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

NCT03760458 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: IMPAACT 201938504
• Study Type: interventional
• Target: 57
• Locations: 4 countries
• Sites: 14

Brief Summary

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.

Conditions

HIV Infections

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (41)

• Population PK: Geometric Mean AUC0-24h for ABC, DTG, and 3TC

  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

  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

  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

  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

  Measured from Week 1 through Week 48 over 24 hours post-dose

Study Arms (5)

Weight Band #1 (6 to less than 10 kg at study entry)

EXPERIMENTAL

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

Weight Band #2 (10 to less than 14 kg at study entry)

EXPERIMENTAL

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

Weight Band #3 (14 to less than 20 kg at study entry)

EXPERIMENTAL

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

Weight Band #4 (20 to less than 25 kg at study entry)

EXPERIMENTAL

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

Weight Band #5 (25 kg or greater at study entry)

EXPERIMENTAL

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)

Interventions

Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Dispersible Tablets DRUG

Fixed-dose combination dispersible tablets containing 60 mg ABC, 5 mg DTG, and 30 mg 3TC; administered orally once daily with or without food

Weight Band #1 (6 to less than 10 kg at study entry); Weight Band #2 (10 to less than 14 kg at study entry); Weight Band #3 (14 to less than 20 kg at study entry); Weight Band #4 (20 to less than 25 kg at study entry)

Abacavir (ABC)/Dolutegravir (DTG)/Lamivudine (3TC) Immediate Release Tablets (Immediate release) DRUG

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

Also known as: Triumeq

Weight Band #5 (25 kg or greater at study entry)

Eligibility Criteria

• Age: Up to 11 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• Documented resistance to ABC, DTG, or 3TC
• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• International Maternal Pediatric Adolescent AIDS Clinical Trials Group: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Institute of Mental Health (NIMH): collaborator
• ViiV Healthcare: collaborator

Study Sites (14)

David Geffen School of Medicine at UCLA NICHD CRS

Los Angeles, California, 90095-1752, United States

Location

Univ. of Colorado Denver NICHD CRS

Aurora, Colorado, 80045, United States

Location

Rush Univ. Cook County Hosp. Chicago NICHD CRS

Chicago, Illinois, 60612, United States

Location

Lurie Children's Hospital of Chicago (LCH) CRS

Chicago, Illinois, 60614-3393, United States

Location

St. Jude Children's Research Hospital CRS

Memphis, Tennessee, 38105-3678, United States

Location

Gaborone CRS

Gaborone, Botswana

Location

Molepolole CRS

Gaborone, Botswana

Location

Soweto IMPAACT CRS

Johannesburg, Gauteng, 1862, South Africa

Location

Wits RHI Shandukani Research Centre CRS

Johannesburg, Gauteng, 2001, South Africa

Location

Umlazi CRS

Umlazi, KwaZulu-Natal, 4066, South Africa

Location

Famcru Crs

Tygerberg, Western Cape, 7505, South Africa

Location

Siriraj Hospital, Mahidol University NICHD CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Chiangrai Prachanukroh Hospital NICHD CRS

Changklan, Muang, Chiang Mai, 50100, Thailand

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

Location

Related Publications (2)

• Brooks KM, Kiser JJ, Ziemba L, Ward S, Rani Y, Cressey TR, Masheto GR, Cassim H, Deville JG, Ponatshego PL, Patel F, Aurpibul L, Barnabas SL, Mustich I, Coletti A, Heckman B, Krotje C, Lojacono M, Yin DE, Townley E, Moye J, Majji S, Acosta EP, Ryan K, Chandasana H, Brothers CH, Buchanan AM, Rabie H, Flynn PM; IMPAACT 2019 Study Team. Pharmacokinetics, safety, and tolerability of dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in children with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1-2 dose-confirmation study. Lancet HIV. 2023 Aug;10(8):e506-e517. doi: 10.1016/S2352-3018(23)00107-8.

  PMID: 37541705 DERIVED

• 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.

  PMID: 34817414 DERIVED

Related Links

• 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)
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• FDA Snapshot Algorithm

MeSH Terms

Conditions

HIV Infections

Interventions

abacavir; abacavir, dolutegravir, and lamivudine drug combination

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

Results Point of Contact

• Title: IMPAACT Clinicaltrials.gov Coordinator
• Organization: Family Health International (FHI 360)

IMPAACT.ctgov@fstrf.org

(919) 405-1429

Study Officials

• 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

  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 29, 2018
• First Posted: November 30, 2018
• Study Start: September 9, 2020
• Primary Completion: December 14, 2021
• Study Completion: May 31, 2022
• Last Updated: June 27, 2023
• Results First Posted: February 13, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

TH (3); BO (2); ZA (4); US (5)