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

NCT03332095 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: IMPAACT 201434150
• Study Type: interventional
• Target: 55
• Locations: 3 countries
• Sites: 8

Brief Summary

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

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (7)

• 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 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 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 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).

  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).

  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.

  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.

  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)

  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)

  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)

  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)

  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)

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

Study Arms (2)

Cohort 1: DOR

EXPERIMENTAL

Participants received a single dose of DOR at study entry (Day 0).

Drug: Doravirine (DOR); Drug: Antiretroviral (ARV) medications

Cohort 2: DOR/3TC/TDF

EXPERIMENTAL

Participants received DOR/3TC/TDF from Day 0 through Week 96.

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

Interventions

Doravirine (DOR) DRUG

100 mg of DOR administered orally

Also known as: MK-1439

Cohort 1: DOR

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) DRUG

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

Cohort 2: DOR/3TC/TDF

Antiretroviral (ARV) medications DRUG

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

Cohort 1: DOR

Eligibility Criteria

• Age: 12 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (8)

Univ. of Colorado Denver NICHD CRS

Aurora, Colorado, 80045, United States

Location

Boston Medical Center Ped. HIV Program NICHD CRS

Boston, Massachusetts, 02118, United States

Location

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, 38105-3678, United States

Location

Seattle Children's Research Institute CRS

Seattle, Washington, 98101, United States

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Chiangrai Prachanukroh Hospital NICHD CRS

Chiang Mai, 50100, Thailand

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

Location

Related Links

• Link to the IMPAACT 2014 study web page
• 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
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections

Interventions

doravirine; Anti-Retroviral Agents; Dosage Forms

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antiviral Agents; Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Pharmaceutical Preparations; Technology, Pharmaceutical; Investigative Techniques

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360)

mallen@fhi360.org

(919) 405-1429

Study Officials

• Ann Melvin, MD, MPH

  University of Washington, Seattle Children's Research Institute

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2017
• First Posted: November 6, 2017
• Study Start: July 2, 2018
• Primary Completion: August 19, 2020
• Study Completion: May 25, 2022
• Last Updated: February 14, 2023
• Results First Posted: December 2, 2021

Record last verified: 2023-01

Locations

ZA (1); TH (3); US (4)