DTG/3TC Fixed Dose Formulations for the Maintenance of Virological Suppression in Children With HIV Infection Aged 2 to <15 Years Old (D3 (Penta21))

A Randomised Non-inferiority Trial With Nested PK to Assess DTG/3TC Fixed Dose Formulations for the Maintenance of Virological Suppression in Children With HIV Infection Aged 2 to <15 Years Old

This study aims to find out whether treating children and young people living with HIV with two anti HIV medicines, dolutegravir and lamivudine, is safe and as effective as the three-medicine anti-HIV treatments currently used in routine practice.

Study Overview

• Status: Active, not recruiting
• Conditions: HIV Infections
• Intervention / Treatment: Drug: SOC; Drug: Dolutegravir (DTG) and lamivudine (3TC)

Detailed Description

This study will include 370 children and young people aged 2 to less than 15 years old who are living with HIV and are being treated with anti-HIV medicines for the first time. Participants will be split into two groups, by chance, by a process called "randomisation". One group will continue to receive the anti-HIV medicines already taken according to country-specific routine practice. The second group will change to the new combination of medicine, dolutegravir and lamivudine (with the combination written usually as "DTG/3TC"). Depending on the weight, participants in the second group will be able take the new medicine either as one tablet a day or as a small number of dispersible tablets that are also taken once a day. All children and young people in the study will have regular clinic assessments that are at a similar frequency to the clinic visits that participants would have outside of the study. Blood tests will be performed to check that the medicine is safe and, at some visits, participants and their carers will also be asked to answer some questions on how they feel about taking their medicine. All children and young people will be followed until the last participant who joins the study has been in the study for 96 weeks.

After 96 weeks, children who were randomised to the DTG/3TC arm will enter the extended follow-up continuing to receive DTG/3TC.

• Study Type: Interventional
• Enrollment (Actual): 386
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• South Africa
  • Durban, South Africa
    • King Edward VIII Hospital
  • Klerksdorp, South Africa
    • PHRU Klerksdorp
  • Soweto, South Africa
    • PHRU
• Spain
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
• Thailand
  • Chanthaburi, Thailand
    • Prapokklao Hospital
  • Chiang Mai, Thailand
    • Nakornping Hospital
  • Chiang Rai, Thailand
    • Chiangrai Prachanukroh Hospital
  • Khon Kaen, Thailand
    • Khon Kaen hospital
• Uganda
  • Kampala, Uganda
    • Joint Clinical Research Centre
  • Kampala, Uganda
    • Baylor
  • Kampala, Uganda
    • MUJHU
• United Kingdom
  • Birmingham, United Kingdom
    • Birmingham Heartlands Hospital
  • London, United Kingdom
    • St. Mary's Hospital
  • London, United Kingdom
    • Great Ormand Street Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 11 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for the Main trial:

1. HIV-1 infected children who are virologically suppressed for at least the last 6 months prior to enrolment
2. Aged 2 to <15 years old
3. Weight 6 kg or higher
4. Children on the same triple-drug PI/r, NNRTI or INSTI containing ART regimen for at least 3 months
5. Girls who have reached menarche must have a negative pregnancy test at screening and randomisation
6. Girls who are sexually active must be willing to adhere to highly effective methods of contraception
7. A parent or legal guardian is willing and able to give informed consent on behalf of the child as per national legislation and willing to adhere to the protocol
8. Participant is willing to give informed assent if the trial site clinician deems them old enough and able to understand the age-appropriate information about participation in the study

Inclusion Criteria for the Extended Follow up:

1. Participants remain on DTG/3TC at the end of the randomised phase, and in the opinion of the treating physician, derive ongoing benefit from DTG/3TC
2. Participants have no access to weight-appropriate DTG/3TC formulation via their national programme

Exclusion Criteria for the Main trial :

1. Any previous switch in ART regimen for virological, immunological or clinical treatment failure
2. Any changes in ART in the last 6 months for reasons other than due to child's growth, drug stock-outs, changes in country guidelines and treatment simplification
3. Evidence of previous resistance to 3TC or INSTI
4. Any prior use of regimens consisting of single or dual NRTIs with the exception of a course of zidovudine for PMTCT
5. Known allergy or contraindications to dolutegravir or lamivudine
6. Diagnosis of tuberculosis and on anti-tuberculosis treatment; children can be enrolled after successful tuberculosis treatment
7. Treatment of co-morbidities with drugs which have significant interactions with antiretroviral treatment, requiring dose adjustment of the study drugs (children can be enrolled after the illness resolves)
8. Randomisation visit more than 12 weeks after the most recent screening visit
9. Evidence of hepatitis B infection with no protective immunity against hepatitis B: participants positive for HBsAg or HBcAb and negative for HBsAb
10. Anticipated need for hepatitis C virus therapy with interferon-based regimen prior to the primary endpoint.
11. Screening ALT equal to 3 or more times the upper limit of normal AND bilirubin equal to 2 or more times the upper limit of normal (ALT ≥3xULN AND bilirubin ≥2xULN)
12. Screening ALT equal to 5 or more times the upper limit of normal ALT (≥5xULN)
13. Patients with severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
14. Screening creatinine clearance <50 mL/min/1.73m2
15. Patients aged ≥6 years at moderate or high risk of suicide as determined by Columbia-Suicide Severity Rating Scale (C-SSRS)
16. Girls who are pregnant or breastfeeding
17. Children who are in the legal custody of the State and do not have a parent or guardian able to provide informed consent on their behalf.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SOC; Standard-of-care (SOC)	Drug: SOC; 2 nucleos(t)ide reverse transcriptase inhibitor (NRTI) and a third (anchor) drug (either an integrase strand transfer inhibitor (INSTI), a protease inhibitor (PI) or a non- nucleoside reverse transcriptase inhibitor (NNRTI)
Experimental: DTG/3TC; Dolutegravir (DTG) and lamivudine (3TC) (known as DTG/3TC)	Drug: Dolutegravir (DTG) and lamivudine (3TC); Children randomised to the DTG/3TC arm will receive once daily DTG/3TC fixed dose combination dispersible or film-coated tablets dosed using WHO weight bands criteria

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of children with confirmed viral rebound (defined as the first of two consecutive HIV-1 RNA ≥50c/mL) by week 96	by Week 96

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of children with confirmed viral rebound (defined as the first of two consecutive HIV-1 RNA ≥50c/mL) by week 48	by Week 48
Proportion of children with confirmed HIV-1 RNA ≥50c/mL at weeks 48 and 96 (modified FDA snapshot)	at Week 48 and 96
Proportion of children with HIV-1 RNA ≥50c/mL at weeks 24, 48 and 96 (including blips and confirmed measures ≥50c/mL)	at Week 24, 48 and 96
New resistance-associated mutations in those with confirmed HIV-1 RNA ≥50c/mL	by Week 96
Time to any new or recurrent WHO 3 or WHO 4 event or death	through study completion, up to 5 years
Change in CD4 (absolute and percentage) from baseline to weeks 24, 48 and 96	Week 24, 48 and 96
Incidence of serious adverse events, grade 3 and 4 clinical and laboratory adverse events	through study completion, up to 5 years
Incidence of adverse events leading to discontinuation or modification of the treatment regimen	through study completion, up to 5 years
Proportion of children with a change in ART for toxicity or switch to second-line	through study completion, up to 5 years
Change in blood lipids from baseline to weeks 48 and 96	Week 48 and 96
Change in creatinine clearance estimated using bedside-Schwartz to weeks 48 and 96	Week 48 and 96

Collaborators and Investigators

• Sponsor: PENTA Foundation
• Collaborators: Baylor College of Medicine; University Hospital Birmingham NHS Foundation Trust; Hospital Universitario 12 de Octubre; Great Ormond Street Hospital for Children NHS Foundation Trust; Joint Clinical Research Center; MRC CTU at UCL; MU-JHU CARE; Khon Kaen Hospital; Chris Hani Baragwanath Academic Hospital; Department of Clinical Pharmacy, University Medical Centre St Radboud, The Netherlands.; Chiangrai Prachanukroh Hospital; St Mary's NHS Trust; AMS-CMU/IRD (PHPT); Durban International Clinical Research Site; Prapokklao Hospital, Chantaburi; Nakornping Hospital; Advanced Pathogens Diagnostics Unit, University College London Hospitals; Centre for Health Economics, University of York; Department of Molecular and Clinical Pharmacology, University of Liverpool; Kalasin Hospital; Chang Mai Univerity

Publications and helpful links

General Publications

• Turkova A, Chan MK, Kityo C, Kekitiinwa AR, Musoke P, Violari A, Variava E, Archary M, Cressey TR, Chalermpantmetagul S, Sawasdichai K, Ounchanum P, Kanjanavanit S, Srirojana S, Srirompotong U, Welch S, Bamford A, Epalza C, Fortuny C, Colbers A, Nastouli E, Walker S, Carr D, Conway M, Spyer MJ, Parkar N, White I, Nardone A, Thomason MJ, Ferrand RA, Giaquinto C, Ford D; D3 trial team. D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years. Contemp Clin Trials. 2024 Jul;142:107540. doi: 10.1016/j.cct.2024.107540. Epub 2024 Apr 16.
• Botha JC, Byott M, Spyer MJ, Grant PR, Gartner K, Chen WX, Burton J, Bamford A, Waters LJ, Giaquinto C, Turkova A, Vavro CL, Nastouli E. Sensitive HIV-1 DNA Pol Next-Generation Sequencing for the Characterisation of Archived Antiretroviral Drug Resistance. Viruses. 2023 Aug 25;15(9):1811. doi: 10.3390/v15091811.

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2022
• Primary Completion (Actual): September 30, 2025
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: March 27, 2020
• First Submitted That Met QC Criteria: April 6, 2020
• First Posted (Actual): April 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; HIV Infections; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Deoxyribonucleosides; Dideoxynucleosides; Zalcitabine; Lamivudine; dolutegravir
• Other Study ID Numbers: D3 (Penta21)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No