The Pharmacokinetics, Safety, and Tolerability of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets in HIV-1-Infected Children Less Than 12 Years of Age

Overview

The purpose of this study is to examine the pharmacokinetics, safety, and tolerability of abacavir/dolutegravir/lamivudine dispersible and immediate release tablets in HIV-1-infected children less than 12 years of age.

Full Title of Study: “Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets in HIV-1-Infected Children Less Than 12 Years of Age”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: February 28, 2021

Detailed Description

This study will examine the pharmacokinetics (PK), safety, and tolerability of fixed-dose combination abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) dispersible and immediate release tablets in HIV-1-infected children less than 12 years of age.

Children will be enrolled into one of five ABC/DTG/3TC dosing groups based on their weight. The first 5-7 children within each weight-band will undergo intensive PK assessments 5-10 days after starting ABC/DTG/3TC to confirm dose selection. Children will remain on their initial dose of ABC/DTG/3TC through Week 4. After Week 4, ABC/DTG/3TC dosing will be adjusted based on PK results at the individual or weight-band level, and/or an individual child's growth and weight gain over time.

Follow-up study visits for all participants will occur at Weeks 1, 4, 12, 24, 36, and 48. Some participants may attend additional study visits at Weeks 2, 6, 8, 16, and/or 20. Study visits may include physical examination, study drug adherence and tolerability questionnaires, blood collection, and intensive PK sampling. Following the Week 48 study visit, some children may continue on the study for up to 144 weeks.

Interventions

  • Drug: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets
    • Fixed-dose combination dispersible tablets containing 60 mg ABC, 5 mg DTG, and 30 mg 3TC; administered orally once daily with or without food
  • Drug: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Immediate Release Tablets (Immediate release)
    • Fixed-dose combination immediate release tablets containing 600 mg ABC, 50 mg DTG, and 300 mg 3TC; administered orally once daily with or without food

Arms, Groups and Cohorts

  • Experimental: Weight Band #1 (6 to less than 10 kg)
    • Children weighing 6 to less than 10 kg will receive 3 dispersible tablets of ABC/DTG/3TC, beginning at study entry, for at least 48 weeks and up to 144 weeks.
  • Experimental: Weight Band #2 (10 to less than 14 kg)
    • Children weighing 10 to less than 14 kg will receive 4 dispersible tablets of ABC/DTG/3TC, beginning at study entry, for at least 48 weeks and up to 144 weeks.
  • Experimental: Weight Band #3 (14 to less than 20 kg)
    • Children weighing 14 to less than 20 kg will receive 5 dispersible tablets of ABC/DTG/3TC, beginning at study entry, for at least 48 weeks and up to 144 weeks.
  • Experimental: Weight Band #4 (20 to less than 25 kg)
    • Children weighing 20 to less than 25 kg will receive 6 dispersible tablets of ABC/DTG/3TC, beginning at study entry, for at least 48 weeks and up to 144 weeks.
  • Experimental: Weight Band #5 (25 kg or greater)
    • Children weighing 25 kg or greater will receive 1 immediate release tablet of ABC/DTG/3TC, beginning at study entry, for at least 48 weeks and up to 144 weeks.

Clinical Trial Outcome Measures

Primary Measures

  • Geometric mean area under the plasma concentration-time curve over 24 hours at steady-state (AUC0-24h) for ABC, DTG, and 3TC
    • Time Frame: Measured at Week 1
    • Based on analysis of intensive PK samples collected at Week 1 and compared within each weight band to the PK targets specified in the study protocol
  • Geometric mean maximum plasma concentration (Cmax) for ABC, DTG, and 3TC
    • Time Frame: Measured at Week 1
    • Based on analysis of intensive PK samples collected at Week 1
  • Geometric mean concentration at 24 hours post-dose (C24h) for ABC, DTG, and 3TC
    • Time Frame: Measured at Week 1
    • Based on analysis of intensive PK samples collected at Week 1 and compared within each weight band to the PK targets specified in the study protocol
  • Number of participants who had adverse events
    • Time Frame: Measured through Week 24
    • 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
  • Number of participants who had Grade 3 or Grade 4 adverse events assessed as related to study drug
    • Time Frame: Measured through Week 24
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had Grade 5 adverse events assessed as related to study drug
    • Time Frame: Measured through Week 24
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had life-threatening adverse events assessed as related to study drug
    • Time Frame: Measured through Week 24
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had serious adverse events assessed as related to study drug
    • Time Frame: Measured through Week 24
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had adverse events assessed as related to study drug that lead to permanent discontinuation of study drug
    • Time Frame: Measured through Week 24
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017

Secondary Measures

  • Area under the plasma concentration-time curve over 24 hours at steady-state (AUC0-24h) for ABC, DTG, and 3TC
    • Time Frame: Measured through Week 48
    • Derived from population PK modeling with sampling
  • Concentration at time 0 (pre-dose) (C0h) for ABC, DTG, and 3TC
    • Time Frame: Measured through Week 48
    • Derived from population PK modeling with sampling
  • Concentration at 24 hours post-dose (C24h) for ABC, DTG, and 3TC
    • Time Frame: Measured through Week 48
    • Derived from population PK modeling with sampling
  • Maximum plasma concentration (Cmax) for ABC, DTG, and 3TC
    • Time Frame: Measured through Week 48
    • Derived from population PK modeling with sampling
  • Time to maximum concentration (Tmax) for ABC, DTG, and 3TC
    • Time Frame: Measured through Week 48
    • Derived from population PK modeling with sampling
  • Apparent oral clearance (CL/F) for ABC, DTG, and 3TC
    • Time Frame: Measured through Week 48
    • Derived from population PK modeling with sampling
  • Half-life (t1/2) for ABC, DTG, and 3TC
    • Time Frame: Measured through Week 48
    • Derived from population PK modeling with sampling
  • Number of participants who had adverse events
    • Time Frame: Measured through Week 48
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had Grade 3 or Grade 4 adverse events assessed as related to study drug
    • Time Frame: Measured through Week 48
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had Grade 5 adverse events assessed as related to study drug
    • Time Frame: Measured through Week 48
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had life-threatening adverse events assessed as related to study drug
    • Time Frame: Measured through Week 48
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had serious adverse events assessed as related to study drug
    • Time Frame: Measured through Week 48
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had adverse events assessed as related to study drug that lead to permanent discontinuation of study drug
    • Time Frame: Measured through Week 48
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had adverse events
    • Time Frame: Measured through Week 144
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had Grade 3 or Grade 4 adverse events assessed as related to study drug
    • Time Frame: Measured through Week 144
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had Grade 5 adverse events assessed as related to study drug
    • Time Frame: Measured through Week 144
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had life-threatening adverse events assessed as related to study drug
    • Time Frame: Measured through Week 144
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had serious adverse events assessed as related to study drug
    • Time Frame: Measured through Week 144
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Number of participants who had adverse events assessed as related to study drug that lead to permanent discontinuation of study drug
    • Time Frame: Measured through Week 144
    • Based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017
  • Proportion of participants with HIV-1 RNA levels meeting virologic response criteria
    • Time Frame: Measured through Week 48
    • Based on laboratory evaluations
  • Proportion of participants with HIV-1 RNA levels meeting virologic response criteria
    • Time Frame: Measured through Week 144
    • Based on laboratory evaluations
  • Number of participant with HIV-1 RNA greater than or equal to 200 copies/mL at Weeks 4, 24, and 48 (snapshot algorithm)
    • Time Frame: Measured through Week 48
    • Based on laboratory evaluations
  • Number of participants with HIV-1 RNA greater than or equal to 50 copies/mL at Weeks 4, 24, and 48 (snapshot algorithm)
    • Time Frame: Measured through Week 48
    • Based on laboratory evaluations
  • Median changes (with IQR) in CD4+ cell count and percentage at Weeks 4, 24, and 48
    • Time Frame: Measured through Week 48
    • Based on laboratory evaluations
  • Median changes (with IQR) in CD4+ cell count and percentage through Week 144
    • Time Frame: Measured through Week 144
    • Based on laboratory evaluations
  • Median changes (with IQR) in total cholesterol, HDL, LDL, and triglycerides at Weeks 24 and 48
    • Time Frame: Measured through Week 48
    • Based on laboratory evaluations
  • Aggregated data on parent/guardian reported adherence to study drug at Weeks 4, 24, and 48
    • Time Frame: Measured through Week 48
    • Based on questionnaire responses
  • Aggregated data on parent/guardian reported tolerability (i.e., palatability and acceptability) of study drug at Weeks 4, 12, 24, and 48
    • Time Frame: Measured through Week 48
    • Based on questionnaire responses
  • ARV resistance mutations at time of virologic failure (and at entry for children with resistance identified at time of virologic failure)
    • Time Frame: Measured through Week 48
    • Based on laboratory evaluations

Participating in This Clinical Trial

Inclusion Criteria

  • Less than 12 years of age at entry
  • Note: Accrual will initially be restricted to children six months (180 days) of age and older. Once the Protocol Team has confirmed that data are available to support the specified weight band dosing for children less than six months of age, this restriction will be lifted.
  • Weight 6 kg to less than 40 kg at entry
  • Antiretroviral therapy (ART)-naïve at entry or has been taking a stable ART regimen for at least six consecutive months at entry
  • Note: For ART-naïve children, receipt of antiretroviral (ARV) prophylaxis prior to diagnosis of HIV infection is permitted. For these children, ascertainment of this criterion may be based on parent or guardian report only, but available medical records should also be reviewed in relation to this criterion.
  • Note: For ART-experienced children (on a stable ART regimen), dose and formulation changes (e.g., for growth) within the six months prior to entry are permitted. For these children, ascertainment of this criterion must be based on medical records.
  • For ART-experienced children (on a stable ART regimen), has had a suppressed HIV viral load (HIV-1 RNA less than 200 copies/mL) for at least six consecutive months prior to entry
  • Note: To fulfill this criterion, at least two documented HIV-1 RNA results less than 200 copies/mL must be available, one based on a specimen collected at least six months prior to entry and one based on a specimen collected within 30 days prior to entry.
  • Note: Any documented HIV-1 RNA result greater than or equal to 200 copies/mL based on a specimen collected within six months prior to entry is exclusionary (see exclusion criterion below).
  • At screening, has normal, Grade 1, or Grade 2 laboratory test results for all of the following, based on testing of specimens collected within 30 days prior to entry and grading per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (refer to the study protocol for guidance on severity grading):
  • Hemoglobin (greater than or equal to 8.5 g/dL or greater than or equal to 5.25 mmol/L)
  • Absolute neutrophil count (greater than or equal to 600 cells/mm^3 or greater than or equal to 0.600 x 10^9 cells/L)
  • Platelet count (greater than or equal to 50,000 cells/mm^3 or greater than or equal to 50.00 x 10^9 cells/L)
  • Estimated glomerular filtration rate (eGFR; bedside Schwartz formula; greater than or equal to 60 ml/min/1.73 m^2)
  • Alanine transaminase (ALT) (less than 5.0 x ULN)
  • Aspartate aminotransferase (AST) (less than 5.0 x ULN)
  • Total bilirubin (less than 2.6 x ULN)
  • Direct bilirubin (less than or equal to ULN)
  • Note: Laboratory tests may be repeated during the screening period (i.e., within 30 days prior to entry), with the latest results used for eligibility determination.
  • Note: For treatment-experienced children on an atazanavir-containing ART regimen, Grade 3 or higher total bilirubin is permitted.
  • At screening, has a negative test result for hepatitis B surface antigen based on testing of a specimen collected within 30 days prior to entry
  • Confirmed HIV-1-infection based on documented testing of two samples collected at different time points:
  • Sample #1 may be tested using any of the following:
  • Two rapid antibody tests from different manufacturers or based on different principles and epitopes
  • One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR chemiluminescence assay
  • One HIV DNA polymerase chain reaction (PCR)
  • One quantitative HIV RNA PCR (above the limit of detection of the assay)
  • One qualitative HIV RNA PCR
  • One HIV total nucleic acid test
  • Sample #2 may be tested using any of the following:
  • Rapid antibody test. If this option is used in combination with two rapid tests for Sample #1, at least one of the three rapid tests must be United States Food and Drug Administration (FDA)-approved, and the third rapid test must be from a third manufacturer or based on a third principle or epitope.
  • One enzyme immunoassay OR Western Blot OR immunofluorescence assay OR chemiluminescence assay
  • One HIV DNA PCR
  • One quantitative HIV RNA PCR (above the limit of detection of the assay)
  • One qualitative HIV RNA PCR
  • One HIV total nucleic acid test
  • Whole blood, plasma, or serum samples must be tested. If both samples are tested using antibody tests, at least one of the samples must be tested in a laboratory that operates according to Good Clinical Laboratory Practice guidelines and participates in an appropriate external quality assurance program. If nucleic acid testing is used, at least one test must be performed in a Clinical Laboratory Improvement Amendments (CLIA) certified (for US sites) or Virology Quality Assurance (VQA) certified (for non-US sites) laboratory. For tests performed in other settings, adequate source documentation including the date of specimen collection, date of testing, test performed, and test result must be available. FDA approved testing methods should be used when possible.
  • HLA-B*5701-negative based on documented testing at any time prior to entry
  • Note: Documented testing is required even if the potential participant has received ABC prior to study entry.
  • For females of reproductive potential (defined as having experienced menarche), not pregnant based on testing performed at screening
  • For females of reproductive potential who are engaging in sexual activity that could lead to pregnancy, willing to use two methods of contraception while receiving study drug, based on participant and parent or guardian report at entry
  • One of the two methods must be highly effective; highly effective methods include surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy) and the following:
  • Contraceptive intrauterine device or intrauterine system
  • Subdermal contraceptive implant
  • Progestogen injections
  • Combined estrogen and progestogen oral contraceptive pills
  • Percutaneous contraceptive patch
  • Contraceptive vaginal ring
  • The highly effective method must be initiated prior to study entry. The second method should ideally be a barrier method. Male or female condom use is recommended with all other methods of contraception for dual protection against pregnancy and to avoid transmission of HIV and other sexually transmitted infections.
  • Based on parent or guardian report at entry, child is expected to be available for 48 weeks of follow-up
  • Parent or legal guardian is willing and able to provide written informed consent for child's study participation and, when applicable per local institutional review board/ethics committee (IRB/EC) policies and procedures, child is willing and able to provide written informed assent for study participation

Exclusion Criteria

  • Documented resistance to ABC, DTG, or 3TC
  • Note: Testing to rule out resistance is not required, and the M184V resistance mutation is not exclusionary.
  • For ART-experienced children (on a stable ART regimen), documented HIV-1 RNA result greater than or equal to 200 copies/mL based on a specimen collected within six months prior to entry
  • History of any of the following as determined by the site investigator based on participant/parent/guardian report and available medical records:
  • Malignancy (ever)
  • Hypersensitivity reaction to ABC (ever)
  • Receipt of any prohibited medication (refer to the study protocol for more information) within 30 days prior to study entry
  • Receipt of systemic interferon or any chronic systemic immunosuppressant medication within 30 days prior to study entry
  • Note: Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg) taken for replacement or short course therapy are permitted. Intranasal or inhaled steroid use is also permitted.
  • Has any of the following as determined by the site investigator based on participant/parent/guardian report and available medical records
  • Current clinical evidence of pancreatitis
  • Currently-active tuberculosis (TB) and/or currently receiving rifampicin-containing TB treatment
  • Currently-active AIDS-defining (WHO Clinical Stage 4) opportunistic infection
  • Has any documented or suspected clinically significant medical condition or any other condition that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives

Gender Eligibility: All

Minimum Age: 6 Months

Maximum Age: 12 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • National Institute of Allergy and Infectious Diseases (NIAID)
  • Collaborator
    • International Maternal Pediatric Adolescent AIDS Clinical Trials Network
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Patricia Flynn, MD, Study Chair, St. Jude Children’s Research Hospital
    • Helena Rabie, MBChB, MMED, FCPaed, Study Chair, University of Stellenbosch
    • Jennifer Kiser, PharmD, PhD, Study Chair, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
  • Overall Contact(s)
    • Kathryn Lypen, MPH, 919-544-7040, Klypen@fhi360.org

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