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Trial registered on ANZCTR


Registration number
ACTRN12617000857303
Ethics application status
Approved
Date submitted
3/05/2017
Date registered
9/06/2017
Date last updated
9/06/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Enhanced community case management to increase access to pneumonia treatment
Scientific title
Enhanced community case management to increase access to pneumonia treatment in children under 5 years of age in sub-Saharan Africa and South Asia
Secondary ID [1] 291840 0
Nil known
Universal Trial Number (UTN)
U1111-1196-2094
Trial acronym
EMPIC
Linked study record
CTRI/2017/02/007761

Health condition
Health condition(s) or problem(s) studied:
Acute respiratory infections 303086 0
Pneumonia 303087 0
Condition category
Condition code
Respiratory 302545 302545 0 0
Other respiratory disorders / diseases
Infection 302546 302546 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In a cluster randomised controlled trial (RCT), in addition to standard Integrated Community Case Mangement (iCCM), (i) young infants 7 to 59 days of age with fast breathing without hypoxaemia and (ii) children 2-59 months of age with chest indrawing without hypoxaemia will be managed by Community Level Health Workers (CLHWs) with oral amoxicillin, 90 mg/kg/day divided into two doses. For this study oral dispersible amoxicillin in 250 mg scored tablets will be used for both age groups. The dispersible tablets would have to be dispersed in clean water and in expressed breast milk for exclusively breastfed young infants. The WHO recommends 5 days of amoxicillin for chest indrawing pneumonia. For young infants less than two months 7 days therapy will be used. The trial strategy will enhance the existing standard iCCM, which currently recommends referral to hospital for these children. Access to pneumonia treatment will be increased to many children whose families cannot access treatment at hospitals due to various reasons. The proposed intervention is to train CLHWs and maintain their skills to manage infants with fast breathing and children with chest indrawing. Commodities including dispensible amoxicillin tables 250 mg, pulse oximeters, and ARI timers will be regularly provided. All enrolled children will be followed up for up to two weeks and their outcomes will be documented by independent assessors.

Before the commencement of original enrolment, 6-8 days standard and enhanced iCCM training will be given to CLHWs in control and intervention clusters, respectively. In standard iCCM training group, CLHWs will be trained on current WHO/UNICEF iCCM. In enhanced iCCM training group, CLHWs will be trained to provide treatment with oral amoxicillin either for 7 days in case of young infants <2 months of age with fast breathing (>=60 breaths per minute) or for 5 days in case of children 2-59 months of age with lower chest indrawing pneumonia. Further, CLHWs will also be trained in pulse oximetry to measure oxygen saturation at the time of enrolment and during subsequent visits. Two day refresher trainings will be provided to all CLHWs every six months during the study period. Training sessions will be conducted by iCCM master trainers at each site. These master trainers have undergone separate trainings under WHO facilitators.

Pulse oximeters will be provided to all CLHWs in the intervention clusters. They will be trained to assess hypoxaemia in children with pneumonia through standard training and using standard protocols for use and interpretation of pulse oximetry results. Hypoxaemic children will be referred to the hospital for further management including oxygen therapy. In intervention clusters where enhanced iCCM will be provided by CLHWs, feasibility, acceptability and accuracy of pulse oximetry as used by CLHW’s will be assessed. Impact on referral rates will also be compared between intervention and control clusters. The outcomes of all children with signs of pneumonia will be compared between the intervention and control clusters. Outcome will be assessed by independent outcome assessors (nurses) which will be hired and trained to evaluate children on day 6 for primary outcome measure and on day 14 for secondary outcome measure. The total duration of intervention is up to 2 years.

CLHWs are based at health posts in Ethiopia in community, village clinics in the community in Malawi, at their homes in India and in community clinics in Bangladesh. All enrolled children are treated at their homes except those who are referred to a hospital as per protocol.

Intervention code [1] 297954 0
Treatment: Other
Intervention code [2] 298241 0
Treatment: Drugs
Comparator / control treatment
In control clusters, standard iCCM will be implemented for (i) young infants 7-59 days of age with fast breathing without hypoxaemia and (ii) children 2-59 months of age with chest indrawing without hypoxaemia. Sick children will be identified by CLHWs in the community through passive surveillance. All sick young infants will be referred to hospital by CLHW. Children with danger signs will be referred by CLHWs. Supervisors will also review young infants identified by CLHWs with fast breathing and 2-59 months old children with chest indrawing to provide comparative data with the intervention clusters. All enrolled children in control clusters will be followed up for 14 days. Outcomes for all pneumonia patients receiving treatment in community, health facilities and hospitals will be documented.
Control group
Active

Outcomes
Primary outcome [1] 301968 0
Treatment failure rate within day 1-6 of enrolment will be the primary outcome.

Definition of treatment failure
1. Death at any time within day 1 to day 6 of enrolment (and 7-14 days as secondary outcome).
2. Child hospitalised for any reason or has any indication of hospitalisation on day 6.
3. Persistence of fast breathing in young infants 7-59 days of age or persistence of chest indrawing in children 2-59 months of age on day 6 of enrolment.
4. Development of serious adverse effect of the study antibiotics (anaphylactic reaction, severe diarrhoea, disseminated and severe rash).

Outcome will be assessed by independent outcome assessors (nurses) which will be hired and trained to evaluate children on day 6 for primary outcome measure and on day 14 for secondary outcome measure.
Timepoint [1] 301968 0
Primary outcome will be assessed at day 6 and for deaths also at day 14 after enrolment.
Secondary outcome [1] 334405 0
Evaluating the feasibility of using a pulse oximeter by CLHWs.
We will use indepth qualitative interviews and structure observations to evaluate the feasibility of using a pulse oximeter by CLHWs. In all intervention clusters CLHWs will use pulse oximeter to measure oxygen saturation in young infants <2 months of age with fast breathing and children 2-59 months of age with lower chest indrawing.
Timepoint [1] 334405 0
This will be a continuous process to capture information about the feasibility of using a pulse oximeter by CLHW throughout the trial duration.

Eligibility
Key inclusion criteria
In selective districts in Bangladesh, Ethiopia, India and Malawi, first level health facilities (with catchment population of 10,000 to 25,000 each) will be randomised either to control or intervention arm. All CLHWs attached to the first level health facility will provide treatmentment to the following children based on intervention status (control or intervention):
- 7-59 days old infants in intervention or control clusters who develop fast breathing (respiratory rate >60 breaths per min).
- 2-59 month old children infants in intervention or control clusters who develop chest indrawing pneumonia.
Minimum age
7 Days
Maximum age
59 Months
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
7-59 days old infants in intervention and control cluster who develop severe chest indrawing or danger signs or fast breathing in <7 days old young infants and if consent not provided for enrolment for eligible young infants.
2-59 month old children infants in intervention or control clusters who develop danger signs or if consent not provided for enrolment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Cluster will be randomised using a randomisation table created by computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Cluster RCT
Phase
Phase 3 / Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size for young infants 7-59 days of age

Assuming that clusters have a population of about 5000 and a birth rate of 3%, each cluster will have about 300 births and therefore 300 young infants over the 2-year study period. It is expected that about 5% of young infants will develop fast breathing during the first two months of life, yielding 15 cases of fast breathing pneumonia per cluster in two years. For sample size calculations, it is assumed that of the above, 10 cases of fast breathing pneumonia among young infants will be enrolled in one cluster. Assuming a 10% treatment failure rate +/- 5% similarity margin, 90% power and 95% confidence level, design effect of 1.2 (ICC 0.02) and attrition of 10%, 990 cases will be needed each in intervention and control clusters, to test non-inferiority of the “enhanced” iCCM strategy vs. the current standard of care. Since there are 10 expected cases per cluster, 198 clusters (99 clusters per group) for this age group would be required for random allocation.

Sample size for children 2-59 months of age

Assuming that clusters have a population of about 5000 and a birth rate of 3%, each cluster will have about 300 births and around 750 under-five children at any point in time over a two year period. Assuming a pneumonia incidence of 0.25 episodes of pneumonia/child/year, it is expected that there will be about 375 cases of pneumonia among children of 2-59 months of age, of which about 50 will have chest indrawing pneumonia in a cluster (15%) over a two year period. It is assumed that about 30 children with chest indrawing pneumonia would be enrolled. Assuming a 10% treatment failure rate +/-5% similarity margin, 90% power and 95% confidence level, design effect of 1.6 (ICC 0.02) and attrition of 10%, 1340 cases each will be needed in intervention and control clusters to test non-inferiority of the “enhanced” iCCM strategy vs. the current standard of care. Since there are 30 expected cases per cluster, 90 clusters (45 clusters per group) for this age group would be required for random allocation.

Enrolment of young infants with fast breathing and children 2-59 months of age with chest indrawing will be carried out concurrently by the same CLHWs at all sites. It will be difficult to operationalize a shorter trial for chest indrawing pneumonia although theoretically it is possible. Furthermore, the cost of the trial will not be reduced much as CLHWs will continue to enrol fast breathing pneumonia patients. As the sample size is higher for the young infants (99 clusters per group), we will conduct enrolment of children 2-59 months of age with chest indrawing in all the clusters. This will give us the ability to show non-inferiority with +/-3% margin for the 2-59 months age group. Thus enrolling more patients of chest indrawing pneumonia will provide us with greater precision in assessing the effectiveness of its treatment by CLHWs.

Statistical analyses
Each age group will be powered to perform specific analyses. Secondary analyses will also be performed to look for gross differences between sites, but such analyses will only be able to detect large differences in treatment failure rates between sites.

Simple comparisons of means and proportions by intervention and control clusters will be used to check whether the randomisation has in fact resulted in baseline comparability of the two comparative groups. The primary analyses will be for non-inferiority between the treatment outcomes such as treatment failure (including deaths and deterioration) between intervention and control clusters. This will be conducted on an intention-to-treat, and would provide the possibility of differences in adherence to treatment. In addition, per protocol analysis will also be done. The treatment outcomes between control and intervention clusters will be compared and the difference in the risk of treatment failure together with a 95% confidence intervals will be calculated.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
16/09/2016
Date of last participant enrolment
Anticipated
30/09/2018
Actual
Date of last data collection
Anticipated
30/09/2018
Actual
Sample size
Target
4700
Accrual to date
Final
Recruitment outside Australia
Country [1] 8864 0
Bangladesh
State/province [1] 8864 0
Barisal
Country [2] 8865 0
Ethiopia
State/province [2] 8865 0
Gondar
Country [3] 8866 0
India
State/province [3] 8866 0
Haryana
Country [4] 8867 0
Malawi
State/province [4] 8867 0
Central Region

Funding & Sponsors
Funding source category [1] 296338 0
Charities/Societies/Foundations
Name [1] 296338 0
Bill and Melinda Gates Foundation
Country [1] 296338 0
United States of America
Primary sponsor type
Other
Name
World Health Organization
Address
Avenue Appia 20, Geneva 1211
Country
Switzerland
Secondary sponsor category [1] 295268 0
None
Name [1] 295268 0
Address [1] 295268 0
Country [1] 295268 0
Other collaborator category [1] 279550 0
Charities/Societies/Foundations
Name [1] 279550 0
Save the Children International, Bangladesh
Address [1] 279550 0
Save the Children, Bangladesh
House no CWN (A) 35, Road No 43, Gulshan – 2, Dhaka – 1212
Country [1] 279550 0
Bangladesh
Other collaborator category [2] 279551 0
University
Name [2] 279551 0
University of Gondar College of Medicine and Health Sciences (CMHS), Gondar, Ethiopia
Address [2] 279551 0
University of Gondar College of Medicine and Health Sciences (CMHS), Ethiopia
P.O.Box 196
Gondar,
Country [2] 279551 0
Ethiopia
Other collaborator category [3] 279552 0
Other
Name [3] 279552 0
Centre for Health and Research Development, Society for Applied Studies (SAS), New Delhi, India
Address [3] 279552 0
Centre for Health and Research Development, Society for Applied Studies (SAS), India
45 Kalu Sarai, New Delhi-110016
Country [3] 279552 0
India
Other collaborator category [4] 279553 0
Charities/Societies/Foundations
Name [4] 279553 0
Save the Children International, Malawi
Address [4] 279553 0
Save the Children, Malawi
Ngerengere House, Off Mchinji Road
P.O Box 30374,
Lilongwe
Country [4] 279553 0
Malawi

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297569 0
WHO ERC
Ethics committee address [1] 297569 0
Ethics committee country [1] 297569 0
Switzerland
Date submitted for ethics approval [1] 297569 0
12/06/2015
Approval date [1] 297569 0
23/10/2015
Ethics approval number [1] 297569 0
MCA00315

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74470 0
Dr Shamim Ahmad Qazi
Address 74470 0
Department of Maternal, Newborn, Child and Adolescent Health
World Health Organization
Avenue Appia 20, Geneva 1211
Country 74470 0
Switzerland
Phone 74470 0
+41-22-791-2547
Fax 74470 0
+41-22-791-4853
Email 74470 0
[email protected]
Contact person for public queries
Name 74471 0
Shamim Ahmad Qazi
Address 74471 0
Department of Maternal, Newborn, Child and Adolescent Health
World Health Organization
Avenue Appia 20, Geneva 1211
Country 74471 0
Switzerland
Phone 74471 0
+41-22-791-2547
Fax 74471 0
+41-22-791-4853
Email 74471 0
[email protected]
Contact person for scientific queries
Name 74472 0
Shamim Ahmad Qazi
Address 74472 0
Department of Maternal, Newborn, Child and Adolescent Health
World Health Organization
Avenue Appia 20, Geneva 1211
Country 74472 0
Switzerland
Phone 74472 0
+41-22-791-2547
Fax 74472 0
+41-22-791-4853
Email 74472 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Plain language summaryNo NA

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseCommunity-based amoxicillin treatment for fast breathing pneumonia in young infants 7-59 days old: A cluster randomised trial in rural Bangladesh, Ethiopia, India and Malawi.2021https://dx.doi.org/10.1136/bmjgh-2021-006578
EmbaseInnovative, enhanced community management of non-hypoxaemic chest-indrawing pneumonia in 2-59-month-old children: A cluster-randomised trial in Africa and Asia.2022https://dx.doi.org/10.1136/bmjgh-2021-006405
N.B. These documents automatically identified may not have been verified by the study sponsor.