A Randomised Trial of Dolutegravir (DTG)-Based Antiretroviral Therapy vs. Standard of Care (SOC) in Children With HIV Infection Starting First-line or Switching to Second-line ART

Study Overview
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Brief Summary
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A new anti-HIV medicine (Dolutegravir) combined with 2 currently used anti-HIV medicines is non-inferior to the standard combination of medicines used in terms of efficacy and better in terms of toxicity.

Detailed Description
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The ODYSSEY study is an ongoing international randomised trial evaluating dolutegravir based antiretroviral therapy versus standard of care in HIV-infected children aged less than 18 years who are starting first line treatment (ODYSSEY A) or switching to second line treatment (ODYSSEY B). Participants have visits 4 weeks and 12 weeks after randomisation and every 12 weeks subsequent of that. They are followed up for a minimum of 96 weeks. The primary objective of the study is to assess the difference in virological or clinical failure by 96 weeks between children receiving a DTG-based regimen and those on standard of care. At the end of study visit for the randomised phase, children and carers will be invited to consent to extended follow-up. Children's visit schedules and care will be as per local clinic guidelines. Participants will be followed up until May 2023 in this phase of the trial. The objectives of the extended follow-up are two-fold: 1. to provide safety data for ViiV Healthcare for participants who, in the opinion of the treating physician, continue to derive benefit from dolutegravir and receive dolutegravir from ViiV Healthcare where it is not available through their country's national HIV treatment programme; 2. to monitor long-term safety and effectiveness of dolutegravir versus standard of care.

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: DTG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ALL PATIENTS: Children ≥28 days and <18 years weighing ≥3kg with confirmed HIV-1 infection Parents/carers and children, where applicable, give informed written consent Girls aged 12 years or older who have reached menses must have a negative pregnancy test at screening and be willing to adhere to effective methods of contraception if sexually active Children with co-infections who need to start ART can be enrolled into ODYSSEY according to local/national guidelines Parents/carers and children, where applicable, willing to adhere to a minimum of 96 weeks' follow-up Children weighing 3 to <14kg must be eligible and willing to participate in the Weight band (WB)-PK1 substudy unless direct enrolment for the child's weight band has opened following the WB-PK1 substudy and/or dosing information has become available from the IMPAACT P1093 DTG dose-finding study. ADDITIONAL CRITERIA FOR ODYSSEY A: • Planning to start first-line ART ADDITIONAL CRITERIA FOR ODYSSEY B: Planning to start second-line ART defined as either: (i) switch of at least 2 ART drugs due to treatment failure; or (ii) switch of only the third agent due to treatment failure where drug sensitivity tests show no mutations conferring NRTI resistance Treated with only one previous ART regimen. Single drug substitutions for toxicity, simplification, changes in national guidelines or drug availability are allowed At least one NRTI with predicted preserved activity available for a background regimen In settings where resistance tests are routinely available, at least one new active NRTI from tenofovir disoproxil fumarate, abacavir or zidovudine should have preserved activity based on cumulative results of resistance tests In settings where resistance tests are not routinely available, children who are due to switch according to national guidelines should have at least one new NRTI predicted to be available from tenofovir disoproxil fumarate, abacavir or zidovudine Viral load ≥ 500 c/ml at screening visit Exclusion Criteria: History or presence of known allergy or contraindications to dolutegravir History or presence of known allergy or contraindications to proposed available NRTI backbone or proposed available SOC third agent. Alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal, OR ALT ≥3x upper limit of normal and bilirubin ≥2x upper limit of normal 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) Anticipated need for Hepatitis C virus (HCV) therapy during the study Pregnancy or breastfeeding Evidence of lack of susceptibility to integrase inhibitors or more than a 2-week exposure to antiretrovirals of this class

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 18 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: SOC arm<br>SOC for ODYSSEY A is defined as a PI or non nucleoside transcriptase inhibitors + 2 or 3 nucleoside transcriptase inhibitor SOC for ODYSSEY B is defined as a PI or non nucleoside transcriptase inhibitor+ 2 nucleoside transcriptase inhibitors | Drug: DTG<br> <br> |
| Experimental: DTG arm<br>DTG + 2 nucleoside transcriptase inhibitors | Drug: DTG<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in proportion with failure (clinical or virological) | estimated using time to the first occurrence of any of the following components: Insufficient virological response defined as < 1 log10 drop at week 24 and switch to second/third line ART for treatment failure VL>400 c/ml at or after 36 weeks confirmed by next visit Death due to any cause Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, adjudicated by the Endpoint Review Committee | 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in proportion with clinical or virological failure (as defined above) |  | over 48 weeks. | 
| Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events adjudicated by the Endpoint Review Committee |  | after 24 weeks from randomisation | 
| Proportion of children with viral load suppression <50 c/ml |  | at 48 and 96 weeks | 
| Proportion of children with viral load suppression <400 c/ml |  | at 48 and 96 weeks | 
| Rate of clinical events : WHO 4, severe WHO 3 events and death |  | over 96 weeks | 
| Change in CD4 count and percentage and CD4/CD8 ratio from baseline |  | to weeks 48 and 96 | 
| Proportion developing new resistance mutations in those with viral load > 400 c/ml |  | 96 weeks | 
| Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) |  | from baseline to weeks 48 and 96 | 
| Incidence of serious adverse events |  | Through study completion, at least 96 weeks | 
| Incidence of new clinical and laboratory grade 3 and 4 adverse events |  | Through study completion, at least 96 weeks | 
| Incidence of adverse events (of any grade) leading to treatment modification |  | Through study completion, at least 96 weeks | 
| Health-related Quality of Life Questionnaire | Adapted from the EuroQol-5D questionnaire | Through study completion, at least 96 weeks | 
| Adherence Questionnaire | The proportion of adherence questionnaires where the participant/carer reports missing a dose within the last week will be compared between randomised groups. | Through study completion, at least 96 weeks | 
| Acceptability Questionnaire | Number of participants reported to have problems with size, taste or swallowing of the medicines as assessed by Acceptability questionnaire | Through study completion, at least 96 weeks |