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Trial registered on ANZCTR


Registration number
ACTRN12618001288213
Ethics application status
Approved
Date submitted
27/07/2018
Date registered
31/07/2018
Date last updated
31/07/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
An observational study of penicillin levels in an urban predominately Aboriginal paediatric cohort receiving secondary prophylaxis for rheumatic heart disease
Scientific title
An Observational study of serum penicillin levels in a predominately Aboriginal paediatric cohort receiving prophylaxis for rheumatic heart disease
Secondary ID [1] 295689 0
none
Universal Trial Number (UTN)
U1111-1214-4236
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute rheumatic fever 307953 0
Rheumatic heart disease 309064 0
Condition category
Condition code
Infection 306986 306986 0 0
Other infectious diseases
Cardiovascular 307948 307948 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
6
Target follow-up type
Months
Description of intervention(s) / exposure
This observational study assesses plasma penicillin levels over a six month period using dried blood spot technology. Individuals will be aged 5-21 and receiving secodary prophyslaxis for rheumatic fever with intramuscular benzathine penicillin G. Additionally, secondary outocomes include measurement of antistreptolysin O titres as well as throat cultures to assess for colonisation and breakthrough infection.
Intervention code [1] 301276 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 305968 0
(i) Penicillin drug concentrations ascertained from laboratory assay of Dried blood spot samples

Timepoint [1] 305968 0
Dried blood spot (DBS) samples collected at: baseline, every 4 weeks (day of injection), for a total of six months, additionally samples at day: 1,3,6,12,21 post injection will be collected twice throughout the study period. Additional samples were collected if the paitent was symptomatic with sore throat throughout the study.
Primary outcome [2] 305969 0
(ii) Anti-streptolysin O titres ascertained from laboratory assay of Dried blood spot samples;
Timepoint [2] 305969 0
Dried blood spot (DBS) samples collected at: baseline, every 4 weeks, for a total of six months, additional samples at day 1,3,6,12,21 post injection will be collected twice throughout the study period.
Additional samples were collected if the paitent was symptomatic with sore throat throughout the study.
Primary outcome [3] 305970 0
(iii) Presence of group A streptococcus (GAS) colonisation and/or infection ascertained from microbiological analysis of throat swabs.
Timepoint [3] 305970 0
Throat swabs are collected at : baseline and every 4 weeks pre penicillin dose for a total of 6 months. Additional samples were collected if the paitent was symptomatic with sore throat throughout the study,
Secondary outcome [1] 347134 0
Pain post injection will be assessed using the visual analogue scale (VAS) or if the child was deemed not to understand the scale by the study nurse, then the Face, Legs Arms, Cry Consolability (FLACC) was used. No definite age cut off was used.
Timepoint [1] 347134 0
Scores collected at: baseline, every 4 weeks, for a total of six months, additional scoring at day 1,3,6,12,21 post injection will be collected twice throughout the study period. Additional scores will be recorded if the paitent was symptomatic with sore throat throughout the study.

Eligibility
Key inclusion criteria
1. Male or female children aged 5 years or more, but less than 22 years at the time written informed consent is obtained.
2. On secondary prophylaxis with benzathine penicillin G for previous diagnosis of acute rheumatic fever and or rheumtic heart disease.
3. Informed assent/consent for the child’s participation in the study has been given by the legally responsible care-giver.
Minimum age
5 Years
Maximum age
21 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participants aged <5 years or receiving SP with oral antibiotics
2. Receipt of an investigational drug/vaccine within 30 days of the participant’s study start date or their planned use during the study period, until 1 month after the administration of the final dose of BPG
3. Any condition arises that the investigator considers warrants exclusion from the study

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
PHARMACOKINETIC MODELLING:
Log concentration-time data sets for plasma penicillin G will be analysed based on a nonlinear mixed effects model using the NONMEM program (version 6.2.0; ICON Development Solutions, Ellicott City, MD) with an Intel Visual Fortran (version 10.0) compiler. A first-order conditional estimation with interaction method (FOCE-INTER) will be used. The minimum value of the objective function (OFV) and conditional weighted residuals (CWRES) plots will be used to choose suitable models during the model-building process, although previous publications suggest a one compartment model is likely most appropriate. Given a range of weights is expected allometric scaling will be employed, with volume terms multiplied by (WT/70)1 (where WT is body weight) and clearance terms multiplied by (WT/70)0.75. Potential additional biologically plausible covariate relationships (for example age, creatinine clearance, disease status) will be assessed using a stepwise forward and backward procedure (p<0.05 to include and p<0.01 to retain a parameter relationship).
For evaluation of the developed population pharmacokinetic model plots of observed vs individual and population predicted values along with CWRES vs time and population estimates (goodness-of-fit plots) will be assessed for bias. Additionally prediction corrected visual predictive check (pcVPC) and numerical predictive check (NPC) will be performed using perl speaks NONMEM (PsN) to further assess bias in the model as well as its predictive performance. Finally, a bootstrap procedure using 1,000 data sets selected with replacement from the original dataset will be used to obtain 95% non-parametric confidence intervals for the model parameters.

PHARMACOKINETIC – PHARMACODYNAMIC MODELLING:
Break-through infection due to GAS, in this highly compliant cohort, is anticipated in <20% of participants, which may limit the complexity of the PK-PD modelling. However, at a minimum, the parameters of the PK model will be used to estimate the percentage of time about the MIC level for GAS (%T>MIC).

Recruitment
Recruitment status
Completed
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 in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 10953 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 22739 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 299541 0
Government body
Name [1] 299541 0
Australian Tropical Medicine Commercialisation
Address [1] 299541 0
Department of Industry, Innovation and Science
Level 12, NAB Building
100 Creek Street, Brisbane QLD 4000
Country [1] 299541 0
Australia
Funding source category [2] 300255 0
Commercial sector/Industry
Name [2] 300255 0
Novartis Institutes for BioMedical Research
Address [2] 300255 0
250 Massachusettes Avenue, Cambridge, MA 02139 USA
Country [2] 300255 0
United States of America
Funding source category [3] 300256 0
Charities/Societies/Foundations
Name [3] 300256 0
Wesfarmers Centre of Vaccines and Infectious Diseases
Address [3] 300256 0
100 Roberts Road
Subiaco, WA, 6008
Country [3] 300256 0
Australia
Primary sponsor type
University
Name
Telethon Kids Institute
Address
100 Roberts Road
Subiaco, WA 6008
Country
Australia
Secondary sponsor category [1] 299679 0
None
Name [1] 299679 0
Address [1] 299679 0
Country [1] 299679 0
Other collaborator category [1] 280118 0
Government body
Name [1] 280118 0
PathWest Laboratories
Address [1] 280118 0
Locked Bag 2009, Nedlands, WA, 6009
Country [1] 280118 0
Australia
Other collaborator category [2] 280119 0
University
Name [2] 280119 0
The University of Western Australia
Address [2] 280119 0
The University of Western Australia
35 Stirling Highway
Perth WA 6009
Australia
Country [2] 280119 0
Australia
Other collaborator category [3] 280269 0
University
Name [3] 280269 0
Curtin University
Address [3] 280269 0
Kent Street, Bentley, Perth
Western Australia, 6102
Country [3] 280269 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300440 0
Child and Adolescent Health Service Human Ethics Research Committee
Ethics committee address [1] 300440 0
Children’s Clinical Research Facility, Princess Margaret Hospital
corner Roberts Rd and Hamilton St
Subiaco, WA, 6008
Ethics committee country [1] 300440 0
Australia
Date submitted for ethics approval [1] 300440 0
08/04/2016
Approval date [1] 300440 0
04/07/2016
Ethics approval number [1] 300440 0
2016064EP
Ethics committee name [2] 300441 0
Western Australian Aboriginal Health Ethics Committee
Ethics committee address [2] 300441 0
450 Beaufort Street
Highgate
Western Australia, 6003
Ethics committee country [2] 300441 0
Australia
Date submitted for ethics approval [2] 300441 0
02/11/2016
Approval date [2] 300441 0
10/03/2017
Ethics approval number [2] 300441 0
709

Summary
Brief summary
This six month observational study was undertaken to better understand the differences in the pharmacokinetics (if any) who receive secondary prophylaxis with benzathine penicillin G in individuals aged 5-21, for acute rheumatic fever and/or rheumatic heart disease. It is well established that plasma levels of penicillin vary greatly. To date no studies have been undertaken in an urban cohort which are predominately Aboriginal. Other aspects such as inflammatory response will be assessed through repeated measurements of anti streptolysin O titres throughout the study
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83674 0
Dr James Ramsay
Address 83674 0
Cardiology Department
Princess Margaret Hospital
Subiaco, WA , 6008
Country 83674 0
Australia
Phone 83674 0
+61 8 9340 8222
Fax 83674 0
Email 83674 0
James.Ramsay@health.wa.gov.au
Contact person for public queries
Name 83675 0
Dr Robert Hand
Address 83675 0
Telethon Kids Institute
100 Roberts Road
Subiaco, WA, 6008
Country 83675 0
Australia
Phone 83675 0
+61 8 9489 7777
Fax 83675 0
Email 83675 0
robert.hand@telethonkids.org.au
Contact person for scientific queries
Name 83676 0
Dr Robert Hand
Address 83676 0
Telethon Kids Institute
100 Roberts Road
Subiaco, WA, 6008
Country 83676 0
Australia
Phone 83676 0
+61 8 9489 7777
Fax 83676 0
Email 83676 0
robert.hand@telethonkids.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary