Clinical trial NCT04337450: DTG/3TC Fixed Dose Formulations for the Maintenance of Virological Suppression in Children With HIV Infection Aged 2 to <15 Years Old
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: HIV Infections
Lead sponsor: PENTA Foundation
Sponsor class: NETWORK
Collaborators: name: MRC CTU at UCL
name: AMS-CMU/IRD (PHPT)
name: Chris Hani Baragwanath Academic Hospital
name: Durban International Clinical Research Site
name: Hospital Universitario 12 de Octubre
name: Prapokklao Hospital, Chantaburi
name: Chiangrai Prachanukroh Hospital
name: Nakornping Hospital
name: Khon Kaen Hospital
name: Kalasin Hospital
name: Joint Clinical Research Center
name: MU-JHU CARE
name: Baylor College of Medicine
name: Great Ormond Street Hospital for Children NHS Foundation Trust
name: University Hospital Birmingham NHS Foundation Trust
name: Department of Clinical Pharmacy, University Medical Centre St Radboud, The Netherlands.
name: Advanced Pathogens Diagnostics Unit, University College London Hospitals
name: Centre for Health Economics, University of York
name: Department of Molecular and Clinical Pharmacology, University of Liverpool
name: St Mary's NHS Trust
name: Chang Mai Univerity
First posted: 2020-04-07
Enrollment: 370
Sex: ALL
Minimum age (years): 2
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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.

Primary outcomes:
measure: Proportion of children with confirmed viral rebound (defined as the first of two consecutive HIV-1 RNA ≥50c/mL) by week 96
timeFrame: by Week 96
Secondary outcomes:
measure: Proportion of children with confirmed viral rebound (defined as the first of two consecutive HIV-1 RNA ≥50c/mL) by week 48
timeFrame: by Week 48
measure: Proportion of children with confirmed HIV-1 RNA ≥50c/mL at weeks 48 and 96 (modified FDA snapshot)
timeFrame: at Week 48 and 96
measure: Proportion of children with HIV-1 RNA ≥50c/mL at weeks 24, 48 and 96 (including blips and confirmed measures ≥50c/mL)
timeFrame: at Week 24, 48 and 96
measure: New resistance-associated mutations in those with confirmed HIV-1 RNA ≥50c/mL
timeFrame: by Week 96
measure: Time to any new or recurrent WHO 3 or WHO 4 event or death
timeFrame: through study completion, up to 5 years
measure: Change in CD4 (absolute and percentage) from baseline to weeks 24, 48 and 96
timeFrame: Week 24, 48 and 96
measure: Incidence of serious adverse events, grade 3 and 4 clinical and laboratory adverse events
timeFrame: through study completion, up to 5 years
measure: Incidence of adverse events leading to discontinuation or modification of the treatment regimen
timeFrame: through study completion, up to 5 years
measure: Proportion of children with a change in ART for toxicity or switch to second-line
timeFrame: through study completion, up to 5 years
measure: Change in blood lipids from baseline to weeks 48 and 96
timeFrame: Week 48 and 96
measure: Change in creatinine clearance estimated using bedside-Schwartz to weeks 48 and 96
timeFrame: Week 48 and 96
Other outcomes:
Locations:
city: Durban
country: South Africa
facility: King Edward VIII Hospital
city: Klerksdorp
country: South Africa
facility: PHRU Klerksdorp
city: Soweto
country: South Africa
facility: PHRU
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Chanthaburi
country: Thailand
facility: Prapokklao Hospital
city: Chiang Mai
country: Thailand
facility: Nakornping Hospital
city: Chiang Rai
country: Thailand
facility: Chiangrai Prachanukroh Hospital
city: Khon Kaen
country: Thailand
facility: Khon Kaen Hospital
city: Kampala
country: Uganda
facility: Baylor
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre
city: Kampala
country: Uganda
facility: MUJHU
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: London
country: United Kingdom
facility: Great Ormand Street Hospital
city: London
country: United Kingdom
facility: St. Mary's Hospital
Study officials:
References: