200, Thailand
Location Countries

South Africa

Thailand

United States

Verification Date

2020-08-01

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Cohort 1: DOR

Type: Experimental

Description: Participants will receive a single dose of DOR at study entry (Day 0).

Label: Cohort 2: DOR/3TC/TDF

Type: Experimental

Description: Participants will receive DOR/3TC/TDF from Day 0 through Week 96.

Study Design Info

Allocation: Non-Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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