Clinical Trials

MainTitle

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

This study is currently recruiting participants. (see Contacts and Locations)

Verified November 2019 by National Institute of Allergy and Infectious Diseases (NIAID)

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)


Information provided by (Responsible Party)
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier
NCT03332095

First received: November 1, 2017
Last updated: November 22, 2019
Last Verified: November 2019
History of Changes
Purpose

Purpose

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

Condition Intervention Phase
HIV Infections

Drug : Doravirine (DOR)
Drug : Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)
Drug : Antiretroviral (ARV) medications
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures

  • Single-dose AUC0-∞ of doravirine (DOR) (Cohort 1) [ Time Frame: Measured through 72-hours post-dose ]
    Based on laboratory evaluations
  • Single-dose Cmax of DOR (Cohort 1) [ Time Frame: Measured through 72-hours post-dose ]
    Based on laboratory evaluations
  • Single-dose C24hr of DOR (Cohort 1) [ Time Frame: Measured through 72-hours post-dose ]
    Based on laboratory evaluations
  • Frequency of all adverse events, regardless of severity grade (Cohort 1) [ Time Frame: Measured through Week 2 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of Grade 3 or higher adverse events assessed as related to study drug (Cohort 1) [ Time Frame: Measured through Week 2 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of serious adverse events assessed as related to study drug (Cohort 1) [ Time Frame: Measured through Week 2 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of permanent discontinuation of study drug due to adverse events assessed as related to study drug (Cohort 1) [ Time Frame: Measured through Week 2 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of Grade 5 adverse events (death) regardless of relationship to study drug (Cohort 1) [ Time Frame: Measured through Week 2 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of all adverse events, regardless of severity grade (Cohort 2) [ Time Frame: Measured through Week 24 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of Grade 3 or higher adverse events assessed as related to study drug (Cohort 2) [ Time Frame: Measured through Week 24 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of serious adverse events assessed as related to study drug (Cohort 2) [ Time Frame: Measured through Week 24 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of permanent discontinuation of study drug due to adverse events assessed as related to study drug (Cohort 2) [ Time Frame: Measured through Week 24 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of Grade 5 adverse events (death) regardless of relationship to study drug (Cohort 2) [ Time Frame: Measured through Week 24 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
Secondary Outcome Measures:
  • AUC0-24hr of DOR, 3TC, tenofovir (Cohort 2) [ Time Frame: Measured at Week 1 ]
    Based on laboratory evaluations
  • Cmax of DOR, 3TC, tenofovir (Cohort 2) [ Time Frame: Measured at Week 1 ]
    Based on laboratory evaluations
  • C24hr of DOR, 3TC, tenofovir (Cohort 2) [ Time Frame: Measured at Week 1 ]
    Based on laboratory evaluations
  • Frequency of plasma HIV-1 RNA less than 200 copies/mL (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on laboratory evaluations
  • Frequency of plasma HIV-1 RNA less than 50 copies/mL (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on laboratory evaluations
  • Frequency of plasma HIV-1 RNA less than 40 copies/mL (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on laboratory evaluations
  • Summary of log10 drop from baseline in plasma HIV-1 RNA (ART-naive participants) (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on laboratory evaluations
  • Summary of changes in CD4 count from baseline (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on laboratory evaluations
  • Summary of changes in CD4 percent from baseline (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on laboratory evaluations
  • Frequency of all adverse events, regardless of severity grade (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of Grade 3 or higher adverse events assessed as related to study drug (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of serious adverse events assessed as related to study drug (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of permanent discontinuation of study drug due to adverse events assessed as related to study drug (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)
  • Frequency of Grade 5 adverse events (death) regardless of relationship to study drug (Cohort 2) [ Time Frame: Measured through Week 96 ]
    Based on Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual)

Estimated Enrollment: 65
Study Start Date: March 21, 2018
Estimated Study Completion Date: September 30, 2022
Estimated Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Cohort 1: DOR
Participants will receive a single dose of DOR at study entry (Day 0).
Drug: Doravirine (DOR)

100 mg of DOR administered orally

Other Name: MK-1439
Drug: Antiretroviral (ARV) medications

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

Experimental: Cohort 2: DOR/3TC/TDF
Participants will receive DOR/3TC/TDF from Day 0 through Week 96.
Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF)

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

Other Name: MK-1439A

Detailed Description:

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

Eligibility

Eligibility

Ages Eligible for Study: 12 Years to 17 Years  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • Age 12 years to less than 18 years at entry
  • Weight greater than or equal 35 kg at entry
  • If not of legal age to provide independent informed consent: Parent or guardian is willing and able to provide written informed consent for study participation; in addition, when applicable per local Institutional Review Board / Ethics Committee (IRB/EC) policies and procedures, potential participant is willing and able to provide written informed assent for study participation. If of legal age to provide independent informed consent as determined by site Standard Operating Procedures (SOPs) and consistent with site IRB/EC policies and procedures: Potential participant is willing and able to provide written informed consent for study participation
  • Confirmed HIV-1-infection based on documented testing of two samples collected at different time points. More information on this criterion can be found in the protocol.
  • Antiretroviral therapy (ART) exposure, virologic suppression, and resistance requirements, as follows:
  • Cohort 1
    • ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records:
    • At entry, receiving combination ART with raltegravir (RAL) or dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs); AND
    • At entry, has not received non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitor (PIs), or cobicistat within the previous 30 days;
    • AND
    • Virologic suppression, as documented in medical records and as defined by:
    • One or more HIV RNA polymerase chain reaction (PCR) result below the level of quantification (BLLQ) within 15 months prior to enrollment, AND
    • If any HIV RNA PCR tests have been done within 3 months prior to enrollment, all results are below the level of quantification, AND
    • HIV RNA PCR result less than 40 copies/mL at screening, performed as per the protocol. Note: A single, unconfirmed HIV-1 RNA result greater than or equal to the level of quantification but less than 500 copies/mL, between 3 and 15 months, prior to enrollment is not exclusionary as long as the other criteria for documentation of virologic suppression are met.
  • Cohort 2 ART-naive
    • ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records:
    • At entry, received no antiretrovirals (ARVs) for treatment of HIV infection including investigational agents (prior receipt of ARVs for prevention of perinatal transmission is permitted);
    • AND
    • Screening genotypic resistance test results indicate susceptibility to doravirine (DOR), tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) (see the protocol for more information; result must be available prior to enrollment), performed as per the protocol;
    • AND
    • If available, as documented in medical records, any prior genotypic resistance test result indicates susceptibility to DOR, TDF, and 3TC (see the protocol for more information). Note: For individuals that are re-screened, the genotypic resistance test does not need to be repeated.
  • Cohort 2 ART-experienced
    • ART exposure requirements, based on individual or parent/guardian's report and, if available, confirmed by medical records:
    • No previous history of change in ARVs due to clinical or virologic failure, in the opinion of the site investigator or designee;
    • AND
    • Virologic suppression, as documented in medical record and as defined by:
    • One or more HIV RNA PCR result BLLQ within 15 months prior to enrollment, AND
    • If any HIV RNA PCR tests have been done within 3 months prior to enrollment, all results are below the level of quantification, AND
    • HIV RNA PCR result less than 40 copies/mL at screening (see the protocol for more information);
    • AND
    • If available, as documented in medical records, any prior genotypic resistance test result indicates susceptibility to DOR, TDF, and 3TC (see the protocol for more information). Note: This group of ARV-experienced, virologically suppressed participants will only enroll once there are data from the adult switch studies indicating virologic efficacy and safety (see the protocol for more information). Sites will be informed via a Clarification Memorandum when ART-experienced participants can be enrolled. Note: A single, unconfirmed HIV-1 RNA result greater than or equal to the level of quantification but less than 500 copies/mL, between 3 and 15 months, prior to enrollment is not exclusionary as long as the other criteria for documentation of virologic suppression are met.
  • Grade 2 or lower hemoglobin, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase, and lipase on specimens obtained at screening
  • For Cohort 2 only, grade 2 or lower creatinine, proteinuria, and glycosuria on specimens obtained at screening
  • Estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m^2, on specimens obtained at screening, based on the Schwartz equation. More information on this criterion can be found in the protocol.
  • For females who have reached menarche or who are engaging in sexual activity (self-reported), negative pregnancy test at entry
  • For females engaging in sexual activity that could lead to pregnancy (self-reported), agrees to use two effective, medically accepted birth control methods while on study and for two weeks after permanently discontinuing study drug
  • For males engaging in sexual activity that could lead to pregnancy (self-reported), agrees to use condoms while on study and for two weeks after permanently discontinuing study drug
  • Able and willing to swallow available formulation(s) (tablet or, as available, oral granules). Note: The study is expected open to accrual with only the tablet formulation available. Sites will be informed when the oral granule formulation is available for participant use. Once the granule formulation is available, participants in Cohort 2 will be asked to choose which formulation they would like to take at Entry. Formulation switches during the study may be allowed, as described in the protocol.


Exclusion Criteria:
  • Evidence of decompensated liver disease manifested by the presence of or a history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy, or other signs or symptoms of advanced liver diseases. Note: Individuals with chronic hepatitis B who have grade 2 or lower ALT and AST and have no significant impairment of hepatic synthetic function (significant impairment of hepatic synthetic function is defined as a serum albumin less than 2.8 mg/dL or an international normalized ratio (INR) greater than 1.7 in the absence of another explanation for the abnormal laboratory value) are eligible.
  • For Cohort 2 only, detectable hepatitis C virus (HCV) by RNA PCR or current or planned treatment with direct antiviral agent for HCV. Note: HCV antibody positivity but undetectable by HCV RNA PCR results are permitted.
  • Presence of any active AIDS-defining opportunistic infection
  • History of malignancy (ever), with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin
  • Clinical evidence of pancreatitis, as determined by the clinician (at entry)
  • Use of nafcillin, dicloxacillin, or any of the prohibited medications, within 30 days prior to study entry (see the protocol for a complete list of prohibited medications)
  • For females, currently breastfeeding an infant at entry
  • Enrolled in another clinical trial of an investigational agent, device, or vaccine
  • Unlikely to adhere to the study procedures or keep appointments, in the opinion of the site investigator or designee
  • Used, or anticipates using, chronic systemic immunosuppressive agents or systemic interferon (e.g., for treatment of HCV infection) within 30 days prior to study entry. Note: Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (less than or equal to 30 days) are permitted. See the protocol for a complete list of prohibited medications.
  • Diagnosed with current active tuberculosis and/or is currently being treated with a rifampicin-containing regimen
  • Individual has any other condition, that in the opinion of the site investigator or
designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03332095

Contacts

Contact:   Rachel Scheckter 919-544-7040 ext 11392 rscheckter@fhi360.org
Contact:   Katie McCarthy 919-544-7040 ext 11439 kmccarthy@fhi360.org

Locations

United States, Colorado
Univ. of Colorado Denver NICHD CRS Recruiting
Aurora, Colorado, United States, 80045
Contact: Emily Barr, C.P.N.P., C.N.M., M.S.N.    720-777-6752    emily.barr@childrenscolorado.org
United States, Florida
Univ. of Florida Jacksonville NICHD CRS Recruiting
Jacksonville, Florida, United States, 32209
Contact: Saniyyah Mahmoudi, A.R.N.P.    904-244-5331    saniyyah.mahmoudi@jax.ufl.edu
United States, Maryland
Johns Hopkins Univ. Baltimore NICHD CRS Recruiting
Baltimore, Maryland, United States, 21287
Contact: Aleisha Collinson-Streng, R.N., A.C.R.N.    443-801-7301    acolli14@jhmi.edu
United States, Massachusetts
Boston Medical Center Ped. HIV Program NICHD CRS Completed
Boston, Massachusetts, United States, 02118
United States, Tennessee
St. Jude Children's Research Hospital CRS Recruiting
Memphis, Tennessee, United States, 38105-3678
Contact: Jill Utech, M.S.N.    901-595-5059    jill.utech@stjude.org
United States, Washington
Seattle Children's Research Institute CRS Recruiting
Seattle, Washington, United States, 98101
Contact: Amanda Robson Nuss, B.S.    206-884-1535    amanda.robson@seattlechildrens.org
Puerto Rico
University of Puerto Rico Pediatric HIV/AIDS Research Program CRS Recruiting
San Juan, Puerto Rico, 00935
Contact: Ruth Santos, B.S.N., R.N., M.P.H.    787-759-9595    ruth.santos@upr.edu
South Africa
Soweto IMPAACT CRS Recruiting
Johannesburg, Gauteng, South Africa, 1862
Contact: Nastassja Ramsagar    27-11-9899858    choonilaln@phru.co.za
Wits RHI Shandukani Research Centre CRS Recruiting
Johannesburg, Gauteng, South Africa, 2001
Contact: Hermien Gous, Pharm.D.    27-11-3585500 ext 5502    hgous@wrhi.ac.za
Thailand
Siriraj Hospital ,Mahidol University NICHD CRS Recruiting
Bangkok, Bangkoknoi, Thailand, 10700
Contact: Watcharee Lermankul    66-2-4197000 ext 5695    watchareeped@gmail.com
Chiangrai Prachanukroh Hospital NICHD CRS Recruiting
Chiang Mai, Thailand, 50100
Contact: Pra-ornsuda Sukrakanchana    66-81-7468858    Pra-ornsuda.Sukrakanchana@phpt.org
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS Recruiting
Chiang Mai, Thailand, 50200
Contact: Daralak Tavornprasit, R.N., M.Sc.    66-5-3936148 ext 176    daralak@rihes-cmu.org

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

Study Chair: Ann Melvin, MD, MPH University of Washington, Seattle Children's Research Institute
More Information

More Information

Additional Information:

Related Info

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)  
ClinicalTrials.gov Identifier: NCT03332095   History of Changes  
Other Study ID Numbers: IMPAACT 2014  
  34150  
Study First Received: November 1, 2017  
Last Updated: November 22, 2019  

Studies a U.S. FDA-regulated Drug Product: Yes  
Studies a U.S. FDA-regulated Device Product: No  

Additional relevant MeSH terms:
HIV Infections
Tenofovir
Lamivudine
Anti-Retroviral Agents

ClinicalTrials.gov processed this data on December 13, 2019
This information is provided by ClinicalTrials.gov.