An Adaptive Platform Trial for Evaluation of Novel Treatment Regimens in Children and Adolescents With HIV in Africa

CHAPAS-5 is a study organised by an international group of researchers from the United Kingdom, Uganda, Mozambique, Zimbabwe, Italy and the Netherlands.

Background HIV is a virus that attacks the cells that help the body fight infection. This means that a person living with HIV may be more likely to become ill as they are not able to fight off other infections and cope with other illnesses. HIV is usually treated by taking three or four different medicines. Some of these medicines can be combined into one tablet. Depending on the medicines used, tablets may need to be taken either once or twice every day. The medicine is called antiretroviral therapy (ART).

The goal of HIV treatment is to make sure the HIV virus in the blood remains very low; this is called virological suppression. If this goal is achieved and sustained life-long, then people with HIV infection can live a healthy life, with a normal life expectancy. Adults living with HIV have many treatment options. This means that they can change treatments more easily if they get side-effects or if a treatment stops working.

Children and adolescents living with HIV have fewer available treatments than adults and only limited alternatives if they develop side-effects or if their current treatment stops working. As HIV treatment needs to be life-long for a person to live a long, healthy and productive life, it is really important that better treatment options are made available to children and adolescents.

A clinical trial is a study that compares different treatments to find out which works best. Traditional trials usually compare only two treatments at a time. CHAPAS-5 uses a newer trial design that can compare several treatments at the same time in two different groups of children. It will test three treatment options for children and adolescents starting ART for the first time (ART-naïve), and four options for those already on ART whose current treatment is not working well (ART-experienced).

Which treatments are being compared?

1. Dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) - naive and experienced
2. Dolutegravir/tenofovir alafenamide/emtricitabine (DTG/TAF/FTC) - naive and experienced
3. Dolutegravir/lamivudine (DTG/3TC) - naive
4. Darunavir/ritonavir (DRV/r) + tenofovir alafenamide/emtricitabine (TAF/FTC) - experienced
5. Darunavir/ritonavir (DRV/r) + abacavir/lamivudine (ABC/3TC) - experienced

Additional treatments, such as long-acting injectables, may be added to the trial as they become available. These could remove the need for daily pills and help improve adherence.

Who can join the trial? CHAPAS-5 will enrol participants in Uganda, Zimbabwe, and Mozambique.

The study includes children and adolescents aged at least 4 weeks to less than 15 years and weighing 3 to less than 30kg who:

* Are starting ART for the first time, or
* Are already on DTG-based ART but their HIV is not suppressed, and
* Have at least two treatment options in the trial that their doctor considers suitable for them.

What will be measured?

* How well the virus is controlled using a blood test called the viral load
* Side effects from the treatment
* How well children are able to take their treatment as prescribed
* How easy the treatment is to take and how well it fits into daily life
* Mental health and quality of life
* The costs of different treatment options and how cost-effective they are

Participants are followed for at least 48 weeks.

Novel design CHAPAS-5 uses a novel design called the Personalised Randomised Controlled Trial (PRACTical) design. This means that each participant will be randomly allocated to receive a treatment from a list which contains only the treatment options that are appropriate for them. The treatments will be ranked from best performing to worst performing based on how well they work for participants. This will researchers to identify which treatments work best for different groups of children.

Why this trial matters? CHAPAS-5 aims to identify the best treatments for children that work well and are easy to take, with fewer side effects. The trial will also evaluate point-of-care CD4 testing to speed up diagnosis and treatment for children with advanced HIV disease and assess targeted resistance testing to identify those who may need to change treatment.

Broader Implications CHAPAS-5 not only tests different treatment options but aims to speed up the testing of HIV treatments for children so that better options can become available more quickly. The trial findings will help inform national and international guidelines and country treatment policies. This could improve future HIV treatment options for children and adolescents living with HIV.

• Dolutegravir (DTG) (Drug): Dosage will be by weight band. Adult and paediatric, and single dose/fixed dose combination tablets will be used depending on availability in country and the weight band of the child.
• Abacavir (ABC) (Drug): Dosage will be by weight band. Adult and paediatric, and single dose/fixed dose combination tablets will be used depending on availability in country and the weight band of the child.
• Lamivudine (3TC) (Drug): Dosage will be by weight band. Adult and paediatric, and single dose/fixed dose combination tablets will be used depending on availability in country and the weight band of the child.
• Tenofovir alafenamide (TAF) (Drug): Dosage will be by weight band. Adult and paediatric, and single dose/fixed dose combination tablets will be used depending on availability in country and the weight band of the child.
• Emtricitabine (FTC) (Drug): Dosage will be by weight band. Adult and paediatric, and single dose/fixed dose combination tablets will be used depending on availability in country and the weight band of the child.
• Darunavir (DRV) (Drug): Dosage will be by weight band. Adult and paediatric, and single dose/fixed dose combination tablets will be used depending on availability in country and the weight band of the child.
• Ritonavir (RTV) (Drug): Dosage will be by weight band. Adult and paediatric, and single dose/fixed dose combination tablets will be used depending on availability in country and the weight band of the child.

Primary outcomes

• The proportion of participants alive with HIV VL <400 c/mL at 48 weeks [Week 48]: For participants with an initial week 48 VL ≥400 copies/mL, a repeat VL is required, and the repeat value will be used for outcome classification.

Secondary outcomes

• The proportion of participants alive with HIV VL<1000 c/mL at 48 weeks [Week 48]: For participants with an initial week 48 VL ≥400 copies/mL, a repeat VL is required, and the repeat value will be used for outcome classification.
• The proportion of participants with cross-sectional HIV VL ≥50 copies/mL, ≥400 copies/mL, and ≥1000 copies/mL at 48 weeks [Week 48]: Using the single VL measurement closest to the week 48 timepoint within the analysis window (will include blips and confirmed measures).
• The proportion of participants with emergent drug resistance by 48 weeks [Week 48]
• Time to first serious adverse events (SAEs), grade ≥3 adverse events (AEs) and ART-modifying events of any grade [From randomisation to the last study visit (minimum of 48 weeks)]
• Time to first new or recurrent WHO 3/4 events, or death [From randomisation to the last study visit (minimum of 48 weeks)]
• Change in CD4 count and CD4 percentage from baseline to week 48 [From baseline to week 48]
• Change in weight and BMI-for-age from baseline to week 48 [From baseline to week 48]

Other outcomes

• Adherence and acceptability [From baseline to last study visit (minimum 48 weeks)]: Participant or parent/carer reported adherence to trial medications via a short series of questions (Adherence Questionnaire). Participant or parent/carer reported acceptability of trial medications using the Paediatric Oral Medicine Acceptability Questionnaire (POMAQ).
• Depression, anxiety, suicidality and sleep [From baseline to last study visit (minimum 48 weeks)]: Participant or parent/carer reported depression, anxiety and sleep using a trial-specific Mood and Sleep questionnaire. Participant or parent/carer reported suicidality at screening using the C-SSRS (Columbia-Suicide Severity Rating Scale) Screener questionnaire.
• Quality of Life using EQ-5D-Y-5L [From baseline to last study visit (minimum 48 weeks)]: Participant and parent/carer reports of health-related quality-of-life using the EuroQol-5 Dimension (EQ-5D) questionnaire. This questionnaire includes a scale of 0-100 where a higher score means a better outcome.

Sex: All, ages: 4 Weeks to 14 Years

INCLUSION CRITERIA:

1. Aged ≥ 4 weeks to <15 years* with confirmed HIV infection
2. Weight ≥3kg and <30kg*
3. Written informed consent obtained (and assent if applicable)
4. Willing to adhere to a minimum of 48 weeks' follow-up

   * Upper limits of 15 years and 30kg are for initial treatment options and may be amended when further treatment options are introduced (through a protocol amendment)

ART-NAÏVE

1. Planning to start first-line ART
2. Virologically unsuppressed with VL ≥400 c/mL at screening

ART-EXPERIENCED

1. ART-experienced, and on DTG-based ART, and have been on DTG-based ART for at least 6-months prior to screening
2. Virologically unsuppressed for at least 3 months, demonstrated by two consecutive VLs ≥400 c/mL in the last year; the second VL must be at screening
3. Received adherence counselling as per standard practice prior to screening

EXCLUSION CRITERIA

1. Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR both ALT ≥3xULN and bilirubin ≥2xULN at screening**
2. 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)
3. Severe renal impairment, defined as creatinine clearance <30 mL/min/1.73m2, at screening**
4. Severe life-threatening illness (not expected to survive beyond two weeks) as determined by the investigator's clinical judgment.
5. Eligible for less than two permitted treatment options based on tables 3 (ART-naive participants) and 4 (ART-experienced participants)
6. Concurrent participation in another clinical trial of an investigational medicinal product (IMP), medical device or other intervention.

   * If ALT, bilirubin or creatinine results are available before randomisation and meet exclusion criteria, the child should not be randomised. However, randomisation may proceed while awaiting these results. If results become available after randomisation and meet exclusion criteria, the participant must be recalled and withdrawn from the trial and the InCTU trial physician contacted to discuss clinical management.