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Trial registered on ANZCTR


Registration number
ACTRN12622000136707
Ethics application status
Approved
Date submitted
19/01/2022
Date registered
27/01/2022
Date last updated
27/01/2022
Date data sharing statement initially provided
27/01/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
An observational study of penicillin concentrations in an Aboriginal paediatric cohort receiving secondary prophylaxis for rheumatic heart disease in the Northern Territory.
Scientific title
An observational study of serum penicillin concentrations in an Aboriginal paediatric cohort receiving prophylaxis for rheumatic heart disease in the Northern Territory.
Secondary ID [1] 306202 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute rheumatic fever 324911 0
Rheumatic heart disease 324912 0
Condition category
Condition code
Infection 322345 322345 0 0
Other infectious diseases
Cardiovascular 322346 322346 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This observational study assesses plasma penicillin concentrations over a six month period using dried blood spot technology. Individuals will be aged 5-21 and receiving secondary prophylaxis for rheumatic fever with intramuscular benzathine penicillin G. Additionally, secondary outcomes include measurement of antistreptolysin O titres as well as throat and skin sore cultures to assess for colonisation and breakthrough infection. For the 6 months of the study, consented participants will have a throat swabs and a dried blood spot card (DBS), collected from a finger-prick, every month just before their penicillin regular injection. For 2 of the 6 months, they will also have a DBS card collected 1, 3, 6, 12 and 21 days after their injection. If they have any sore throats or skin sores noted during a study visit, an additional swab and DBS will be collected and a referral made for GP review. All DBS and swabs will be sent to a central laboratory for freezing, and analysis at the end of the study.
Intervention code [1] 322606 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330108 0
Penicillin drug concentrations ascertained from laboratory assay of dried blood spot samples
Timepoint [1] 330108 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 patient was symptomatic with sore throat throughout the study.
Primary outcome [2] 330109 0
Anti-streptolysin O titres ascertained from laboratory assay of dried blood spot samples;
Timepoint [2] 330109 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 patient was symptomatic with sore throat throughout the study.
Primary outcome [3] 330110 0
Presence of group A streptococcus (GAS) colonisation and/or infection ascertained from microbiological analysis of throat and skin swabs.
Timepoint [3] 330110 0
Throat swabs are collected at : baseline and every 4 weeks pre penicillin dose for a total of 6 months. Additional microbiological swabs were collected if the patient was symptomatic with sore throat or developed new skin sores throughout the study
Secondary outcome [1] 404910 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] 404910 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 patient was symptomatic with sore throat or new skin sores 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 rheumatic 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
Sex
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
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
7/12/2017
Date of last participant enrolment
Anticipated
Actual
9/05/2018
Date of last data collection
Anticipated
Actual
10/08/2018
Sample size
Target
24
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
NT
Recruitment hospital [1] 21468 0
Danila Dilba Health Service - Darwin
Recruitment postcode(s) [1] 36371 0
0800 - Darwin

Funding & Sponsors
Funding source category [1] 310549 0
Government body
Name [1] 310549 0
Australian Tropical Medicine Commercialisation
Country [1] 310549 0
Australia
Funding source category [2] 310550 0
Commercial sector/Industry
Name [2] 310550 0
Novartis Institutes for BioMedical Research
Country [2] 310550 0
United States of America
Funding source category [3] 310551 0
Charities/Societies/Foundations
Name [3] 310551 0
Wesfarmers Centre of Vaccines and Infectious Diseases
Country [3] 310551 0
Australia
Primary sponsor type
Other
Name
Telethon Kids Institute
Address
15 Hospital Avenue
Nedlands, WA 6009
Country
Australia
Secondary sponsor category [1] 311720 0
None
Name [1] 311720 0
Not applicable
Address [1] 311720 0
Not applicable
Country [1] 311720 0
Other collaborator category [1] 282121 0
Government body
Name [1] 282121 0
PathWest Laboratories
Address [1] 282121 0
Locked Bag 2009, Nedlands, WA, 6009
Country [1] 282121 0
Australia
Other collaborator category [2] 282122 0
University
Name [2] 282122 0
Curtin University
Address [2] 282122 0
Kent Street, Bentley, Perth
Western Australia, 6102
Country [2] 282122 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310161 0
Northern Territory Department of Health and Menzies School of Health Research
Ethics committee address [1] 310161 0
John Mathews Building (Bldg. 58)
Royal Darwin Hospital Campus
Rocklands Drive
Casuarina NT 0810
Ethics committee country [1] 310161 0
Australia
Date submitted for ethics approval [1] 310161 0
28/06/2017
Approval date [1] 310161 0
05/12/2017
Ethics approval number [1] 310161 0
2017-2900

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

Contacts
Principal investigator
Name 116702 0
Dr Joshua Francis
Address 116702 0
Paediatric Department
Royal Darwin Hospital
Rocklands Drive, Tiwi
Casuarina NT 0811
Country 116702 0
Australia
Phone 116702 0
+61 423 528 381
Fax 116702 0
Email 116702 0
[email protected]
Contact person for public queries
Name 116703 0
Joseph Kado
Address 116703 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands WA6009
Country 116703 0
Australia
Phone 116703 0
+61 8 6319 1454
Fax 116703 0
Email 116703 0
[email protected]
Contact person for scientific queries
Name 116704 0
Joseph Kado
Address 116704 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands WA6009
Country 116704 0
Australia
Phone 116704 0
+61 8 6319 1454
Fax 116704 0
Email 116704 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices)
When will data be available (start and end dates)?
Immediately following publication. No end date.
Available to whom?
Researchers who provide a methodologically sound proposal.
Available for what types of analyses?
For individual participant data meta-analysis.
How or where can data be obtained?
Proposals should be directed to [email protected]
To gain access, data requestors will need to sign a data access agreement.


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
SourceTitleYear of PublicationDOI
EmbasePopulation pharmacokinetic study of benzathine penicillin G administration in Indigenous children and young adults with rheumatic heart disease in the Northern Territory, Australia.2022https://dx.doi.org/10.1093/jac/dkac231
N.B. These documents automatically identified may not have been verified by the study sponsor.