Children with human immunodeficiency virus (HIV) in Africa - pharmacokinetics and acceptability/adherence of simple antiretroviral regimens (CHAPAS-3 trial)

ISRCTN	ISRCTN69078957
DOI	https://doi.org/10.1186/ISRCTN69078957
Protocol serial number	Version 1.0
Sponsor	Medical Research Council (UK)
Funders	The European Developing Countries Clinical Trials Partnership (EDCTP), Medical Research Council (UK), Department for International Development (DfID) (UK), The Ministerio de Sanidad y Consumo (Spain), Health Research Board (Ireland)

Submission date: 31/03/2010
Registration date: 15/04/2010
Last edited: 15/11/2019

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Diana Gibb
Scientific

MRC Clinical Trials Unit
222 Euston Road
London
NW1 2DA
United Kingdom

Study information

Primary study design	Interventional
Study design	Three-arm phase II/III open-label randomised trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	A randomised trial to compare the toxicity and pharmacokinetics of three fixed-dose combination based antiretroviral regimens for treatment of human immunodeficiency virus (HIV) infected children in Africa
Study acronym	CHAPAS-3
Study objectives	The overall hypothesis to be tested is that new paediatric fixed dose combination (FDC) baby and junior tablets which contain abacavir (ABC) or zidovudine (ZDV) rather than stavudine (d4T) will provide superior toxicity and/or adherence/acceptability profiles, whilst maintaining adequate pharmacokinetics and similar cost-effectiveness and viral load suppression in human immunodeficiency virus (HIV)-infected children taking combination antiretroviral therapy (ART).
Ethics approval(s)	Ethics approval sought from (pending as of 31/03/2010): 1. University College London (UCL) (UK) 2. Ugandan National Council for Science and Technology (UNCST) (Uganda) 3. Joint Clinical Research Centre IRB (Uganda) 4. Baylor College of Medicine (Uganda) 5. University of Zambia (Zambia)
Health condition(s) or problem(s) studied	Human immunodeficiency virus (HIV)
Intervention	Participants will be randomised in a 1:1:1 ratio at trial entry to start or continue antiretroviral therapy with either stavudine (d4T), abacavir (ABC) or zidovudine (ZDV) in combination with lamivudine (3TC) and a non-nucleoside reverse transcriptase inhibitor, NNRTI (nevirapine (NVP) or efavirenz (EFV)). All arms will use either triple fixed dose combination tablets or dual FDCs with separate NNRTI, as below: 1. Arm d4T: d4T/3TC/NVP or d4T/3TC + EFV 2. Arm ABC: ABC/3TC/NVP or ABC/3TC + EFV 3. Arm ZDV: ZDV/3TC/NVP or ZDV/3TC + EFV Children will be enrolled over 12 - 18 months and followed for 96 weeks after the last child is enrolled. Treatment will continue throughout the trial.
Intervention type	Drug
Phase	Phase II/III
Drug / device / biological / vaccine name(s)	Stavudine (d4T), abacavir (ABC), zidovudine (ZDV), lamivudine (3TC), nevirapine (NVP), efavirenz (EFV)
Primary outcome measure(s)	All children: Grade 2/3/4 clinical and/or grade 3 (confirmed) or 4 (any grade) laboratory adverse events. For PK substudies: Plasma pharmacokinetic parameters (AUC, Cmin, Cmax) of ABC, ZDV and 3TC in FDCs with or without NVP and of EFV from the full PK curves determined per age group at week 6.
Key secondary outcome measure(s)	All children: 1. Change in skinfold thicknesses from week 0 to 48 and 96 weeks (converted to age and sex-adjusted z-scores) 2. Change in body circumferences from week 0 to 48 and 96 weeks 3. Clinical and/or laboratory adverse events Grade 3 or 4, possibly or probably related to ABC, ZDV or d4T 4. Anaemia, neutropenia, lipodystrophy/lipoatrophy, mitochondrial disease, peripheral neuropathy and hypersensitivity reactions of any grade 5. Any AE leading to dose reduction or permanent/temporary interruption/substitution of ART 6. Changes in endothelial injury (functional and cellular) and inflammatory markers (D-Dimer, CRP, interleukin 6) from week 0 to 48 and 96 weeks. Vascular function parameters (Intima Media Thickness (IMT) of the carotid artery) and pulse wave velocity), CECs and EMPs will be measured using portable equipment, by a single investigator in each site. 7. Adherence as measured by electronic recording devices (MEMScaps) clinic-based pill counts, carer and child questionnaire including visual analogue scale from randomisation 8. Acceptability of once versus twice daily dosing by carer questionnaire 9. Change in HIV RNA viral load and proportion of children with HIV RNA less than 50 and less than 400 copies/ml from week 0 to 48 and 96 weeks (assayed retrospectively) 10. Cost and cost effectiveness 11. Change in CD4 and CD4 percent from week 0 to 48 and 96 weeks 12. Change in growth parameters (weight-for-age, height-for-age, weight-for-height) from week 0 to 48 and 96 weeks (converted to age and sex-adjusted z-scores) 13. Mortality and disease progression For PK substudies: Variability in pharmacokinetic parameters (AUC, Cmin, Cmax) at week 6 according to degree of malnourishment, degree of immune activation, age, weight, demographic characteristics, adherence measures, response to treatment, side effects and genetic polymorphisms.
Completion date	01/09/2013

Eligibility

Participant type(s)	Patient
Age group	Child
Lower age limit	1 Month
Upper age limit	13 Years
Sex	All
Target sample size at registration	420
Total final enrolment	480
Key inclusion criteria	1. Aged 1 month to 13 years, either sex: 1.1. ART naive children in Uganda being randomised to commence therapy on a d4T based regimen must be 0 - 4 years old in accordance with local guidelines 1.2. ART experienced children being randomised to continue therapy on a d4T based regimen must be 5 years or older with no clinical symptoms of lipodystrophy. If severe clinical symptoms of lipodystrophy develop whilst randomised to d4T then children will switch to another regimen. 2. Weighing greater than 3 kg and less than 25 kg (heavier children should receive adult tablets and not be enrolled in CHAPAS-3) 3. Participants must have a confirmed documented diagnosis of HIV-1 infection 4. Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to first-line ART strategy and participation in the PK substudy if eligible 5.1. ART naive (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission), meeting World Health Organisation (WHO) or national (WHO modified) criteria for initiating therapy and ready to start an initial 2NRTI+NNRTI based regimen according to local guidelines (i.e. according to WHO stage/CD4 and guidelines concerning first-line ART in children who have been exposed to NVP perinatally), or 5.2. Currently taking d4T based regimen for at least 2 years with screening HIV RNA viral load less than 50 copies/ml, no history of receiving other ARV drugs and CD4 count and/or CD4 percent stable over the previous 6 months 6. Able and willing to take each of the possible regimens
Key exclusion criteria	1. Cannot, or unlikely to attend regularly (e.g. usual residence too far from study centre) 2. Likelihood of poor adherence 3. Presence of acute infection 4. In receipt of medication contraindicated by ART or on chemotherapy for malignancy. Children under three years of age receiving anti-tuberculosis therapy should not be enrolled (as they will have to receive nevirapine). 5. Laboratory abnormalities which are a contra-indication for the child to start ART/change to any of the 3 possible regimens 6. Being pregnant or breast-feeding an infant 7. Perinatal exposure to NVP (either through pMTCT or breastfeeding) for children aged 3 - 6 months only
Date of first enrolment	01/05/2010
Date of final enrolment	01/09/2013

Locations

Countries of recruitment

United Kingdom
England
Uganda
Zambia

Study participating centre

MRC Clinical Trials Unit

London
NW1 2DA
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/02/2016	15/11/2019	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

15/11/2019: The following changes have been made:
1. Publication reference added.
2. The final enrolment number was added from the reference.