CompletedNCT03332095Updated Feb 14, 2023Results posted

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

A Phase 1/2 interventional study of Doravirine (DOR) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) in HIV Infections, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 8 sites in 3 countries. Open to participants aged 12 Years to 17 Years. Per ClinicalTrials.gov, last updated 2023-02-14.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 1/2, Interventional, and Treatment

Phase: Phase 1/2
Study type: Interventional
Enrollment: 55
Allocation: Non-randomized
Ages: 12 Years to 17 Years
Sex: All

Study 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.

Read the 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 studied

HIV Infections

Browse trials for

HIV Infections 4,256

Who can participate

Ages eligible: 12 Years to 17 Years
Sexes eligible: All
Accepts healthy volunteers: No

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

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

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 55 participants (actual)

Study arms

Experimental
Cohort 1: DOR
Participants received a single dose of DOR at study entry (Day 0).
Drug: Doravirine (DOR) · Drug: Antiretroviral (ARV) medications
Experimental
Cohort 2: DOR/3TC/TDF
Participants received DOR/3TC/TDF from Day 0 through Week 96.
Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)

Interventions

DrugDoravirine (DOR)
100 mg of DOR administered orally
Also known as: MK-1439
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
Also known as: MK-1439A
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.
Also known as: ARVs

What researchers measure

Primary outcomes

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.
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.
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.
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.
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.
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.
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.

Secondary outcomes

PK Parameter: AUC0-24hr of DOR (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 2, 4, 12 and 24 hours post-dose.
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.
PK Parameter: AUC0-24hr of Tenofovir (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.
PK Parameter: Cmax of DOR (Cohort 2)
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.
Time frame: Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.
PK Parameter: Cmax 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). 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.
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.
PK Parameter: Cmax of Tenofovir (Cohort 2)
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.
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.
PK Parameter: C24hr of DOR (Cohort 2)
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.
Time frame: Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.
PK Parameter: C24hr 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). 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.
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.
PK Parameter: C24hr of Tenofovir (Cohort 2)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Summary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
The differences between log10 HIV RNA at Week 24 minus at Day 0 are summarized.
Time frame: Measured at Day 0 and week 24.
Summary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
The differences between log10 HIV RNA at Week 48 minus at Day 0 are summarized.
Time frame: Measured at Day 0 and week 48.
Summary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
The differences between log10 HIV RNA at Week 96 minus at Day 0 are summarized.
Time frame: Measured at Day 0 and week 96.
Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)
The mean difference is calculated as CD4 count at Week 24 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.
Time frame: Measured at Day 0 and week 24.
Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)
The mean differences is calculated as CD4 count at Week 48 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.
Time frame: Measured at Day 0 and week 48.
Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)
The mean difference is calculated as CD4 count at Week 96 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.
Time frame: Measured at Day 0 and week 96.
Summary of Changes in CD4% From Baseline to Week 24 (Cohort 2)
The mean difference is calculated as CD4% at Week 24 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI.
Time frame: Measured at Day 0 and week 24.
Summary of Changes in CD4% From Baseline to Week 48 (Cohort 2)
The mean difference is calculated as CD4% at Week 48 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI.
Time frame: Measured at Day 0 and week 48.
Summary of Changes in CD4% From Baseline to Week 96 (Cohort 2)
The mean difference is calculated as CD4% at Week 96 minus CD4% at the Day 0 with associated 95% Clopper-Pearson CI.
Time frame: Measured at Day 0 and week 96.
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.
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.
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.
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.

Results

Posted Dec 2, 2021

Participant flow

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

Participant flow — Overall Study
Milestone	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Started	10	45
Received at least one dose of study treatment	9	45
Completed	9	44
Not completed	1	1
Withdrew: Lost to follow-up	1	0
Withdrew: Pregnancy	0	1

Outcome measures

PrimaryPharmacokinetic (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.
Reported as:: Geometric mean · µM*hr

Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1)
µM*hr	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1)	34.8 ± 43.2	—

PrimaryPK 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.
Reported as:: Geometric mean · µM

PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1)
µM	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: Single-dose Maximum Concentration (Cmax) of DOR (Cohort 1)	2.14 ± 25.9	—

PrimaryPK 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.
Reported as:: Geometric mean · nM

PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1)
nM	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: Single-dose 24 Hour-concentration (C24hr) of DOR (Cohort 1)	514 ± 56.5	—

PrimaryPercentage 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.
Reported as:: Number · percentage of participants

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug
percentage of participants	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug	0 (0 to 33.6)	0 (0 to 7.9)

PrimaryPercentage 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.
Reported as:: Number · percentage of participants

Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug
percentage of participants	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Percentage of Participants With Serious Adverse Events (SAEs) Assessed as Related to Study Drug	0 (0 to 33.6)	0 (0 to 7.9)

PrimaryPercentage 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.
Reported as:: Number · percentage of participants

Percentage of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events Assessed as Related to Study Drug
percentage of participants	Cohort 1: DOR	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 (0 to 33.6)	0 (0 to 7.9)

PrimaryPercentage 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.
Reported as:: Number · percentage of participants

Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug
percentage of participants	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug	0 (0 to 33.6)	0 (0 to 7.9)

SecondaryPK Parameter: AUC0-24hr of DOR (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 2, 4, 12 and 24 hours post-dose.
Reported as:: Geometric mean · µM*hr

PK Parameter: AUC0-24hr of DOR (Cohort 2)
µM*hr	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: AUC0-24hr of DOR (Cohort 2)	—	22.9 ± 47.0

SecondaryPK Parameter: AUC0-24hr of 3TC (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.
Reported as:: Geometric mean · h.ng/mL

PK Parameter: AUC0-24hr of 3TC (Cohort 2)
h.ng/mL	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: AUC0-24hr of 3TC (Cohort 2)	—	11300 ± 27.9

SecondaryPK Parameter: AUC0-24hr of Tenofovir (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.
Reported as:: Geometric mean · h.ng/mL

PK Parameter: AUC0-24hr of Tenofovir (Cohort 2)
h.ng/mL	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: AUC0-24hr of Tenofovir (Cohort 2)	—	2550 ± 14.3

SecondaryPK Parameter: Cmax of DOR (Cohort 2)

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.

Time frame:: Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.
Reported as:: Geometric mean · µM

PK Parameter: Cmax of DOR (Cohort 2)
µM	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: Cmax of DOR (Cohort 2)	—	2.13 ± 42.7

SecondaryPK Parameter: Cmax 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). 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.

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.
Reported as:: Geometric mean · ng/mL

PK Parameter: Cmax of 3TC (Cohort 2)
ng/mL	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: Cmax of 3TC (Cohort 2)	—	2100 ± 23.6

SecondaryPK Parameter: Cmax of Tenofovir (Cohort 2)

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.

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.
Reported as:: Geometric mean · ng/mL

PK Parameter: Cmax of Tenofovir (Cohort 2)
ng/mL	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: Cmax of Tenofovir (Cohort 2)	—	293 ± 36.6

SecondaryPK Parameter: C24hr of DOR (Cohort 2)

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.

Time frame:: Measured at Week 1 visit. Blood samples were drawn at pre-dose, and at 2, 4, 12 and 24 hours post-dose.
Reported as:: Geometric mean · nM

PK Parameter: C24hr of DOR (Cohort 2)
nM	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: C24hr of DOR (Cohort 2)	—	282 ± 73.8

SecondaryPK Parameter: C24hr 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). 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.

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.
Reported as:: Geometric mean · ng/mL

PK Parameter: C24hr of 3TC (Cohort 2)
ng/mL	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: C24hr of 3TC (Cohort 2)	—	66.3 ± 54.7

SecondaryPK Parameter: C24hr of Tenofovir (Cohort 2)

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.

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.
Reported as:: Geometric mean · ng/mL

PK Parameter: C24hr of Tenofovir (Cohort 2)
ng/mL	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
PK Parameter: C24hr of Tenofovir (Cohort 2)	—	50.2 ± 9.4

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 24 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (88.0 to 99.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (88.0 to 99.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (80.5 to 98.5)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (87.7 to 99.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (87.4 to 99.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (79.6 to 98.4)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (87.7 to 99.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (87.4 to 99.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2)
Percentage of participants	Cohort 1: DOR	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 (79.6 to 98.4)

SecondarySummary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)

The differences between log10 HIV RNA at Week 24 minus at Day 0 are summarized.

Time frame:: Measured at Day 0 and week 24.
Reported as:: Mean · Log10 plasma HIV-1 RNA

Summary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
Log10 plasma HIV-1 RNA	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of log10 Drop From Baseline to Week 24 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)	—	-2.6 (-5.8 to 19.0)

SecondarySummary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)

The differences between log10 HIV RNA at Week 48 minus at Day 0 are summarized.

Time frame:: Measured at Day 0 and week 48.
Reported as:: Mean · Log10 plasma HIV-1 RNA

Summary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
Log10 plasma HIV-1 RNA	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of log10 Drop From Baseline to Week 48 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)	—	-2.1 (-5.8 to 26.1)

SecondarySummary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)

The differences between log10 HIV RNA at Week 96 minus at Day 0 are summarized.

Time frame:: Measured at Day 0 and week 96.
Reported as:: Mean · Log10 plasma HIV-1 RNA

Summary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)
Log10 plasma HIV-1 RNA	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of log10 Drop From Baseline to Week 96 in Plasma HIV-1 RNA (ART-naive Participants) (Cohort 2)	—	-4.3

SecondarySummary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)

The mean difference is calculated as CD4 count at Week 24 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.

Time frame:: Measured at Day 0 and week 24.
Reported as:: Mean · cells/mm^3

Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)
cells/mm^3	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)	—	84.8 (21.1 to 148.4)

SecondarySummary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)

The mean differences is calculated as CD4 count at Week 48 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.

Time frame:: Measured at Day 0 and week 48.
Reported as:: Mean · cells/mm^3

Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)
cells/mm^3	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)	—	80.1 (14.2 to 146.0)

SecondarySummary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)

The mean difference is calculated as CD4 count at Week 96 minus CD4 count at Day 0 with associated 95% Clopper-Pearson CI.

Time frame:: Measured at Day 0 and week 96.
Reported as:: Mean · cells/mm^3

Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)
cells/mm^3	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)	—	42.5 (-31.1 to 116.1)

SecondarySummary of Changes in CD4% From Baseline to Week 24 (Cohort 2)

The mean difference is calculated as CD4% at Week 24 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI.

Time frame:: Measured at Day 0 and week 24.
Reported as:: Mean · Percent of total lymphocytes

Summary of Changes in CD4% From Baseline to Week 24 (Cohort 2)
Percent of total lymphocytes	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of Changes in CD4% From Baseline to Week 24 (Cohort 2)	—	-1.5 (-2.8 to -0.2)

SecondarySummary of Changes in CD4% From Baseline to Week 48 (Cohort 2)

The mean difference is calculated as CD4% at Week 48 minus CD4% at Day 0 with associated 95% Clopper-Pearson CI.

Time frame:: Measured at Day 0 and week 48.
Reported as:: Mean · Percent of total lymphocytes

Summary of Changes in CD4% From Baseline to Week 48 (Cohort 2)
Percent of total lymphocytes	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of Changes in CD4% From Baseline to Week 48 (Cohort 2)	—	-0.4 (-1.7 to 0.9)

SecondarySummary of Changes in CD4% From Baseline to Week 96 (Cohort 2)

The mean difference is calculated as CD4% at Week 96 minus CD4% at the Day 0 with associated 95% Clopper-Pearson CI.

Time frame:: Measured at Day 0 and week 96.
Reported as:: Mean · Percent of total lymphocytes

Summary of Changes in CD4% From Baseline to Week 96 (Cohort 2)
Percent of total lymphocytes	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Summary of Changes in CD4% From Baseline to Week 96 (Cohort 2)	—	-0.5 (-2.5 to 1.5)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Grade 3 or Higher Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study
Percentage of participants	Cohort 1: DOR	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 (0 to 7.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

Percentage of Participants With Serious Adverse Events Assessed as Related to Study Drug (Cohort 2) Through End of Study
Percentage of participants	Cohort 1: DOR	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 (0 to 7.9)

SecondaryPercentage 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.
Reported as:: Number · Percentage of participants

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 of participants	Cohort 1: DOR	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 (0 to 7.9)

SecondaryPercentage 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.
Reported as:: Number · percentage of participants

Percentage of Participants With Grade 5 Adverse Events (Death) Regardless of Relationship to Study Drug (Cohort 2) Through End of Study
percentage of participants	Cohort 1: DOR	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 (0 to 7.9)

Adverse events

Collected over From start of study treatment to study completion at Week 2 in Cohort 1 or at Week 96 in Cohort 2.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Cohort 1: DOR	0/9 (0%)	0/9 (0%)	4/9 (44.4%)
Cohort 2: DOR/3TC/TDF	0/45 (0%)	2/45 (4.4%)	45/45 (100%)

Most frequent serious events

Most frequent serious events
Event	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
COVID-19Infections and infestations	0/9	1/45
GastroenteritisInfections and infestations	0/9	1/45
Hepatitis CInfections and infestations	0/9	1/45
Scrotal abscessInfections and infestations	0/9	1/45
Lip injuryInjury, poisoning and procedural complications	0/9	1/45
Alanine aminotransferase increasedInvestigations	0/9	1/45

Most frequent other events

Showing 10 of 122

Most frequent other events
Event	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF
Glomerular filtration rate decreasedInvestigations	0/9	25/45
Alanine aminotransferase increasedInvestigations	0/9	21/45
Blood creatinine increasedInvestigations	0/9	21/45
Aspartate aminotransferase increasedInvestigations	2/9	15/45
Blood alkaline phosphatase increasedInvestigations	1/9	14/45
Blood bicarbonate decreasedInvestigations	0/9	12/45
Carbon dioxide decreasedInvestigations	0/9	11/45
Blood potassium decreasedInvestigations	0/9	9/45
HeadacheNervous system disorders	0/9	9/45
CoughRespiratory, thoracic and mediastinal disorders	0/9	9/45

Baseline characteristics

Participants who received at least one dose of study treatment.

Age, Continuous
Age, Continuous(years)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
Mean	14.3 ± 1.6	15.0 ± 1.6	14.9 ± 1.6

Sex: Female, Male
Sex: Female, Male(Participants)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
Female	2	26	28
Male	7	19	26

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
Hispanic or Latino	0	1	1
Not Hispanic or Latino	9	44	53
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
American Indian or Alaska Native	0	0	0
Asian	0	35	35
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	7	10	17
White	2	0	2
More than one race	0	0	0
Unknown or Not Reported	0	0	0

Weight
Weight(kg)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
Mean	55.9 ± 15.8	53.8 ± 8.0	54.1 ± 9.5

Weight Band (kg)
Weight Band (kg)(Participants)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
35 - <45 kg	1	0	1
≥ 45 kg	8	45	53

Region
Region(Participants)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
Africa	0	9	9
Asia/Pacific	0	35	35
North America	9	1	10

Class of Prior ARTs
Class of Prior ARTs(Participants)	Cohort 1: DOR	Cohort 2: DOR/3TC/TDF	Total
Nucleoside Reverse Transcriptase Inhibitors (NRTI)	9	43	52
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)	0	32	32
Integrase Strand Transfer Inhibitors (INSTI)	9	1	10
Protease Inhibitors (PI)	0	10	10
Not Applicable	0	2	2

5 further baseline measures are reported on the registry.

Study locations

8 sites

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

References and documents

Study documents

Study protocol · Apr 28, 2021
Statistical analysis plan · Jun 4, 2020
Informed consent form · Apr 26, 2019

Documents are hosted by the registry — open the source record to download them.

Registry details

Key details

Study ID: NCT03332095
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Responsible party: Sponsor
First posted: Nov 6, 2017
Start date: Jul 2, 2018
Primary completion: Aug 19, 2020
Completion: May 25, 2022
Results posted: Dec 2, 2021
Last update: Feb 14, 2023

Study contacts

Ann Melvin, MD, MPH

study chair · University of Washington, Seattle Children's Research Institute

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Jan 2023. You cannot join it, but the record below documents what was studied.

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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

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