Condition category
Respiratory
Date applied
12/03/2020
Date assigned
15/05/2020
Last edited
15/05/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Children with severe chest infections often receive long courses of antibiotics that are given by injection. Children have to stay in hospital for these injections, which is costly for parents/carers and the health system, and means the children may pick up other infections, including new infections which cannot be treated by standard antibiotics (antibiotic-resistant infections). Some doctors change children onto antibiotics that can be taken by mouth (oral antibiotics) as soon as they are well enough. Once children are doing better, oral antibiotics are likely to be as good as continuing with antibiotic injections. It also means that children can go home sooner as they don’t need injections for as long. However, to date no studies have looked at this specifically in this group of children in hospital with severe chest infections in low- and middle-income settings, so changing to oral antibiotics cannot be recommended by governments. It is also not known how long children with serious chest infections actually need to take antibiotics for. The longer antibiotics are taken, the more likely it is that other bacteria living in the body become more resistant to antibiotics, meaning that antibiotics won’t work as well for infections in the future. So, children need to be given just enough antibiotics to make them well, but not so much that bacteria develop more resistance and perhaps won’t work next time. Surprisingly almost no studies have looked at exactly how long children need to take antibiotics to get better. The aim of this study is to answer the following questions:
1. Is the rate of clinical cure better if children move from injectable antibiotics to oral co-amoxiclav or oral amoxicillin antibiotics once they are well enough to take drugs by mouth, and how does this compare to staying on injectable antibiotics?
2. What is the best duration of antibiotic treatment for children that gives good rates of clinical cure while reducing how long they have to stay in hospital, the side effects they experience and the presence of other antibiotic-resistant bacteria?
3. Does this best duration depend on other factors, such as age, having been exposed to HIV, having malnutrition or how serious the chest infection is, suggesting that how long children get antibiotics for should be vary based on these risk factors?
4. What ratio of amoxicillin to clavulanate should be used in co-amoxiclav for children?

Who can participate?
Children aged 2 months to 6 years of age, who weigh between 3 kg and 30 kg, and who have pneumonia (chest infection) that has developed while they are at home and is so serious that they need to be treated in hospital.

What does the study involve?
All children will start on the World Health Organisation (WHO)-recommended injectable antibiotics. When they are well enough to take drugs by mouth, they will be randomly allocated to move to one oral antibiotic called co-amoxiclav, or another oral antibiotic called amoxicillin, or they will stay on injectable antibiotics. Both of these oral drugs should be highly effective, but the researchers want to find out if co-amoxiclav is actually any better. Co-amoxiclav is mostly given to children as a liquid, and needs to be kept cool. In the study tablets are used that become liquid when mixed with small amounts of other liquids (e.g. water). If co-amoxiclav really is better, these tablet formulations need to become more widely available. It is not known how long the antibiotic treatment needs to last. Children will be randomly allocated to get their antibiotics for 4, 5, 6, 7 or 8 days in total. These durations are used in different parts of the world and there is no evidence that any one is better than the other. The researchers will follow the children for 28 days over the telephone and through face-to-face visits to find out whether they have had any problems. They will focus on whether they have to be admitted to hospital again or whether they have died. They will also look at how long they have to stay in hospital (since parents/carers typically have to pay for this), how many antibiotics children take during the month after being admitted to hospital, how much they need other treatments like extra oxygen, and how much all their care costs. In an extra part of the study, the researchers will look at the amount of the two drugs that make co-amoxiclav. Across the world, different ratios are used and there are no data to tell us which might be the best for children. In the main part of the study, the researchers will use a tablet with 7 parts amoxicillin to 1 part clavulanate, because this is most commonly used in Europe. In a subset of these children, they will measure how much of the drug gets into their blood. In the extra part of the study, the researchers will measure drug levels in children getting either 4 parts amoxicillin to 1 part clavulanate or 14 parts amoxicillin to 1 part clavulanate. These ratios are each used elsewhere in the world. The researchers will also look to see whether these ratios lead to different rates of side-effects like tummy upsets which are important for parents.

What are the possible benefits and risks of participating?
Entering this study may not directly benefit the participants, but the information learnt from the PediCAP study will help to work out the best way to treat other children who have severe chest infections in the future. The child may also receive closer hospital care than in the general hospital. The main possible side effects associated with the antibiotics used are as follows. Diarrhoea and tummy upsets: these are common, but are usually mild and stop when the antibiotic is finished. Rashes: these are less common, but usually happen very soon after starting the drugs, which would be whilst children are still in hospital. Thrush: again this is less common, it is usually mild and stops when the antibiotic is finished. Very rarely, children can have an allergic reaction immediately after starting an antibiotic. This would happen in hospital and will be managed by hospital doctors in the same way whether or not the child joins the study. In the future, it may become apparent that a child may or may not have received what proved to be the best treatment. However, at the moment it is not known what the best treatment is, which is the reason the researchers are doing the study.

Where is the study run from?
1. Wits Health Consortium (South Africa)
2. Africa Health Research Institute (AHRI) (South Africa)
3. Makerere University (Uganda)
4. University of Zambia (Zambia)
5. University of Zimbabwe Clinical Research Centre (UZCRC) (Zimbabwe)

When is the study starting and how long is it expected to run for?
April 2019 to April 2024

Who is funding the study?
European Developing Countries Clinical Trials Partnership (EDCTP)

Who is the main contact?
Prof. Michael Sharland
mrcctu.pedicap@ucl.ac.uk

Trial website

https://penta-id.org/antimicrobials/pedicap/

Contact information

Type

Scientific

Primary contact

Prof Michael Sharland

ORCID ID

Contact details

Chief Investigator
St George’s University of London
Cranmer Terrace
Tooting
London
SW17 0RE
United Kingdom
+44 (0)20 8725 0666
msharland@sgul.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

Nil known

Study information

Scientific title

Impact of oral step-down to amoxicillin or co-amoxiclav and of duration of antibiotic therapy on effectiveness, safety and selection of antibiotic resistance in severe childhood community-acquired pneumonia (CAP): a randomised controlled trial

Acronym

PediCAP

Study hypothesis

PediCAP-A:
1. Oral co-amoxiclav step-down is superior to oral amoxicillin step-down for preventing readmission or death within 28 days of commencing treatment.
2. Randomising children between 5 different total durations of antibiotics including intravenous plus oral step-down will identify the minimum duration providing outcome rates within specific thresholds of the WHO-recommended 5 days' intravenous regimen.

PediCAP-A plus PediCAP-B:
1. Clavulanate PK exposures will be linear across the three formulation strengths used worldwide (4:1, 7:1, 14:1).

Ethics approval

1. Approval pending, University College London Research Ethics Committee, UK
2. Approval pending, University of Witwatersrand Human Research Ethics Committee: (Medical), South Africa, ref: 190913B
3. Approved 12/12/2019, Makerere University School of Medicine Research Ethics Committee, Uganda, ref: 2019-162
4. Approval pending, University of Zambia Biomedical Research Ethics Committee, Zambia, ref: 328-2019
5. Approval pending, Joint Research Ethics Committee for the University of Zimbabwe, College of Health Sciences and Parirenyatwa Group of Hospitals, Zimbabwe

Study design

Open-label parallel-group 2x5 factorial randomised trial plus a parallel Phase II pharmacokinetic 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 contact details to request a participant information sheet

Condition

Paediatric community-acquired pneumonia

Intervention

Open-label parallel-group 2x5 factorial randomised trial assessing 2 different oral step-down antibiotics (amoxicillin and co-amoxiclav (amoxicillin:clavulanate 7:1)) given after intravenous antibiotics for a total of 5 different durations (factorial design) with an additional continued intravenous control group, using a novel design to optimise duration of treatment (main trial, PediCAP-A)

Plus a parallel Phase II pharmacokinetic (PK) trial comparing two additional different ratios for one of the oral step-down options, co-amoxiclav (14:1 and 4:1) (PediCAP-B), to enable the PK of all three ratios to be compared across the main trial (PediCAP-A) and the PK trial (PediCAP-B)

All children will initiate or have already initiated treatment with WHO-recommended intravenous antibiotics.

In the main trial (PediCAP-A), children who have received at most 24 hours of intravenous antibiotics will be randomised to step-down from intravenous antibiotics when they are clinically stable and able to take oral medication to either oral amoxicillin or oral co-amoxiclav (7:1 amoxicillin:clavulanate) (1:1), both as dispersible tablets for a total duration of 4, 5, 6, 7 or 8 days antibiotics (1:1:1:1:1) (from start of intravenous antibiotics) (total 10 groups), or to remain on intravenous antibiotics for a total of 5 days following current WHO recommendation (additional eleventh group of the same size as each duration/drug group).

In the parallel Phase II PK trial (PediCAP-B), children who have received at most 24 hours of intravenous antibiotics will be randomised to step-down from intravenous antibiotics when they are clinically stable and able to take oral medication to either oral co-amoxiclav 4:1 or 14:1 (1:1) for a total duration of 6 days antibiotics (from start of intravenous antibiotics) (two groups). All children will receive at least 24 hours of intravenous antibiotics before stepping down to oral medication.

Intervention type

Drug

Phase

Phase II

Drug names

Amoxicillin, clavulanate

Primary outcome measure

For the main trial (PediCAP-A):
Hospital readmission occurring from the date of initial discharge to day 28 or death (all-cause) occurring from the date of randomisation to day 28

For the Phase II PK trial (PediCAP-B):
Plasma exposure to amoxicillin and clavulanate measured using LC-MS/MS methods in samples taken when children start oral antibiotics

Secondary outcome measures

For the main trial (PediCAP-A), within 28 days of randomisation:
1. CAP-related readmission occurring at any time from the date of initial discharge to day 28 or CAP-related mortality occurring at any time from the date of randomisation to day 28
2. Length of stay required during the index hospitalisation calculated from the date of randomisation to the initial date of discharge, and overall through 28 days calculated from the date of randomisation to the initial date of discharge plus any additional days of hospitalisation from the date of discharge to day 28
3. Mortality (all-cause) occurring at any time during the 28 days of trial follow-up
4. Duration of supplemental oxygen during the index hospitalisation calculated from the date of randomisation to the date of discharge
5. Total days of antibiotic exposure through 28 days calculated from the date of randomisation to day 28
6. Modification of randomised antibiotics for any reason except early stopping or receipt of subsequent course of antibiotics for any reason occurring at any time during the 28 days of trial follow-up
7. Modification of randomised antibiotics for inadequate response or additional courses for CAP relapse occurring at any time during the 28 days of trial follow-up
8. Serious adverse events occurring at any time during the 28 days of trial follow-up
9. Grade 3 or 4 adverse events occurring at any time during the 28 days of trial follow-up
10. Adverse events of any grade related to antibiotics occurring at any time during the 28 days of trial follow-up
11. Key solicited events, specifically diarrhoea, vomiting and gastrointestinal disorders, skin rash, thrush/candida occurring at any time during the 28 days of trial follow-up
12. Modification of antibiotics for adverse reactions occurring at any time during the 28 days of trial follow-up
13. Specific clinical complications, including sepsis, lung abscess, empyema occurring at any time during the 28 days of trial follow-up
14. Line complications occurring at any time during hospitalisation
15. Antimicrobial resistance measured using antimicrobial susceptibility testing or whole-genome sequencing of isolates cultured from nasal and faecal swabs taken at baseline, the earlier of discharge and day 3, and day 28
16. Cost and cost-effectiveness measured using a questionnaire at day 28

Overall trial start date

01/04/2019

Overall trial end date

01/04/2024

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Aged 2 months to 6 years inclusive
2. Weighing >= 3 kg and <30 kg
3. Admitted to hospital with severe pneumonia judged to require at least 24h of intravenous antibiotics by the treating physician
4. Difficulty breathing (with or without cough reported by parent/carer) PLUS one or more of
4.1. Central cyanosis or hypoxaemia (room air pulse oximetry <90%)
4.2. Any sign of severe respiratory distress (e.g. severe chest indrawing, grunting, nasal flaring, head nodding)
4.3. Signs of pneumonia (fast breathing (defined as respiratory rate ≥50 breaths per minute at age 2-11 months and ≥40 breaths per minute at age 1 years or older) or chest indrawing) PLUS a general danger sign (inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions) occurring at any time from admission up to randomisation.
5. About to initiate or already initiated intravenous benzylpenicillin plus gentamicin, ampicillin plus gentamicin, benzylpenicillin or ampicillin alone, ceftriaxone alone or cefotaxime alone
6. Received at most 24h of these intravenous antibiotics at the point of randomisation (that is, first dose of any intravenous antibiotics must have been administered no more than 24h previously at randomisation)
7. Parent/carer willing to accept and adhere to all possible randomised allocations for their child, including 5 days of intravenous antibiotics, and signed written informed consent available from parent/carer
8. Available for follow-up for the entire study period; specifically, parent/carer willing to return with their child to clinic at 4 weeks, and be contacted at minimum by telephone at weeks 1, 2 and 3

For children enrolled in PK (Section 10.1) or microbiology (Section 10.2) substudies, additional inclusion criteria are:
9. If undergoing additional PK sampling: willing to provide samples and potentially to stay in hospital for up to an additional 12h (separate consent will be obtained for PK sampling which may be refused and the child still join the main trial (PediCAP-A): consent for PK sampling is required for inclusion in the Phase II PK trial (PediCAP-B))

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

1220 (1100 in PediCAP-A and 120 in PediCAP-B)

Participant exclusion criteria

1. Point-of-care semi-quantitative C-reactive protein (CRP) test < 10 mg/l at screening (very unlikely to represent severe pneumonia requiring antibiotics)
2. Likely nosocomial pneumonia (onset >48h post-admission)
3. Admitted to hospital overnight in the last 28 days (possibility of nosocomially-acquired pneumonia)
4. Known or anticipated need for invasive ventilation or admission to intensive care
5. Clinician considers this episode to be predominantly due to reactive airways disease (e.g. asthma) (wheeze responsive to bronchodilators, see Manual of Operations (MOP) for more details)
6. Clinician considers this episode to be due to viral bronchiolitis alone in a child under 1 year
7. Documented penicillin allergy or contra-indications to penicillin/amoxicillin/co-amoxiclav
8. Anticipated need for systemic treatment with an antibiotic other than trial regimens during hospital admission or in the following 28 days (e.g. for Pneumocystis jiroveci)
9. On long-term antibiotics for prophylaxis or treatment (e.g. for tuberculosis treatment or cotrimoxazole prophylaxis for HIV infection)
10. Previously enrolled in PediCAP

Recruitment start date

01/06/2020

Recruitment end date

30/04/2022

Locations

Countries of recruitment

South Africa, Uganda, Zambia, Zimbabwe

Trial participating centre

Wits Health Consortium
Chris Hani Baragwanath Academic Hospital, Soweto, Gautang Province Wits Health Consortium 31 Princess of Wales Terrace Parktown
Johannesburg
2193
South Africa

Trial participating centre

Africa Health Research Institute (AHRI)
King Edward VIII Hospital Sydney Road Umbilo
Durban
4013
South Africa

Trial participating centre

Makerere University
College of Health Sciences PO Box 7072
Kampala
PO Box 7072
Uganda

Trial participating centre

University of Zambia
School of Medicine University Teaching Hospitals - Children Hospital PO Box 50110
Lusaka
PO Box 50110
Zambia

Trial participating centre

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

Sponsor information

Organisation

PENTA Foundation

Sponsor details

Torre di Ricerca Pediatrica
Corso Stati Uniti 4
Padova
35127
Italy
+39 (0)49 964 0122
info@penta-id.org

Sponsor type

Research organisation

Website

https://www.penta-id.org/

Funders

Funder type

Research organisation

Funder name

European and Developing Countries Clinical Trials Partnership

Alternative name(s)

Le partenariat Europe-Pays en développement pour les essais cliniques, A Parceria entre a Europa e os Países em Desenvolvimento para a Realização de Ensaios Clínicos, The European & Developing Countries Clinical Trials Partnership, EDCTP

Funding Body Type

private sector organisation

Funding Body Subtype

international

Location

Netherlands

Results and Publications

Publication and dissemination plan

The PediCAP TSC is the custodian of the data and specimens generated from the PediCAP trial; PediCAP trial data are not the property of individual participating investigators or health care facilities where the data were generated.

It is anticipated that a number of opportunities will arise for publication during the course of and following completion of the PediCAP trial. Publications include papers (including abstracts) for presentation at national and international meetings, as well as the preparation of manuscripts for peer-reviewed publication. In order to avoid disputes regarding authorship, it is important to establish a consensus approach that will provide a framework for all publications derived in full or in part from this clinical trial. The following approach is derived from the Lancet and from the publication policies used in other clinical trials coordinated by the MRC CTU at UCL:

All publications are to be approved by the TMG and TSC before submission for publication. Any publication arising before the end of the trial (not by randomised groups) will also be approved by the DMC in order to ensure that the primary objective of the trial (the randomised comparison) is not compromised. In particular, no analyses by randomised group of any outcome (primary, secondary or other) in either the main trial (PediCAP-A) or the Phase II PK trial (PediCAP-B) or any of the associated substudies will be conducted or presented before the end of the trial, other than those for interim review by the DMC. The TMG and TSC will resolve problems of authorship and maintain the quality of publications.

In line with MRC policy that the results of publicly-funded research should be freely available, manuscripts arising from the trial will, wherever possible, be submitted to peer-reviewed journals which enable Open Access via UK PubMed Central (PMC) within six months of the official date of final publication. All conference presentations will be made available as soon as possible after the event via the PediCAP website. All publications will acknowledge the trial's funding sources.

For all publications, the TMG will nominate a chairperson or approve an individual’s request to chair a manuscript writing committee. The chair will usually be the primary or senior author. The chairperson is responsible for identifying fellow authors and for determining with that group the order of authorship that will appear on the manuscript. The TSC will resolve any problems of authorship and maintain the quality of publications.

The TMG will maintain a list of investigators to be presented in an appendix at the end of the paper. This list will include investigators who contributed to the investigation being reported but who are not members of the writing committee, together with all relevant expert advisors and members of the ERC, TSC and DMC. All families who participated in the trial will be thanked as a group (not by name). In principle, substudy reports should include all investigators for the main study, although in some instances where a smaller number of investigators have made any form of contribution, it may be appropriate to abbreviate the listing. All headline authors in any publication arising from the main study or sub-studies must have a made a substantive academic or project management contribution to the work that is being presented. “Substantive” must be defined by a written declaration of exactly what the contribution of any individual is believed to have been. In addition to fulfilling the criteria based on contribution, additional features that will be considered in selecting an authorship group will include the recruitment of children who contributed data to any set of analyses contained in the manuscript and/or the conduct of analyses (laboratory and statistical), leadership and coordination of the project in the absence of a clear academic contribution.

The data derived from this clinical trial are considered the property of the PediCAP TSC. The presentation or publication of any data collected by the participating investigators on children entered into this trial is under the direct control of the TMG and TSC (and the DMC before the end of the trial). This is true whether the publication or presentation is concerned directly with the results of the trial or is associated with the trial in some other way. However, although individual participating investigators will not have any inherent right to perform analyses or interpretations or to make public presentations or seek publication of any of the data other than under the auspices of and with the approval of the TMG and TSC (and the DMC before the end of the trial), they will be encouraged to develop sub-studies or propose analyses subject to the approval by the TMG and TSC (and the DMC before the end of the trial). Any requests for access to raw data will be welcomed as long as they are scientifically valid and do not conflict with the integrity of the trial or ongoing analyses by the trial team.

Outcome data by randomised group will not be revealed to the participating investigators until the data collection phase and primary full analysis of the trial has been completed. This policy safeguards against possible bias affecting the data collection. The DMC will be monitoring the outcome results and may recommend that the trial be stopped for safety reasons, or if a definitive answer is reached earlier than the scheduled end of the trial.

IPD sharing statement
All data requests should be sent to mrcctu.pedicap@ucl.ac.uk. Data will be available for sharing after the publication of the primary trial results. All data will be anonymised. The possibility of data sharing is outlined in the Patient Information Sheet.
Data will be shared based on the following principles:
1. No data should be released that would compromise an ongoing trial or study.
2. There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose.
3. Investigators who have invested time and effort into developing a trial or study should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers.
4. The resources required to process requests should not be under-estimated, particularly successful requests which lead to preparing data for release. Therefore adequate resources must be available in order to comply in a timely manner or at all, and the scientific aims of the study must justify the use of such resources.
5. Data exchange complies with Information Governance and Data Security Policies in all of the relevant countries.

Intention to publish date

31/03/2024

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

03/04/2020: Trial's existence confirmed by European and Developing Countries Clinical Trials Partnership.