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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] 1586 0
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 257105 0
Condition category
Condition code
Infection 257263 257263 0 0
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] 256274 0
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] 258168 0
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] 258168 0
Within 7 days (day 1-8 of enrolment) of enrolment and treatment initation. Once daily clinical assessment.
Secondary outcome [1] 263811 0
Adherence to study therapy by daily direct administration/obsvervation of therapy by study health worker and recording on a treatment form.
Timepoint [1] 263811 0
Within 7 days of enrolment and treatment initation
Secondary outcome [2] 263812 0
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] 263812 0
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] 263813 0
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] 263813 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 2572 0
Congo, The Democratic Republic Of The
State/province [1] 2572 0
Equateur
Country [2] 2573 0
Nigeria
State/province [2] 2573 0
Oyo
Country [3] 2574 0
Kenya
State/province [3] 2574 0
Eldoret

Funding & Sponsors
Funding source category [1] 256775 0
Other
Name [1] 256775 0
World Health Organization
Address [1] 256775 0
20 Avenue Appia, Geneva 1211
Country [1] 256775 0
Switzerland
Primary sponsor type
Other
Name
World Health Organization
Address
20 Avenue Appia, Geneva 1211
Country
Switzerland
Secondary sponsor category [1] 256054 0
Charities/Societies/Foundations
Name [1] 256054 0
Bill and Melinda Gates Foundation
Address [1] 256054 0
PO Box 23350
Seattle, WA 98102
Country [1] 256054 0
United States of America
Other collaborator category [1] 1191 0
University
Name [1] 1191 0
Ahmadu Bello University
Address [1] 1191 0
PO Box 06, Shika
Zaria
Kaduna State
Country [1] 1191 0
Nigeria
Other collaborator category [2] 1192 0
University
Name [2] 1192 0
University of Ibadan
Address [2] 1192 0
College of Medicine
PMB 5116
Ibadan, Oyo State
Country [2] 1192 0
Nigeria
Other collaborator category [3] 1193 0
University
Name [3] 1193 0
Obafemi Awolowo University
Address [3] 1193 0
Obafemi Awolowo University Teaching Hospital
Ile-Ife
Osun State
Country [3] 1193 0
Nigeria
Other collaborator category [4] 1194 0
University
Name [4] 1194 0
Moi University
Address [4] 1194 0
P.O. Box 4606 - 030100
Eldoret
Country [4] 1194 0
Kenya
Other collaborator category [5] 1197 0
University
Name [5] 1197 0
London University
Address [5] 1197 0
London School of Hygiene and Tropical Medicine (LSHTM)
Keppel Street
London WC1E 7HT
Country [5] 1197 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258797 0
WHO Ethical Review Committee (ERC)
Ethics committee address [1] 258797 0
20 Avenue Appia, Geneva 1211
Ethics committee country [1] 258797 0
Switzerland
Date submitted for ethics approval [1] 258797 0
15/12/2009
Approval date [1] 258797 0
23/02/2010
Ethics approval number [1] 258797 0
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 31028 0
Address 31028 0
Country 31028 0
Phone 31028 0
Fax 31028 0
Email 31028 0
Contact person for public queries
Name 14275 0
Shamim Qazi
Address 14275 0
20 Avenue Appia, Geneva 1211
Country 14275 0
Switzerland
Phone 14275 0
+41227912547
Fax 14275 0
+41227914853
Email 14275 0
qazis@who.int
Contact person for scientific queries
Name 5203 0
Shamim Qazi
Address 5203 0
20 Avenue Appia, Geneva 1211
Country 5203 0
Switzerland
Phone 5203 0
+41227912547
Fax 5203 0
+41227914853
Email 5203 0
qazis@who.int

No information has been provided regarding IPD availability
Summary results
No Results