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Trial registered on ANZCTR

Registration number

ACTRN12610000286044

Ethics application status

Approved

Date submitted

7/04/2010

Date registered

9/04/2010

Date last updated

11/07/2012

Type of registration

Prospectively registered

Titles & IDs

Public title

Simplified Regimens for Management of Possible Serious Bacterial Infections in Neonates and Young Infants for Use in Outpatient and Community Settings: A multi-centre Randomized Controlled Trial in Africa

Scientific title

A comparison of treatment failure rate between three simplified regimens and a reference regimen for management of possible serious bacterial infections in neonates and young infants.: A multi-centre randomized controlled trial in Africa

Secondary ID [1]

nil

Universal Trial Number (UTN)

U1111-1114-6362

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Possible serious bacterial infection

Condition category

Condition code

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Stratum I (severe infection)
To test the efficacy of the following three simpler regimens, compared to the reference regimen, in children who have 'severe infection'
- Treatment regimen B: injection gentamicin once daily (4-6.5 mg/kg/day) and oral amoxicillin (75-100 mg/kg/day) twice daily for 7 days (7 injections in total)
- Treatment regimen C: injection gentamicin (4-6.5 mg/kg/day) once daily and injection procaine penicillin (40,000-60,000 units/kg/day) once daily for 2 days, thereafter oral amoxicillin (75-100 mg/kg/day) for 5 days (4 injections in total)
- Treatment regimen D: injection gentamicin (4-6.5 mg/kg/day) once daily and oral amoxicillin (75-100 mg/kg/day) for 5 days twice daily for 2 days, thereafter oral amoxicillin (75-100 mg/kg/day) twice daily for 5 days (2 injections in total)

Stratum II (fast breathing only)
To test the efficacy of the following simpler regimen, compared to the reference regimen, in children who have fast breathing:
- Treatment regimen E: Oral amoxicillin (75-100 mg/kg/day) twice daily for 7 days

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

- Reference Treatment Regimen A: injection gentamicin (4-6.5 mg/kg/day)once daily and injection procaine penicillin (40,000-60,000 units/kg/day) once daily for 7 days (14 injections in total)

Control group

Active

Outcomes

Primary outcome [1]

Treatment failure based on clinical criteria, which will be assessed clinically.
Definition of treatment failure in Stratum I

1. Death anytime within 7 days after randomization (day 1-8 of enrolment).
2. Persistence of the presenting sign/symptom suggestive of severe infection (if single presenting sign) or persistence of >1 presenting sign/symptom suggestive of severe infection (if multiple presenting signs) after 72 hours of randomization (day 4 of enrolment).
3. After initial disappearance within 72 hours after randomization, re-emergence of any presenting sign (temperature should be at least 38.0 degree Centigrade or higher on 2 or more days)
4. Clinical deterioration: emergence of any sign of being critically ill at any time after randomization [as defined in exclusion criteria]
5. Emergence of any new sign of severe infection (any of the 5 signs) after 24 hours of randomization (day 3 of enrolment)
6. Persistence of any sign of severe infection at 7 days (day 8 of enrolment).
7. Development of serious adverse effect of the study antibiotics (death, organ failure, anaphylactic reaction, severe diarrhoea, disseminated and severe rash).
8. Hospitalization decided by the family, anytime after admission in the study.

Definition of treatment failure in Stratum II

1. Death anytime within 7 days after randomization (day 1-8 of enrolment).
2. No improvement in respiratory rate at 72 hours (reduction in respiratory rate of <10 breaths per minute compared to baseline) (day 4 of enrolment)
3. Clinical deterioration: emergence of any sign of being critically ill or severe infection at any time after randomization [as defined in exclusion criteria]
4. Persistence of fast breathing at 7 days (day 8 of enrolment).
5. Development of serious adverse effect of the study antibiotics (death, organ failure, anaphylactic reaction, severe diarrhoea, disseminated and severe rash).
6. Hospitalization decided by the family, anytime after admission in the study.

Timepoint [1]

Within 7 days (day 1-8 of enrolment) of enrolment and treatment initation. Once daily clinical assessment.

Secondary outcome [1]

Adherence to study therapy by daily direct administration/obsvervation of therapy by study health worker and recording on a treatment form.

Timepoint [1]

Within 7 days of enrolment and treatment initation

Secondary outcome [2]

Relapse through clinical observation. Definition signs of 'severe infection' (stratum I) or' fast breathing' (stratum II) disappear on day 8 of enrolment, but develop any sign of severe infection or being critically ill between day 9 and day 14. In stratum II, an additional sign would be re-emergence of fast breathing.

Timepoint [2]

Between 8-14 days of initiation of treatment. Observed on day 11 and day 15 of enrollment by the health worker. But if needed a patient could be seen on other days between this time.

Secondary outcome [3]

Serious adverse effects (such as death, organ failure, anaphylactic reaction, severe diarrhoea, disseminated and severe rash) due to study drugs observed and recorded on serious adverse event or death form.

Timepoint [3]

1-8 days after initiation of treatment (once daily observation)

Eligibility

Key inclusion criteria

Stratum 1 (severe infection): One or more of the following five signs of 'severe infection' - not feeding well, movement only when stimulated, severe chest indrawing, axillary temperature >38.0 degree Centigrade or <35.5 degree Centigrade and informed consent is provided by a parent (or legal guardian).

Stratum II (fast breathing only): Fast breathing i.e., respiratory rate 60 or more per minute and Informed consent is provided by a parent (or legal guardian)

Minimum age

1 Days

Maximum age

59 Days

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Stratum I: Exclusion Criteria
- Critically ill infant characterized by presence of any of the following signs - unconscious, convulsions, unable to feed at all, apnea, unable to cry, cyanosis, bulging fontanelle, major congenital malformations inhibiting oral antibiotic intake, active bleeding requiring transfusion, surgical conditions needing hospital referral, persistent vomiting defined as vomiting following three attempts to feed the baby within ½ hour
- Very low weight (<1500g at the time of presentation)
- Hospitalization for illness in the last two weeks
- Previous inclusion in the study

Stratum II: Exclusion Criteria
- Any signs of severe infection: not feeding well, movement only when stimulated, severe chest in-drawing, axillary temperature >38.0 degree Centigrade or <35.5 degree Centigrade ,
- Any sign of being critically ill
- Very low weight (<1500g at the time of presentation)
- Hospitalization for illness in the last two weeks
- Previous inclusion in the study

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)

For allocation concealment, treatment code for each enrolled study infant will be sealed in an opaque envelope (different colour envelopes for Stratum I and Stratum II).

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

There would be two randomization schemes, one each for stratum I young infants with "severe infection" and stratum II "fast breathing only"¨. Block randomization schemes will be computer-generated off site at World Health Organization (WHO).

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

This is an open (un-blinded) study because a double injection regimen is being compared to single injection-oral regimen combinations, and an oral only “switch” regimen; blinding participants and investigators by using placebo injections would thus not be justifiable.

Phase

Phase 3

Type of endpoint/s

Bio-equivalence

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/10/2010

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

6900

Accrual to date

Final

Recruitment outside Australia

Country [1]

Congo, The Democratic Republic Of The

State/province [1]

Equateur

Country [2]

Nigeria

State/province [2]

Oyo

Country [3]

Kenya

State/province [3]

Eldoret

Funding & Sponsors

Funding source category [1]

Other

Name [1]

World Health Organization

Address [1]

20 Avenue Appia, Geneva 1211

Country [1]

Switzerland

Primary sponsor type

Other

Name

World Health Organization

Address

20 Avenue Appia, Geneva 1211

Country

Switzerland

Secondary sponsor category [1]

Charities/Societies/Foundations

Name [1]

Bill and Melinda Gates Foundation

Address [1]

PO Box 23350
Seattle, WA 98102

Country [1]

United States of America

Other collaborator category [1]

University

Name [1]

Ahmadu Bello University

Address [1]

PO Box 06, Shika
Zaria
Kaduna State

Country [1]

Nigeria

Other collaborator category [2]

University

Name [2]

University of Ibadan

Address [2]

College of Medicine
PMB 5116
Ibadan, Oyo State

Country [2]

Nigeria

Other collaborator category [3]

University

Name [3]

Obafemi Awolowo University

Address [3]

Obafemi Awolowo University Teaching Hospital
Ile-Ife
Osun State

Country [3]

Nigeria

Other collaborator category [4]

University

Name [4]

Moi University

Address [4]

P.O. Box 4606 - 030100
Eldoret

Country [4]

Kenya

Other collaborator category [5]

University

Name [5]

London University

Address [5]

London School of Hygiene and Tropical Medicine (LSHTM)
Keppel Street
London WC1E 7HT

Country [5]

United Kingdom

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

WHO Ethical Review Committee (ERC)

Ethics committee address [1]

20 Avenue Appia, Geneva 1211

Ethics committee country [1]

Switzerland

Date submitted for ethics approval [1]

15/12/2009

Approval date [1]

23/02/2010

Ethics approval number [1]

NCH09008

Summary

Brief summary

Objective: To conduct a multi-centre randomized controlled trial in three countries in Africa (Democratic Republic of Congo, Kenya and Nigeria) to test the safety and efficacy of simplified antibiotic regimens for treating possible serious bacterial infection in 0-59 day-old infants 
Participants: Study participants will be young infants 0 to 59 days old, from settings in low- and middle-income countries with a high infant mortality (at least 60/1000 live births), with clinical signs of possible serious bacterial infection whose families do not accept or cannot access referral level care. Infants who are critically ill will be excluded, and the study participants will be stratified into two groups according to the severity of the possible serious bacterial infection on admission:
- severe infection: not feeding well, movement only when stimulated, severe chest in-drawing, axillary temperature >38.0 degree Centigrade or <35.5 degree Centigrade; and
- fast breathing alone: respiratory rate 60 or more per minute.
The study will enroll a total of 6,200 young infants -- 3,600 in the stratum of young infants with possible severe infection and 2,600 in the stratum of less severe infection.
Reference treatment (Comparison): The comparison group will receive injection gentamicin once daily and injection procaine penicillin once daily for 7 days (Treatment Regimen A, 14 injections in total).
Experimental treatments (Intervention): The treatment regimens under evaluation will be:
1.	For severe infection: 
     Treatment Regimen B: injection gentamicin once daily and oral amoxicillin twice daily for 7 days (7 injections in total);
     Treatment Regimen C: injection gentamicin once daily and injection procaine penicillin once daily for 2 days, thereafter oral amoxicillin for 5 days (4 injections in total)
     Treatment Regimen D: injection gentamicin once daily and oral amoxicillin twice daily for 2 days, thereafter oral amoxicillin twice daily for 5 days (2 injections in total)
2.	Fast breathing alone:
	Treatment Regimen E: oral amoxicillin twice daily for 7 days
Outcomes:  Treatment failure in the first week following initiation of treatment (primary outcome); death in the first week following initiation of treatment, death the week following completion of treatment, relapse in the week following completion of treatment, and severe adverse effects related to the antibiotics (secondary outcomes).

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Shamim Qazi

Address

20 Avenue Appia, Geneva 1211

Country

Switzerland

Phone

+41227912547

Fax

+41227914853

qazis@who.int

Contact person for scientific queries

Name

Shamim Qazi

Address

20 Avenue Appia, Geneva 1211

Country

Switzerland

Phone

+41227912547

Fax

+41227914853

qazis@who.int

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

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: A randomised, open-label, equivalence trial.	2015	https://dx.doi.org/10.1016/S0140-6736%2814%2962284-4
Embase	Simplified antibiotic regimens for treating neonates and young infants with severe infections in the Democratic Republic of Congo: A comparative efficacy trial.	2018	https://dx.doi.org/10.1186/s40748-018-0076-2
Embase	Clinical signs of possible serious infection and associated mortality among young infants presenting at first-level health facilities.	2021	https://dx.doi.org/10.1371/journal.pone.0253110
Embase	Costs and cost-effectiveness of management of possible serious bacterial infections in young infants in outpatient settings when referral to a hospital was not possible: Results from randomized trials in Africa.	2021	https://dx.doi.org/10.1371/journal.pone.0247977
Embase	Prevalence of clinical signs of possible serious bacterial infection and mortality associated with them from population-based surveillance of young infants from birth to 2 months of age.	2021	https://dx.doi.org/10.1371/journal.pone.0247457
Dimensions AI	Incidence of possible serious bacterial infection in young infants in the three high-burden countries of the Democratic Republic of the Congo, Kenya, and Nigeria: A secondary analysis of a large, multi-country, multi-centre clinical trial.	2024	https://doi.org/10.7189/jogh.14.04009

N.B. These documents automatically identified may not have been verified by the study sponsor.

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