Strategy for Maintenance of HIV Suppression With Once Daily Integrate Inhibitor+Darunavir/Ritonavir in Children

Study Overview
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Brief Summary
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A two-arm, Phase 2/3 multicentre, open-label, randomised study evaluating safety and antiviral effect of current standard antiretroviral therapy compared to once daily integrase inhibitor administered with darunavir/ritonavir (DRV/r) in HIV-1 infected, virologically suppressed paediatric participants.

Detailed Description
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A two arm parallel group, non-inferiority, open-label, multi-centre, randomised controlled trial.

Official Title
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A Two-arm, Phase 2/3 Multicentre, Open-label, Randomised Study Evaluating Safety and Antiviral Effect of Current Standard Antiretroviral Therapy Compared to Once Daily Integrase Inhibitor Administered With Darunavir/Ritonavir (DRV/r) in HIV-1 Infected, Virologically Suppressed Paediatric Participants.

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: DTG +DRV/r
* Drug: SOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infected children aged ≥ 12 years old and weighing ≥40kg* at the screening visit Aged 12 to < 18 years old** Parents or guardians, and children where appropriate, willing and able to give informed consent and to adhere to the protocol Children must have all HIV-1 RNA viral loads <50c/mL for at least 12 months with a minimum of two separate results before screening. Children on a 3-drug PI/r or NNRTI containing regimen for at least 24 weeks Children/parents/guardians prepared to switch if randomised to once daily integrase inhibitor + DRV/RTV arm Children and parents prepared to restart the current ART regimen after simplification if viral load restart criteria are met (see Section 5.5) Be affiliated or beneficiary to Health Social security scheme (in countries where this is mandatory) Initially enrolment will be of participants ≥ 12 years old and ≥40kg only. DTG 50 mg will be supplied by ViiV Healthcare. As more data become available on younger children, a protocol amendment is planned to include younger children and/or lower weight bands. Exclusion Criteria: Receiving or requiring agents with interactions with DRV, RTV, or any once daily integrase inhibitor (Appendix 14) Evidence of resistance to DRV or integrase inhibitors (for participants in clinical sites where resistance testing is standard of care) Previous exposure to integrase inhibitors for more than 2 weeks Intercurrent illness (randomisation can take place after the illness resolves) Creatinine ≥ 1.8ULN or ALT ≥ 5ULN or ALT ≥ 3ULN and bilirubin ≥2ULN at screening. 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), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Diagnosis of tuberculosis and on anti-tuberculosis treatment (children can be enrolled after successful tuberculosis treatment) Hepatitis B or Hepatitis C co-infection Pregnancy or risk of pregnancy in girls of child-bearing potential unless committed to taking effective contraception History or presence of known allergy or some other contraindication to the study drugs or their components as described in the SmPC

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care group (SOC)<br>triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI | Drug: SOC<br>* Standard of care (continuing triple anti-retroviral therapy including 2 NRTIs + boosted PI/NNRTI)<br>|
| Experimental: DTG+DRV/r<br>NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r) | Drug: DTG +DRV/r<br>* NRTI-sparing regimen: Once daily integrase inhibitor (INSTI) + darunavir/ritonavir (DRV/r)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with HIV-1 RNA ever ≥ 50 c/mL (confirmed within 4 weeks) |  | at any time up to week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with HIV-1 RNA < 50 c/mL |  | at week 48 | 
| Percentage of patients with HIV-1 RNA ≥ 50 c/mL |  | at week 24 | 
| Percentage of patients withHIV-1 RNA ≥ 400c/mL |  | at week 24 and week 48 | 
| Percentage of patients with any grade 3 or 4 clinical adverse events (particularly lipodystrophy); any grade 3 or 4 laboratory adverse events |  | over 48 weeks | 
| All grade 3 or 4 laboratory adverse events |  | over 48 weeks | 
| Any adverse event at least possibly related to study drugs or leading to treatment modifications |  | over 48 weeks | 
| Occurrence of new resistance mutations |  | over 48 weeks | 
| Changes in CD4 (absolute and percentage) |  | from baseline to weeks 24 and 48 | 
| Change in ART (defined as any change from the ART regimen at randomisation) |  | at week 0 | 
| New or recurrent CDC/WHO stage C or severe stage B event or death |  | over 48 weeks | 
| Blood lipids |  | over 48 weeks | 
| Adherence as measured by questionnaire and visual analogue scale |  | over 48 weeks | 
| Acceptability and quality of life over 48 weeks as assessed by patient completed questionnaires |  | over 48 weeks | 
| Tanner scales (in participants aged over 8 years) |  | over 48 weeks | 
| Date of first menses |  | over 48 weeks | 
| Height |  | Over 48 weeks | 
| Weight |  | over 48 weeks |