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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03332095

Enrollment

Registered

2017-11-06

Start date

2018-07-02

Completion date

2022-05-25

Last updated

2023-02-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Infections

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.

Interventions

DRUGDoravirine (DOR)

100 mg of DOR administered orally

DRUGDoravirine/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

DRUGAntiretroviral (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.

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

12 Years to 17 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1)	Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to infinity. Steady state AUC0-24 is equivalent to single dose AUC0-∞.
PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1)	Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA).
PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1)	Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA).
Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug	Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.	Percentage and Clopper-Pearson 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on 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 (see References).
Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug	Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.	Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) (see references).
Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug	Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.	Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug.
Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug	Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.	Percentage and Clopper-Pearson 95% CI of participants with Grade 5 AEs (death) regardless of relationship to study drug.

Secondary

Measure	Time frame	Description
PK Parameter: C24hr of 3TC (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
PK Parameter: C24hr of Tenofovir (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 24 (Cohort 2)	Measured at week 24.	Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>200 copies/mL; otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2)	Measured at week 48.	Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>200 copies/mL; otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2)	Measured at week 96.	Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>200 copies/mL; otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2)	Measured at week 24.	Virologic responses were assessed at week 24 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>50 copies/mL. Otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2)	Measured at week 48.	Virologic responses were assessed at week 48 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>50 copies/mL. Otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2)	Measured at week 96.	Virologic responses were assessed at week 96 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>50 copies/mL. Otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2)	Measured at week 24.	Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>40 copies/mL; Otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2)	Measured at week 48.	Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>40 copies/mL; Otherwise participants with missing values were excluded.
Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2)	Measured at week 96.	Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>40 copies/mL; Otherwise participants with missing values were excluded.
Summary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)	Measured at Day 0 and week 24.	The differences between log10 HIV RNA at Week 24 minus at Day 0 are summarized.
PK Parameter: AUC0-24hr of DOR (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
Summary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)	Measured at Day 0 and week 96.	The differences between log10 HIV RNA at Week 96 minus at Day 0 are summarized.
Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)	Measured at Day 0 and week 24.	The mean difference is calculated as CD4 count at Week 24 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.
Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)	Measured at Day 0 and week 48.	The mean differences is calculated as CD4 count at Week 48 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.
Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)	Measured at Day 0 and week 96.	The mean difference is calculated as CD4 count at Week 96 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.
Summary of Changes in CD4% From Baseline to Week 24 (Cohort 2)	Measured at Day 0 and week 24.	The mean difference is calculated as CD4% at Week 24 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI.
Summary of Changes in CD4% From Baseline to Week 48 (Cohort 2)	Measured at Day 0 and week 48.	The mean difference is calculated as CD4% at Week 48 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI.
Summary of Changes in CD4% From Baseline to Week 96 (Cohort 2)	Measured at Day 0 and week 96.	The mean difference is calculated as CD4% at Week 96 minus CD4% at the Day 0 with associated 95% Clopper-Pearson CI.
Percentage of Participants With Grade 3 or Higher Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study	Measured from Day 0 through Week 96.	Percentage and Clopper-Pearson 95% CI of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on 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 (DAIDS) AE Grading table corrected version 2.1 (see References).
Percentage of Participants With Serious Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study	Measured from Day 0 through Week 96.	Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) (see references).
Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study	Measured from Day 0 through Week 96.	Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug.
Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug (Cohort 2) Through End of Study	Measured from Day 0 through Week 96.	Percentage and Clopper-Pearson 95% CI of participants with Grade 5 adverse events (death).
Summary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)	Measured at Day 0 and week 48.	The differences between log10 HIV RNA at Week 48 minus at Day 0 are summarized.
PK Parameter: AUC0-24hr of 3TC (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
PK Parameter: AUC0-24hr of Tenofovir (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
PK Parameter: Cmax of DOR (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
PK Parameter: Cmax of 3TC (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
PK Parameter: Cmax of Tenofovir (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Cmax was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.
PK Parameter: C24hr of DOR (Cohort 2)	Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.	Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). C24hr was projected from individual plasma concentration-time profiles using the non-parametric superposition function in WinNonLin v6.3. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.

Countries

South Africa, Thailand, United States

Participant flow

Recruitment details

Participants were enrolled from July 2018 to February 2020. Participants were recruited from 8 medical clinics in the United States, Thailand and South Africa.

Pre-assignment details

There was no randomization. Enrollment started with Cohort 1, then Cohort 2 was open.

Participants by arm

Arm	Count
Cohort 1: DOR Participants received a single dose of DOR at study entry (Day 0). Doravirine (DOR): 100 mg of DOR administered orally 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 be provided by the study.	9
Cohort 2: DOR/3TC/TDF Participants received DOR/3TC/TDF from Day 0 through Week 96. 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	45
Total	54

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	0
Overall Study	Pregnancy	0	1

Baseline characteristics

Characteristic	Cohort 2: DOR/3TC/TDF	Cohort 1: DOR	Total
Age, Continuous	15.0 years STANDARD_DEVIATION 1.6	14.3 years STANDARD_DEVIATION 1.6	14.9 years STANDARD_DEVIATION 1.6
Baseline Plasma HIV-1 RNA (copies/mL) 0 - <40	43 Participants	9 Participants	52 Participants
Baseline Plasma HIV-1 RNA (copies/mL) 40 - <500,000	0 Participants	0 Participants	0 Participants
Baseline Plasma HIV-1 RNA (copies/mL) 500,000 - <1,000,000	2 Participants	0 Participants	2 Participants
CD4%	33.1 percent STANDARD_DEVIATION 9.1	36.2 percent STANDARD_DEVIATION 5.4	33.6 percent STANDARD_DEVIATION 8.6
CD4 Cell Count	717.8 cells/mm^3 STANDARD_DEVIATION 283.1	788.2 cells/mm^3 STANDARD_DEVIATION 203.9	729.7 cells/mm^3 STANDARD_DEVIATION 270.9
Class of Prior ARTs Integrase Strand Transfer Inhibitors (INSTI)	1 Participants	9 Participants	10 Participants
Class of Prior ARTs Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)	32 Participants	0 Participants	32 Participants
Class of Prior ARTs Not Applicable	2 Participants	0 Participants	2 Participants
Class of Prior ARTs Nucleoside Reverse Transcriptase Inhibitors (NRTI)	43 Participants	9 Participants	52 Participants
Class of Prior ARTs Protease Inhibitors (PI)	10 Participants	0 Participants	10 Participants
Duration of Prior ARTs	1882.3 days STANDARD_DEVIATION 1649.6	614.2 days STANDARD_DEVIATION 511.3	1662.8 days STANDARD_DEVIATION 1589.4
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	44 Participants	9 Participants	53 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
HIV-1 log10 RNA	1.8 log10 copies/mL STANDARD_DEVIATION 0.9	1.6 log10 copies/mL STANDARD_DEVIATION 0	1.7 log10 copies/mL STANDARD_DEVIATION 0.8
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	35 Participants	0 Participants	35 Participants
Race (NIH/OMB) Black or African American	10 Participants	7 Participants	17 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	0 Participants	2 Participants	2 Participants
Region Africa	9 Participants	0 Participants	9 Participants
Region Asia/Pacific	35 Participants	0 Participants	35 Participants
Region North America	1 Participants	9 Participants	10 Participants
Sex: Female, Male Female	26 Participants	2 Participants	28 Participants
Sex: Female, Male Male	19 Participants	7 Participants	26 Participants
Weight	53.8 kg STANDARD_DEVIATION 8	55.9 kg STANDARD_DEVIATION 15.8	54.1 kg STANDARD_DEVIATION 9.5
Weight Band (kg) 35 - <45 kg	0 Participants	1 Participants	1 Participants
Weight Band (kg) ≥ 45 kg	45 Participants	8 Participants	53 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 9	0 / 45
other Total, other adverse events	4 / 9	45 / 45
serious Total, serious adverse events	0 / 9	2 / 45

Outcome results

Primary

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug

Percentage and Clopper-Pearson 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on 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 (see References).

Time frame: Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.

Population: Study participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 1: DOR	Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug	0 percentage of participants
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug	0 percentage of participants

Primary

Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug

Percentage and Clopper-Pearson 95% CI of participants with Grade 5 AEs (death) regardless of relationship to study drug.

Time frame: Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.

Population: Study participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 1: DOR	Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug	0 percentage of participants
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug	0 percentage of participants

Primary

Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug

Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug.

Time frame: Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.

Population: Study Participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 1: DOR	Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug	0 percentage of participants
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug	0 percentage of participants

Primary

Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug

Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) (see references).

Time frame: Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.

Population: Study participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 1: DOR	Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug	0 percentage of participants
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug	0 percentage of participants

Primary

Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1)

Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to infinity. Steady state AUC0-24 is equivalent to single dose AUC0-∞.

Time frame: Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.

Population: Cohort 1 participants who received the study treatment.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1: DOR	Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1)	34.8 µM*hr	Geometric Coefficient of Variation 43.2

Primary

PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1)

Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA).

Time frame: Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.

Population: Cohort 1 participants who received the study treatment.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1: DOR	PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1)	514 nM	Geometric Coefficient of Variation 56.5

Primary

PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1)

Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA).

Time frame: Measured during the entry (day 0) visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 hours post-dose.

Population: Cohort 1 participants who received the study treatment.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Cohort 1: DOR	PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1)	2.14 µM	Geometric Coefficient of Variation 25.9

Secondary

Percentage of Participants With Grade 3 or Higher Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study

Percentage and Clopper-Pearson 95% CI of participants with Grade 3 or higher AEs judged by the medical clinic as related to the study drug. AEs were graded based on 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 (DAIDS) AE Grading table corrected version 2.1 (see References).

Time frame: Measured from Day 0 through Week 96.

Population: Study participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Grade 3 or Higher Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study	0 Percentage of participants

Secondary

Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug (Cohort 2) Through End of Study

Percentage and Clopper-Pearson 95% CI of participants with Grade 5 adverse events (death).

Time frame: Measured from Day 0 through Week 96.

Population: Study participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug (Cohort 2) Through End of Study	0 percentage of participants

Secondary

Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study

Percentage and Clopper-Pearson 95% CI of participants with permanent discontinuation of study drug due to AEs judged by the medical clinic as related to the study drug.

Time frame: Measured from Day 0 through Week 96.

Population: Study Participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study	0 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 24 (Cohort 2)

Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>200 copies/mL; otherwise participants with missing values were excluded.

Time frame: Measured at week 24.

Population: Cohort 2 participants who received at least one dose of study treatment. Participants who discontinued study for reasons other than virologic failure were excluded.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 24 (Cohort 2)	97.7 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2)

Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>200 copies/mL; otherwise participants with missing values were excluded.

Time frame: Measured at week 48.

Population: Cohort 2 participants who received at least one dose of study treatment. Participants who discontinued study for reasons other than virologic failure were excluded.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2)	97.7 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2)

Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>200 copies/mL; otherwise participants with missing values were excluded.

Time frame: Measured at week 96.

Population: Cohort 2 participants who received at least one dose of study treatment. Participants who discontinued study for reasons other than virologic failure were excluded.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2)	92.9 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2)

Virologic responses were assessed at week 24 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>40 copies/mL; Otherwise participants with missing values were excluded.

Time frame: Measured at week 24.

Population: Cohort 2 participants who received at least one dose of study treatment. Participants who discontinued study for reasons other than virologic failure were excluded. One participant whose sample was diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL was excluded.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2)	97.7 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2)

Virologic responses were assessed at week 48 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>40 copies/mL; Otherwise participants with missing values were excluded.

Time frame: Measured at week 48.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2)	97.6 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2)

Virologic responses were assessed at week 96 as percentage (%) of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>40 copies/mL; Otherwise participants with missing values were excluded.

Time frame: Measured at week 96.

Population: Cohort 2 participants who received at least one dose of study treatment. Participants who discontinued study for reasons other than virologic failure were excluded. Two participants whose sample was diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL were excluded.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2)	92.5 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2)

Virologic responses were assessed at week 24 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>50 copies/mL. Otherwise participants with missing values were excluded.

Time frame: Measured at week 24.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2)	97.7 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2)

Virologic responses were assessed at week 48 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>50 copies/mL. Otherwise participants with missing values were excluded.

Time frame: Measured at week 48.

Population: Cohort 2 participants who received at least one dose of study treatment. Participants who discontinued study for reasons other than virologic failure were excluded. Two participants whose sample was diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL were excluded.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2)	97.6 Percentage of participants

Secondary

Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2)

Virologic responses were assessed at week 96 as percentage of participants and Clopper-Pearson 95% CI. Missing values were considered as failures for participants with missing data due to discontinuation of study drug as a result of virologic failure or for non-treatment related reasons with last available RNA \>50 copies/mL. Otherwise participants with missing values were excluded.

Time frame: Measured at week 96.

Population: Cohort 2 participants who received at least one dose of study treatment. Participants who discontinued study for reasons other than virologic failure were excluded. Two participant whose sample was diluted due to low volume, resulting in increased assay limit of quantification from 40 to 200 copies/mL were excluded.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2)	92.5 Percentage of participants

Secondary

Percentage of Participants With Serious Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study

Percentage and Clopper-Pearson 95% CI of participants with SAEs judged by the medical clinic as related to the study drug. SAEs were reported according to version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) (see references).

Time frame: Measured from Day 0 through Week 96.

Population: Study participants who received at least one dose of study treatment were included.

Arm	Measure	Value (NUMBER)
Cohort 2: DOR/3TC/TDF	Percentage of Participants With Serious Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study	0 Percentage of participants

Secondary

PK Parameter: AUC0-24hr of 3TC (Cohort 2)

Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (WinNonlin, version 6.3, Pharsight Corp., Mountain View, CA). Area under the curve (AUC) was determined using non-compartmental analyses and estimated by the linear up/log down trapezoidal rule, from time zero to 24 hours. Intensive PK samples were collected for the first ten participants enrolled in Cohort 2.

Time frame: Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 1, 2, 4, 8, 12 and 24 hours post-dose.