HIV InfectionsPhase 1/2NCT03332095
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 study testing Doravirine (DOR), Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) and Antiretroviral (ARV) medications in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in 3 countries.
Trial 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 more about this study
- Who is it for?
- Ages 12 to 17 years
- Conditions the study is for
- HIV Infections
- What is being tested?
- Doravirine (DOR), Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) and Antiretroviral (ARV) medications
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 55 participants
- Where
- 8 sitesin 3 countries
- Study dates
- 2 Jul 2018to 25 May 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 17 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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:
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- 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).
Who cannot join
- 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
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- 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
Trial locations and contacts
8 sites in 3 countries.
8 sites in 3 countries
United States4 sites
Univ. of Colorado Denver NICHD CRS
Aurora, Colorado, 80045
Boston Medical Center Ped. HIV Program NICHD CRS
Boston, Massachusetts, 02118
St. Jude Children's Research Hospital CRS
Memphis, Tennessee, 38105-3678
Seattle Children's Research Institute CRS
Seattle, Washington, 98101
Thailand3 sites
Siriraj Hospital ,Mahidol University NICHD CRS
Bangkok, Bangkoknoi, 10700
Chiangrai Prachanukroh Hospital NICHD CRS
Chiang Mai, 50100
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
Chiang Mai, 50200
About this study
Official title: 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
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
- HIV Infections
- Being tested
- Doravirine (DOR), Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF), Antiretroviral (ARV) medications
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Doravirine (DOR)Drug
Also called MK-1439
100 mg of DOR administered orally
Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)Drug
Also called MK-1439A
DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily
Antiretroviral (ARV) medicationsDrug
Also called ARVs
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 group | Role | What they receive |
|---|---|---|
| Cohort 1: DOR | Experimental | Participants received a single dose of DOR at study entry (Day 0). Receives: Drug: Doravirine (DOR); Drug: Antiretroviral (ARV) medications |
| Cohort 2: DOR/3TC/TDF | Experimental | Participants received DOR/3TC/TDF from Day 0 through Week 96. Receives: Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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-∞.
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: Cohort 1: Measured from Day 0 through Week 2; Cohort 2: Measured from Day 0 through Week 24.
Secondary outcomes (31)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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).
Measured: Measured from Day 0 through Week 96.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Nov 2017
- Study start2 Jul 2018
- Primary completion19 Aug 2020
- Study completion25 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 55 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Ann Melvin, MD, MPH, Study chair, University of Washington, Seattle Children's Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03332095
- Sponsor's protocol ID
- IMPAACT 2014
- Other IDs
- 34150
- Status last verified
- Jan 2023
- First submitted
- 1 Nov 2017
- Last updated
- 14 Feb 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03332095
- Acronym / sponsor ID
- IMPAACT 2014
- Conditions
- HIV Infections
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 55 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 2 Jul 2018 (actual)
- Primary completion
- 19 Aug 2020 (actual)
- Study completion
- 25 May 2022 (actual)
- First posted
- 6 Nov 2017 (actual)
- Results
- Posted 2 Dec 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort 1: DOR | Experimental | Drug: Doravirine (DOR), Drug: Antiretroviral (ARV) medicationsParticipants received a single dose of DOR at study entry (Day 0). |
| Cohort 2: DOR/3TC/TDF | Experimental | Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)Participants received DOR/3TC/TDF from Day 0 through Week 96. |
Who may qualify
- Ages
- 12 to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (34 listed)
- 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
Key exclusion criteria (15 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Doravirine (DOR)Also: MK-1439100 mg of DOR administered orally | Drug | Cohort 1: DOR |
| Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)Also: MK-1439ADOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily | Drug | Cohort 2: DOR/3TC/TDF |
| Antiretroviral (ARV) medicationsAlso: ARVsParticipants 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. | Drug | Cohort 1: DOR |
Primary outcome
Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1)
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.
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)
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.
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)
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.
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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
31 secondary outcomes
PK Parameter: AUC0-24hr of DOR (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)
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)
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)
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)
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)
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)
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)
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)
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)
Time frame: Measured at week 24.
Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 48 (Cohort 2)
Time frame: Measured at week 48.
Percentage of Participants With Plasma HIV-1 RNA Less Than 200 Copies/mL at Week 96 (Cohort 2)
Time frame: Measured at week 96.
Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 24 (Cohort 2)
Time frame: Measured at week 24.
Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 48 (Cohort 2)
Time frame: Measured at week 48.
Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/mL at Week 96 (Cohort 2)
Time frame: Measured at week 96.
Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 24 (Cohort 2)
Time frame: Measured at week 24.
Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 48 (Cohort 2)
Time frame: Measured at week 48.
Percentage of Participants With Plasma HIV-1 RNA Less Than 40 Copies/mL at Week 96 (Cohort 2)
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)
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)
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)
Time frame: Measured at Day 0 and week 96.
Summary of Changes in CD4 Count From Baseline to Week 24 (Cohort 2)
Time frame: Measured at Day 0 and week 24.
Summary of Changes in CD4 Count From Baseline to Week 48 (Cohort 2)
Time frame: Measured at Day 0 and week 48.
Summary of Changes in CD4 Count From Baseline to Week 96 (Cohort 2)
Time frame: Measured at Day 0 and week 96.
Summary of Changes in CD4% From Baseline to Week 24 (Cohort 2)
Time frame: Measured at Day 0 and week 24.
Summary of Changes in CD4% From Baseline to Week 48 (Cohort 2)
Time frame: Measured at Day 0 and week 48.
Summary of Changes in CD4% From Baseline to Week 96 (Cohort 2)
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
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
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
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
Time frame: Measured from Day 0 through Week 96.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Feb 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Link to the IMPAACT 2014 study web pageLink provided by the sponsor.
- 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 2017Link provided by the sponsor.
- Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010Link provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ann Melvin, MD, MPH study chair
University of Washington, Seattle Children's Research Institute
8 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Doravirine (DOR), Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) and Antiretroviral (ARV) medications in people with HIV Infections, run by National Institute of Allergy and Infectious Diseases (NIAID) at 8 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 34 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Thailand, South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Dec 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pharmacokinetic (PK) Parameter: Single-dose Area-under-the-curve (AUC0-∞) of Doravirine (DOR) (Cohort 1) (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.). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Feb 2023.