Condition category
Infections and Infestations
Date applied
11/08/2017
Date assigned
20/10/2017
Last edited
20/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Human immunodeficiency virus (HIV) is a virus that damages the cells in the immune system and weakens the body’s ability to fight everyday infections and disease. HIV is treated with antiretroviral medications which stop the virus replicating in the body. In 2014, an estimated 823,000 HIV-infected children and adolescents aged up to 15 years were receiving anti-retroviral therapy (ART) in low- and middle-income countries. From 2015, World Health Organisation (WHO) guidelines recommended all HIV-infected adults and children take ART, regardless of the strength of their immune system (CD4 count) or their clinical status. The numbers of HIV-infected children on first-line ART in low-income countries is therefore likely to continue to increase, despite reductions in many countries of new infections through mother-to child transmission. The growing number of children on ART, coupled with increased detection of ART treatment failure, will increase the number of children needing to switch from their first ART drug treatment (first line) to second-line treatment. This raises the question of whether current second-line ART is optimal in terms of maximising children’s health gains and minimising toxicity (side effects) from the treatment long-term, given the need for children to receive life-long ART. The current WHO-recommended second-line ART for children failing standard first-line treatment is not ideal, as it is based on a fixed dose combination drug which needs to be taken as whole (non-crushed) pills, mini-pill pellets or unpalatable liquid, and also interacts with anti-tuberculosis drugs. The aim of this study is to optimise second-line treatment in HIV-infected children by testing new antiretroviral drugs/formulations, in order to maximise long-term health gains.

Who can participate?
HIV-infected children aged 3-15 years weighing 14 kg or higher and failing first-line antiretroviral treatment

What does the study involve?
A screening visit involving blood tests is carried out to confirm that the child is eligible. Participants are then randomly allocated to one ‘third-drug’ and one ‘NRTI based regimen’.
The four ‘third-drug’ options are:
1. The current standard of care, called lopinavir/ritonavir (LPV/r)
2. A different drug which belongs to the same family as LPV/r, called atazanavir/ritonavir (ATV/r). This drug is used a lot in adults but has not previously been available as a single pill for children
3. A different drug that also belongs to the same drug family as LPV/r, called darunavir/ritonavir (DRV/r)
4. A drug which belongs to a different family, called dolutegravir (DTG)
The two ‘NRTI based regimens’ are:
1. The current standard of care, which is lamivudine (3TC) combined with whichever of abacavir (ABC) or zidovudine (ZDV) is not taken as first-line ART
2. A new drug called‘TAF (tenofovir alafenamide) combined with a drug very similar to lamivudine called emtricitabine (FTC). TAF is a new type of an existing ART drug called tenofovir which is much kinder on people’s bones and kidneys and so can be tested in children
Enough ART is prescribed for the participant to take daily until they are seen at their next clinic visit. Participants are followed up for 2 years with clinic visits every 3 months. At the visits side effects and responses to treatment are carefully checked by a nurse and a doctor. A small amount of blood is collected and stored at each visit. The first children enrolled into the study, plus children who receive anti- tuberculosis treatment during the study have additional blood tests to look at levels of the antiretroviral drugs in their blood.

What are the possible benefits and risks of participating?
There may be no direct benefit to the children participating in the study. However, the information from this study will help to improve treatment for children with HIV in the future. These children need to be treated with second-line ART regardless of whether or not they participate in the study, and all treatment has risks and side effects. The common side effects of ART are stomach upsets, changes in the liver, problems with kidney and bones, difficulty sleeping, hypersensitivity reactions and tiredness. Participating children need to attend the clinic more frequently than if they were receiving treatment outside of the study. In addition there are some extra blood tests.

Where will the study be run?
1. University of Zimbabwe Clinical Research Centre (UZCRC), Harare (Zimbabwe)
2. University Teaching Hospital, Lusaka (Zambia)
3. Joint Clinical Research Centre (JCRC), Kampala (Uganda)
4. It is coordinated by the Medical Research Council Clinical Trials Unit at UCL, London (UK)

When is the study starting and how long is it expected to run for?
April 2017 to March 2022

Who is funding the study?
European and Developing Countries Clinical Trials Partnership

Who is the main contact?
CHAPAS-4 Trial Management Team
mrcctu.chapas4@ucl.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Prof Diana Gibb

ORCID ID

http://orcid.org/0000-0002-9738-5490

Contact details

MRC Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
90 High Holborn
2nd Floor
London
WC1V 6LJ
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

Children with HIV in Africa – pharmacokinetics and acceptability of simple antiretroviral regimens (CHAPAS-4 trial): a randomised controlled trial

Acronym

CHAPAS-4

Study hypothesis

The CHAPAS 4 trial will evaluate four new drugs/formulations (dolutegravir (DTG), tenofovir alafenamide (TAF), darunavir/ritonavir (DRV/r) and atazanavir/ritonavir (ATV/r)) to optimise treatment for children, and better harmonise with adult anti-retroviral therapy (ART). CHAPAS-4 will also evaluate options for second-line treatment given concomitantly with anti-tuberculosis drugs.

There are four main hypotheses:
1. DTG will provide superior virological suppression 96 weeks after starting second-line ART compared to second-line ART based on the bPIs LPV/r or ATV/r
2. DRV/r will provide superior virological suppression 96 weeks after starting second-line ART compared to second-line ART based on the bPIs LPV/r or ATV/r
3. ATV/r will provide non-inferior virological efficacy compared to lopinavir/ritonavir (LPV/r) in second-line ART
4. TAF will provide non-inferior virological efficacy compared to standard of care NRTIs in second-line ART

Ethics approval

1. UCL Research Ethics Committee, 21/07/2017, ref: 11205/001
2. Ethics approval sought from the appropriate national ethics committees in Uganda, Zambia and Zimbabwe

Study design

4x2 open-label factorial multi-centre randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

HIV

Intervention

A screening visit involving blood tests will be carried out to confirm that the child is eligible. Consented participants will then be randomly assigned to one ‘third-drug’ and one ‘NRTI based regimen’. Randomisation lists will be prepared by the trial statistician using permuted blocks and sites will randomise using the trial database.

Specifically, one third drug from (randomised in a 1:1:1 ratio):
1. Research: dolutegravir (DTG) once-daily (OD) (an integrase inhibitor, INI)
2. Research: atazanavir/ritonavir (ATV/r) OD (boosted protease inhibitor, bPI)
3. Research: darunavir/ritonavir (DRV/r) OD (boosted protease inhibitor, bPI)
4. Standard of care: lopinavir/ritonavir (LPV/r) twice-daily (BD) (bPI)

Together with one nucleoside reverse transcriptase inhibitor (NRTI) backbone from (randomised in a 1:1 ratio):
1. Research: tenofovir-alafenamide (TAF) plus emtricitabine (FTC) OD
2. Standard of care: whichever of abacavir (ABC) (OD) or zidovudine (ZDV) (BD) has not been used first-line, plus lamivudine (3TC)

The route of administration will be oral and each drug will be dosed according to weight bands.

Enough ART will be prescribed for the participant to take daily until they are seen at their next clinic visit. Participants will be followed up for 2 years with clinic visits every 3 months. At the visits side-effects and responses to treatment will be carefully checked by a nurse and a doctor. A small amount of blood will be collected and stored at each visit. The first children enrolled into the study, plus children who receive anti-TB treatment during the study will have additional blood tests to look at levels of the antiretroviral drugs in their blood.

Children will be enrolled over 18 months and followed for 96 weeks. Treatment will continue throughout the trial.

Intervention type

Drug

Phase

Phase III

Drug names

Dolutegravir, atazanavir, darunavir, ritonavir, lopinavir, tenofovir, alafenamide, emtricitabine, abacavir, lamivudine, zidovudine

Primary outcome measure

Percentage of children alive with viral load <400 copies/mL, measured with lab test at baseline and weeks 6, 24, 48, 72, 96

Secondary outcome measures

Secondary outcome measures through 96 weeks are:
1. Percentage of children alive with viral load <50 and <1000 copies/mL, measured with lab test at baseline and weeks 6, 24, 48, 72, 96
2. Change in Stanford drug resistance, accumulation of new NRTI, PI and INI resistance-associated mutations in those with VL> 400 copies/mL, measured with lab test at weeks 48, 96
3. Percentage modifying ART due to adverse events (AEs), incidence/type of grade 3/4 AEs and serious AEs, measured throughout the study as they occur (investigator reported, reviewed by blinded Endpoint Review Committee)
4. Changes in total, LDL, HDL cholesterol and triglycerides, measured using lab test at baseline, weeks 48, 96
5. Changes in renal function (creatinine clearance estimated using bedside-Schwartz) and bilirubin, measured using lab test at baseline, weeks 6, 24, 48, 96
6. Changes in absolute and percentage CD4, measured using lab test at baseline, weeks 24, 48, 72, 96
7. New or recurrent WHO 3 or 4 events or death, reported on an event form by the site clinician and initially clinically reviewed at MRC CTU by the trial physician and finally reviewed and adjudicated by an independent endpoint committee
8. Self-reported adherence and acceptability, measured using nurse-led questionnaires and pill counts at all visits (baseline, weeks 2, 6, 12, 24, 36, 48, 60, 72, 84, 96)

Other outcome measures are:
1. Hospital inpatient episodes and total days admitted through 96 weeks, measured throughout the study as they occur (investigator reported)
2. Changes in bone mineral density Z-scores assessed by calcaneal ultrasound at baseline, weeks 6, 24, 48, 72, 96 and in a sub-set of patients measured by DEXA scan at baseline, weeks 48, 96
3. Changes in weight-for-age, height-for-age and body mass index-for-age Z scores, measured at all visits (baseline, weeks 2, 6, 12, 24, 36, 48, 60, 72, 84, 96)
4. Body composition, measured by bioelectrical impedance analysis
5. Population pharmacokinetics, measured using lab test at weeks 6, 24, 48, 72, 96
6. Cost-effectiveness: at the end of the trial health economists will analyse data collected on medical resource utilisation (e.g. hospital stays, drug usage) with data on clinical, virological and quality of life outcomes

Overall trial start date

01/04/2017

Overall trial end date

01/03/2022

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. HIV-infected failing first-line treatment with abacavir-, zidovudine- or stavudine-containing NRTI+NNRTI regimens as per current WHO criteria
2. Aged 3-15 years inclusive
3. Weight 14 kg or higher
4. Viral load >400 copies/ml at screening visit
5. Able to swallow trial drug tablets (all children will have been receiving tablets within first-line ART)
6. Parents/carers give informed written consent; child provides informed written assent as appropriate based on age, knowledge of HIV status and local country guidelines

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

1000

Participant exclusion criteria

1. History or presence of known allergy or other contraindication to the study drugs or their
components
2. Treatment of co-morbidities, except TB, with significant drug interactions with the study drugs, requiring their dose adjustment
3. More than 3 months (>91 days) from the screening visit

Recruitment start date

01/04/2018

Recruitment end date

01/10/2020

Locations

Countries of recruitment

Uganda, Zambia, Zimbabwe

Trial participating centre

University of Zimbabwe Clinical Research Centre (UZCRC)
Harare
1578 Avondale
Zimbabwe

Trial participating centre

Joint Clinical Research Centre (JCRC)
Kampala
PO Box 10005
Uganda

Trial participating centre

University Teaching Hospital
Lusaka
PO Box 50110
Zambia

Sponsor information

Organisation

University College London (UK)

Sponsor details

Gower Street
London
WC1E 6BT
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Research organisation

Funder name

European and Developing Countries Clinical Trials Partnership

Alternative name(s)

EDCTP

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

Netherlands

Results and Publications

Publication and dissemination plan

1. The protocol will be available on the MRC CTU at UCL webpage
2. Planned publication of study results in a high-impact peer reviewed journal

IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Gibb (mrcctu.chapas4@ucl.ac.uk) after main publication following the Unit’s Data Sharing SOP and after approval from the Trial Steering Committee, which has majority independent membership, for any approved analyses, all data is anonymised.

Intention to publish date

01/03/2023

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes