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

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

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

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets; Drug: Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Immediate Release Tablets (Immediate release)

Detailed Description

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

Children were enrolled into one of five ABC/DTG/3TC dosing groups based on their weight. The first 5-7 children within each weight-band underwent intensive PK assessments 5-10 days after starting ABC/DTG/3TC to confirm dose selection. Children remained on their initial dose of ABC/DTG/3TC through Week 4. After Week 4, ABC/DTG/3TC dosing was 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 occurred at Weeks 1, 4, 12, 24, 36, and 48. If participants had a known M184 resistance mutation, they had additional study visits at Weeks 8, 16, and 20. Study visits included physical examination, study drug adherence and tolerability questionnaires, blood collection, and intensive PK sampling. Following the Week 48 study visit, some children were allowed to continue follow-up through up to 144 weeks if alternative post-study drug supply was not yet available.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Botswana
  • Gaborone, Botswana
    • Gaborone CRS
  • Gaborone, Botswana
    • Molepolole CRS
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 1862
      • Soweto IMPAACT CRS
    • Johannesburg, Gauteng, South Africa, 2001
      • Wits RHI Shandukani Research Centre CRS
  • Kwa Zulu Natal
    • Umlazi, Kwa Zulu Natal, South Africa, 4066
      • Umlazi CRS
  • Western Cape Province
    • Tygerberg, Western Cape Province, South Africa, 7505
      • Famcru Crs
• Thailand
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
  • Bangkoknoi
    • Bangkok, Bangkoknoi, Thailand, 10700
      • Siriraj Hospital, Mahidol University NICHD CRS
  • Chiang Mai
    • Changklan, Muang, Chiang Mai, Thailand, 50100
      • Chiangrai Prachanukroh Hospital NICHD CRS
• United States
  • California
    • Los Angeles, California, United States, 90095-1752
      • David Geffen School of Medicine at UCLA NICHD CRS
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Univ. of Colorado Denver NICHD CRS
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Cook County Hosp. Chicago NICHD CRS
    • Chicago, Illinois, United States, 60614-3393
      • Lurie Children's Hospital of Chicago (LCH) CRS
  • Tennessee
    • Memphis, Tennessee, United States, 38105-3678
      • St. Jude Children's Research Hospital CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 11 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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*
  • For participants who are less than two years of age, or who are two years of age and older with any exposure to breast milk in the past 28 days, HIV-1 infection must be confirmed using the tests indicated above with an asterisk (*) for Sample #1 and Sample #2.
  • 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Weight Band #1 (6 to less than 10 kg at study entry); Children weighing 6 to less than 10 kg at study entry. These children received 3 dispersible tablets of ABC/DTG/3TC daily while weighing 6-<10 kg; as their weight increased, they received higher doses consistent with their new weight band.	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
Experimental: Weight Band #2 (10 to less than 14 kg at study entry); Children weighing 10 to less than 14 kg at study entry. These children received 4 dispersible tablets of ABC/DTG/3TC daily while weighing 10-<14 kg; as their weight increased, they received higher doses consistent with their new weight band.	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
Experimental: Weight Band #3 (14 to less than 20 kg at study entry); Children weighing 14 to less than 20 kg at study entry. These children received 5 dispersible tablets of ABC/DTG/3TC daily while weighing 14-<20 kg; as their weight increased, they received higher doses consistent with their new weight band.	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
Experimental: Weight Band #4 (20 to less than 25 kg at study entry); Children weighing 20 to less than 25 kg at study entry. These children received 6 dispersible tablets of ABC/DTG/3TC daily while weighing 20-<25 kg; as their weight increased, they received higher doses consistent with their new weight band.	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
Experimental: Weight Band #5 (25 kg or greater at study entry); Children weighing 25 kg or greater at study entry. These children received 1 immediate release tablet of ABC/DTG/3TC daily.	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; Other Names: Triumeq

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric Mean Area Under the Plasma Concentration-time Curve Over 24 Hours (AUC0-24h) for ABC, DTG, and 3TC	Based on analysis of intensive pharmacokinetic (PK) samples. The geometric mean AUC0-24h for each Weight Band was compared to the lower and upper reference values (in ug*h/mL) for DTG (35.1, 134), ABC (6.3, 50.4), and 3TC (6.3, 26.5). Steady state was measured at Week 1, but was re-collected later for two participants due to a specimen handling error for the Week 1 specimens.	Week 1; Blood samples were drawn at pre-dose and 1, 2, 3, 4, 6, 8, and 24 hours post dosing.
Geometric Mean Maximum Plasma Concentration (Cmax) for ABC, DTG, and 3TC	Based on analysis of intensive PK samples. Steady state was measured at Week 1, but was re-collected later for two participants due to a specimen handling error for the Week 1 specimens.	Week 1; Blood samples were drawn at pre-dose and 1, 2, 3, 4, 6, 8, and 24 hours post dosing.
Geometric Mean Concentration at 24 Hours Post-dose (C24h) for ABC, DTG, and 3TC	Based on analysis of intensive PK samples. The geometric mean C24h for each Weight Band was compared to the lower and upper reference values (in ug/mL) for DTG (0.67, 2.97). Steady state was measured at Week 1, but was re-collected later for two participants due to a specimen handling error for the Week 1 specimens.	Week 1; Blood samples were drawn at pre-dose and 1, 2, 3, 4, 6, 8, and 24 hours post dosing.
Percentage of Participants Who Had at Least One Adverse Event Through Week 24	Adverse event (AE) grading was 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. AEs of any grade were reported.	Measured from treatment initiation through Week 24
Percentage of Participants Who Had at Least One Grade 3 or Grade 4 Adverse Event Assessed as Related to Study Drug Through Week 24	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 24
Percentage of Participants Who Had a Grade 5 Adverse Event Assessed as Related to Study Drug Through Week 24	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 24
Percentage of Participants Who Had at Least One Life-threatening Adverse Event Assessed as Related to Study Drug Through Week 24	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Life-threatening was defined according to Version 2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual).	Measured from treatment initiation through Week 24
Percentage of Participants Who Had at Least One Serious Adverse Event Assessed as Related to Study Drug Through Week 24	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Seriousness was defined according to Version 2.0 of the DAIDS EAE Manual.	Measured from treatment initiation through Week 24
Percentage of Participants Who Had at Least One Adverse Event Assessed as Related to Study Drug That Led to Permanent Discontinuation of Study Drug Through Week 24	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With at Least One Adverse Event Through Week 48	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported.	Measured from treatment initiation through Week 48
Percentage of Participants Who Had at Least One Grade 3 or Grade 4 Adverse Event Assessed as Related to Study Drug Through Week 48	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 48
Percentage of Participants Who Had a Grade 5 Adverse Event Assessed as Related to Study Drug Through Week 48	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 48
Percentage of Participants Who Had at Least One Life-threatening Adverse Event Assessed as Related to Study Drug Through Week 48	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Life-threatening was defined according to Version 2.0 of the DAIDS EAE Manual.	Measured from treatment initiation through Week 48
Percentage of Participants Who Had at Least One Serious Adverse Event Assessed as Related to Study Drug Through Week 48	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Seriousness was defined according to Version 2.0 of the DAIDS EAE Manual.	Measured from treatment initiation through Week 48
Percentage of Participants Who Had at Least One Adverse Event Assessed as Related to Study Drug That Led to Permanent Discontinuation of Study Drug Through Week 48	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 48
Percentage of Participants Who Had at Least One Adverse Event Through Week 60	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported.	Measured from treatment initiation through Week 60
Percentage of Participants Who Had at Least One Grade 3 or Grade 4 Adverse Event Assessed as Related to Study Drug Through Week 60	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 60
Percentage of Participants Who Had a Grade 5 Adverse Event Assessed as Related to Study Drug Through Week 60	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 60
Percentage of Participants Who Had at Least One Life-threatening Adverse Event Assessed as Related to Study Drug Through Week 60	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Life-threatening was defined according to Version 2.0 of the DAIDS EAE Manual.	Measured from treatment initiation through Week 60
Percentage of Participants Who Had at Least One Serious Adverse Event Assessed as Related to Study Drug Through Week 60	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator. Seriousness was defined according to Version 2.0 of the DAIDS EAE Manual.	Measured from treatment initiation through Week 60
Percentage of Participants Who Had at Least One Adverse Event Assessed as Related to Study Drug That Led to Permanent Discontinuation of Study Drug Through Week 60	AE grading was based on DAIDS AE Grading Table, Corrected Version 2.1, dated July 2017. AEs of any grade were reported. The relationship to study drug was assessed by the site investigator.	Measured from treatment initiation through Week 60
Percentage of Participants Who Experienced Virologic Failure Through Week 48	Percentage of participants who experienced virologic failure based on the following definition: ART-experienced participants who had two subsequent viral loads greater or equal to 200 copies/mL at any time, or for ART-naive participants, two subsequent viral loads greater to or equal to 200 copies/mL at 24 weeks or after. The results are presented by ART experienced, ART naïve, and overall.	Measured from treatment initiation through Week 48
Percentage of Participants Who Experienced Virologic Failure Through Week 60	Percentage of participants who experienced virologic failure based on the following definition: ART-experienced participants who had two subsequent viral loads greater or equal to 200 copies/mL at any time, or for ART-naive participants, two subsequent viral loads greater to or equal to 200 copies/mL at 24 weeks or after. The results are presented by ART experienced, ART naïve, and overall.	Measured from treatment initiation through Week 60
Percentage of Participants With HIV-1 RNA Less Than 200 Copies/mL	Viral loads less than the lower limit of quantification were imputed as one less than the lower limit.	Weeks 4, 24, and 48
Percentage of Participants With Virologic Success of HIV-1 RNA Less Than 200 Copies/mL Using FDA Snapshot Algorithm	Percentage of participants with virologic success of HIV-1 RNA less than 200 copies/mL using FDA snapshot algorithm at Weeks 4, 24, and 48. Viral loads less than the lower limit of quantification were imputed as one less than the lower limit.	Weeks 4, 24, and 48
Percentage of Participants With Virologic Success of HIV-1 RNA Less Than 50 Copies/mL Using FDA Snapshot Algorithm	Percentage of participants with virologic success of HIV-1 RNA less than 50 copies/mL using FDA snapshot algorithm at Weeks 4, 24, and 48. Viral loads less than the lower limit of quantification were imputed as one less than the lower limit.	Weeks 4, 24, and 48
Median (Q1, Q3) CD4+ Cell Count	Per protocol, CD4 + cell counts were not required at Week 60. CD4 results were therefore analyzed through Week 48. For participants who discontinued study drug prior to the other timepoints due to safety or virologic failure, results imputed using the baseline value.	Weeks 4, 24, and 48
Median (Q1, Q3) CD4+ Percentage	Per protocol, CD4+ cell count percentages were not required at Week 60. CD4 results were therefore analyzed through Week 48. For participants who discontinued study drug prior to the other timepoints due to safety or virologic failure, results imputed using the baseline value.	Weeks 4, 24, and 48
Median (Q1,Q3) Change From Baseline in Total Cholesterol	Baseline is defined as the latest pre-dose assessment with a non-missing value. Where time was not collected, assessments on the day of treatment initiation are assumed to be taken prior to first dose. Missing results for participants who discontinued study treatment prior to the specified timepoint due to safety or virologic failure were imputed using the baseline value. Per protocol, there was no expectation of evaluating lipids in a fasting state for this study. A relative few participants were identified as having been in a fasted state at a given study visit, but the majority did not fast for this evaluation.	Baseline, Weeks 24 and 48
Median (Q1,Q3) Change From Baseline in HDL	Baseline is defined as the latest pre-dose assessment with a non-missing value. Where time was not collected, assessments on the day of treatment initiation are assumed to be taken prior to first dose. Missing results for participants who discontinued study treatment prior to the specified timepoint due to safety or virologic failure were imputed using the baseline value. Per protocol, there was no expectation of evaluating lipids in a fasting state for this study. A relative few participants were identified as having been in a fasted state at a given study visit, but the majority did not fast for this evaluation.	Baseline, Weeks 24 and 48
Median (Q1,Q3) Change From Baseline in LDL	Baseline is defined as the latest pre-dose assessment with a non-missing value. Where time was not collected, assessments on the day of treatment initiation are assumed to be taken prior to first dose. Missing results for participants who discontinued study treatment prior to the specified timepoint due to safety or virologic failure were imputed using the baseline value. Per protocol, there was no expectation of evaluating lipids in a fasting state for this study. A relative few participants were identified as having been in a fasted state at a given study visit, but the majority did not fast for this evaluation.	Baseline, Weeks 24 and 48
Median (Q1,Q3) Change From Baseline in Triglycerides	Baseline is defined as the latest pre-dose assessment with a non-missing value. Where time was not collected, assessments on the day of treatment initiation are assumed to be taken prior to first dose. Missing results for participants who discontinued study treatment prior to the specified timepoint due to safety or virologic failure were imputed using the baseline value. Per protocol, there was no expectation of evaluating lipids in a fasting state for this study. A relative few participants were identified as having been in a fasted state at a given study visit, but the majority did not fast for this evaluation.	Baseline, Weeks 24 and 48
Parent/Guardian-reported Percent Adherence to Study Drug	Parent/guardian-reported percent adherence to study drug in the 30 days prior to the study visit according to adherence questionnaire responses.	Weeks 4, 24, and 48
Parent/Guardian-reported Number of Missed Doses of Study Drug	Parent/guardian-reported number of missed doses of study drug in the 30 days prior to the study visit according to adherence questionnaire responses.	Weeks 4, 24, and 48
Parent/Guardian-reported Reason for Missed Doses of Study Drug	Parent/guardian-reported reason for missed doses of study drug in the 30 days prior to the study visit according to adherence questionnaire responses.	Weeks 4, 24, and 48
Parent/Guardian-reported Response of How Well the Person Usually Responsible Administered the Study Drug in the Way They Were Supposed to	Parent/guardian-reported response of how well the person usually responsible administered the study drug in the way they were supposed to in the 30 days prior to the study visit according to adherence questionnaire responses.	Weeks 4, 24, and 48
Parent/Guardian-reported Response of How Often the Child Received the Study Drug in the Way They Were Supposed to	Parent/guardian-reported response of how often the child received the study drug in the way they were supposed to in the 30 days prior to the study visit according to adherence questionnaire responses.	Weeks 4, 24, and 48
Parent/Guardian-reported Response of Child's Face When Taking Study Drug	Parent/guardian-reported response of child's face when taking study drug according to palatability questionnaire responses.	Weeks 4, 12, 24, and 48
Parent/Guardian-reported Response of Child's Face When Taking Favorite Food	Parent/guardian-reported response of child's face when taking favorite food according to palatability questionnaire responses.	Weeks 4, 12, 24, and 48
Parent/Guardian-reported Time for Study Drug Tablets to Dissolve	Parent/guardian-reported time for study drug tablets to dissolve according to acceptability questionnaire responses	Weeks 4, 12, 24, and 48
Parent/Guardian-reported Satisfaction With the Number of Study Drug Tablets to Dissolve	Parent/guardian-reported satisfaction with the number of study drug tablets to dissolve according to acceptability questionnaire responses	Weeks 4, 12, 24, and 48
Antiretroviral (ARV) Resistance Mutations	ARV resistance mutations at time of virologic failure and at entry for children with virologic failure.	Entry and confirmation of virologic failure
Population PK: Geometric Mean AUC0-24h for ABC, DTG, and 3TC	Population PK: Geometric Mean Area Under the Plasma Concentration-time Curve for ABC, DTG, and 3TC derived from population PK model. Population apparent oral clearance and apparent volume of distribution were determined with non-linear mixed effects modeling. DTG and 3TC were fit to a 1-compartment model and ABC was fit to 2-compartment model. Weight was a covariate on clearance and volume for all drugs and enzyme maturation as a covariate on apparent oral clearance for DTG. The posthoc parameter of AUC0-24 was estimated using non-compartmental analysis of simulated steady-state concentration-time profiles and stratified by weight band.	Measured from Week 1 through Week 48 over 24 hours post-dose
Population PK: Geometric Mean Concentration at Time 0 (Pre-dose) (C0h) for ABC, DTG, and 3TC	Population PK: Geometric Mean Area Under the Plasma Concentration-time Curve for ABC, DTG, and 3TC derived from population PK model. Population apparent oral clearance and apparent volume of distribution were determined with non-linear mixed effects modeling. DTG and 3TC were fit to a 1-compartment model and ABC was fit to 2-compartment model. Weight was a covariate on clearance and volume for all drugs and enzyme maturation as a covariate on apparent oral clearance for DTG. The posthoc parameter of AUC0-24 was estimated using non-compartmental analysis of simulated steady-state concentration-time profiles and stratified by weight band.	Measured from Week 1 through Week 48 over 24 hours post-dose
Population PK: Geometric Mean Concentration at 24 Hours Post-dose (C24h) for ABC, DTG, and 3TC	Population PK: Geometric Mean Area Under the Plasma Concentration-time Curve for ABC, DTG, and 3TC derived from population PK model. Population apparent oral clearance and apparent volume of distribution were determined with non-linear mixed effects modeling. DTG and 3TC were fit to a 1-compartment model and ABC was fit to 2-compartment model. Weight was a covariate on clearance and volume for all drugs and enzyme maturation as a covariate on apparent oral clearance for DTG. The posthoc parameter of AUC0-24 was estimated using non-compartmental analysis of simulated steady-state concentration-time profiles and stratified by weight band.	Measured from Week 1 through Week 48 over 24 hours post-dose
Population PK: Geometric Mean Maximum Plasma Concentration (Cmax) for ABC, DTG, and 3TC	Population PK: Geometric Mean Area Under the Plasma Concentration-time Curve for ABC, DTG, and 3TC derived from population PK model. Population apparent oral clearance and apparent volume of distribution were determined with non-linear mixed effects modeling. DTG and 3TC were fit to a 1-compartment model and ABC was fit to 2-compartment model. Weight was a covariate on clearance and volume for all drugs and enzyme maturation as a covariate on apparent oral clearance for DTG. The posthoc parameter of AUC0-24 was estimated using non-compartmental analysis of simulated steady-state concentration-time profiles and stratified by weight band.	Measured from Week 1 through Week 48 over 24 hours post-dose
Population PK: Geometric Mean Time to Maximum Concentration (Tmax) for ABC, DTG, and 3TC	Population PK: Geometric Mean Area Under the Plasma Concentration-time Curve for ABC, DTG, and 3TC derived from population PK model. Population apparent oral clearance and apparent volume of distribution were determined with non-linear mixed effects modeling. DTG and 3TC were fit to a 1-compartment model and ABC was fit to 2-compartment model. Weight was a covariate on clearance and volume for all drugs and enzyme maturation as a covariate on apparent oral clearance for DTG. The posthoc parameter of AUC0-24 was estimated using non-compartmental analysis of simulated steady-state concentration-time profiles and stratified by weight band.	Measured from Week 1 through Week 48 over 24 hours post-dose
Population PK: Geometric Mean Apparent Oral Clearance (CL/F) for ABC, DTG, and 3TC	Population PK: Geometric Mean Area Under the Plasma Concentration-time Curve for ABC, DTG, and 3TC derived from population PK model. Population apparent oral clearance and apparent volume of distribution were determined with non-linear mixed effects modeling. DTG and 3TC were fit to a 1-compartment model and ABC was fit to 2-compartment model. Weight was a covariate on clearance and volume for all drugs and enzyme maturation as a covariate on apparent oral clearance for DTG. The posthoc parameter of AUC0-24 was estimated using non-compartmental analysis of simulated steady-state concentration-time profiles and stratified by weight band.	Measured from Week 1 through Week 48 over 24 hours post-dose
Population PK: Geometric Mean Half-life (t1/2) for ABC, DTG, and 3TC	Population PK: Geometric Mean Area Under the Plasma Concentration-time Curve for ABC, DTG, and 3TC derived from population PK model. Population apparent oral clearance and apparent volume of distribution were determined with non-linear mixed effects modeling. DTG and 3TC were fit to a 1-compartment model and ABC was fit to 2-compartment model. Weight was a covariate on clearance and volume for all drugs and enzyme maturation as a covariate on apparent oral clearance for DTG. The posthoc parameter of AUC0-24 was estimated using non-compartmental analysis of simulated steady-state concentration-time profiles and stratified by weight band.	Measured from Week 1 through Week 48 over 24 hours post-dose
Parent/Guardian-reported Ease of Giving Study Drug	Parent/guardian-reported ease of giving study drug according to palatability questionnaire responses.	Weeks 4, 12, 24, and 48

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH); ViiV Healthcare; International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Investigators: Study Chair: Patricia Flynn, MD, St. Jude Children's Research Hospital; Study Chair: Helena Rabie, MBChB, MMED, FCPaed, University of Stellenbosch; Study Chair: Jennifer Kiser, PharmD, PhD, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences

Publications and helpful links

General Publications

• Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366.

Helpful Links

• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1 (July 2017)
• FDA Snapshot algorithm

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2020
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): May 31, 2022

Study Registration Dates

• First Submitted: November 29, 2018
• First Submitted That Met QC Criteria: November 29, 2018
• First Posted (Actual): November 30, 2018

Study Record Updates

• Last Update Posted (Actual): June 27, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Urogenital Diseases; Genital Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir; Abacavir; Dideoxynucleosides
• Other Study ID Numbers: IMPAACT 2019; 38504 (Registry Identifier: DAIDS-ES Registry Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.

IPD Sharing Access Criteria

• With whom?

  • Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network.

• For what types of analyses?

  • To achieve aims in the proposal approved by the IMPAACT Network.

• By what mechanism will data be made available?

  • Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/studies/submit-research-proposal. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No