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

CHAPAS-5: An Adaptive Platform Trial for Evaluation of Novel Treatment Regimens in Children and Adolescents With HIV in Africa

The goal of the CHAPAS-5 clinical trial is to find out how well different HIV treatments work in children and young people (from 4 weeks up to under 15 years old) living with HIV, including those starting treatment for the first time and those whose current treatment is not working well.

The study aims to learn whether newer or different combinations of medicines can better control the virus, be safer, and be easier to take.

The main questions it aims to answer are:

• Can these treatments help children stay alive and keep their HIV virus at very low levels (viral load below 400) after 48 weeks?
• Which treatment options are most effective, safest, and easiest for children and their carers to use?

Researchers will compare different treatment groups to see if some medicines work better than others. Participants will be given one of several HIV treatment combinations (all already used in care), and these will be compared to see if they lead to:

• Better control of HIV
• Fewer side effects
• Improved quality of life

Participants will:

• Be randomly assigned (like flipping a coin by computer) to one suitable HIV treatment
• Take their HIV medication every day as prescribed
• Attend clinic visits over about 1-2 years

At these visits, they will:

• Have blood tests to check HIV levels and general health

• Have health check-ups (e.g. weight, symptoms, side effects)

• Answer simple questionnaires about:

  • How easy the treatment is to take
  • Mood, sleep, and wellbeing
  • Quality of life

• Receive support to help them take their medication regularly

Some participants may also take part in optional extra studies (for example, to understand how the drugs work in the body).

Overall, this study aims to identify the best HIV treatments for children and young people, so future care can be more effective, safer, and easier to follow.

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.

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.