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Trial registered on ANZCTR


Registration number
ACTRN12618001435279
Ethics application status
Approved
Date submitted
21/08/2018
Date registered
27/08/2018
Date last updated
3/06/2021
Date data sharing statement initially provided
10/12/2019
Date results provided
3/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
How does the absorption of benzathine penicillin G (BPG) used for Group A Streptococcus (GAS) treatment and secondary prophylaxis for rheumatic fever (RF) differ when injected into the fat layer compared to injection in the muscle in healthy adult men?
Scientific title
Determining the rate of absorption of intramuscular versus subcutaneous administration of Benzathine Penicillin G (BPG) in healthy adult males using ultrasound guidance in a single -blinded 2x2 crossover trial with a 10-week washout period.
Secondary ID [1] 295858 0
Telethon Kids Institute Protocol Number U1111-1216-5903
Secondary ID [2] 295859 0
CTN registration number: CT-2018-CTN-02439-1-v1
Universal Trial Number (UTN)
U1111-1216-5903
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Group A streptococcal infections 309322 0
Rheumatic fever 309323 0
Syphilis 309324 0
Condition category
Condition code
Infection 308189 308189 0 0
Other infectious diseases
Infection 308190 308190 0 0
Sexually transmitted infections

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
15 healthy adult males will be randomised in a single-blinded 2x2 crossover trial to receive a first dose 1,200,000 Units of BPG administered via the standard deep intramuscular route or the subcutaneous route under ultrasound guidance with a 10-week washout period (sampling will occur for 6 weeks to monitor penicillin levels, pain and adverse effects and follwed by a rest period of 4 weeks before they repeat the cycle using the alternate route of injection for the second dose of 1,200,000 Units of BPG and a further 6 weeks of similar follow up). Blood levels of benzylpenicillin will be measured at pre-determined time intervals around each injection using dry blood spots (13 points) and plasma level (2 points for quality assurance) to determine the rate of absortion, time above the minimum inhibitory concentration (MIC) for Streptococcus pyogenes and duration of measureable benzylpenicllin levels above the limit of quantification of the analyser. Pain and other adverse events will be reported and monitored to determine the safety and adverse effect profile of BPG. Ultrasound will used 4-weeks after each injection to document the number and types of local changes.

Summary of study periods: Dosing day Period 1 (IM or SC) --> 6 weeks sampling --> 4 weeks rest --> Dosing Day Period 2 (Alternate route SC or IM) --> 6 weeks sampling --> 2 weeks end of study phone call.

Sampling Intervals around each of the injections:
Dry blood spot sampling: 0 hours (prre-injection/baseline), 2 hours, 6 hours, 12 hours (+ QC venous PK sample), 24 hours, 48 hours, 72 hours, 5 days, 7 days, 14 days (+ QC venous PK sample), 21 days, 28 days (with ultrasound scan of injection site), 42 days.
Intervention code [1] 312195 0
Treatment: Drugs
Comparator / control treatment
This study compares the recommended intramuscular route of administration of 1,200,000 units of BPG against the subcutaneous route of administration of the same drug and dose.

SC injection= Intervention
IM injection (standard treatment) = comparator/control
Control group
Active

Outcomes
Primary outcome [1] 307155 0
Plasma levels of benzylpenicillin measured using dry blood spots measured at pre-dose (baseline), 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, and then 5, 7, 14, 21, 28 and 42 days post dose.
Timepoint [1] 307155 0
pre-dose (baseline), 2 hours, 6 hours, 12 hours (primary time point), 24 hours, 48 hours, 72 hours, and then 5, 7, 14, 21, 28 and 42 days post dose.
Secondary outcome [1] 350924 0
Plasma levels of benzylpenicillin measured above MIC for Streptococcus pyogenes measured at pre-dose (baseline), 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, and then 5, 7, 14, 21, 28 and 42 days post dose.
Timepoint [1] 350924 0
pre-dose (baseline), 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, and then 5, 7, 14 (secondary timepoint), 21, 28 and 42 days post dose.

"secondary timepoint" here reflects the timepoint at which the investigators 'think' there may be a noted difference between the IM and the SC route of injection.
Secondary outcome [2] 350925 0
Pain at injection site using a Numeric Pain Rating Scale at baseline, 2 hours, 6hours, 12 hours, 24 hours, 48 hours (secondary timepoint), 72 hours post-dose (further assessments to continue if pain persists to 5, 7 or until resolved).
Timepoint [2] 350925 0
baseline, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours (secondary) and 72 hours post-dose

"secondary" here reflects where the investigators are interested to determine if the presence and intensity of pain will be different between the IM and SC injection route.
Secondary outcome [3] 350926 0
Types of ultrasound-detected local changes 28 days post dose
Timepoint [3] 350926 0
28 days post-dose
Secondary outcome [4] 350930 0
Redness at or around the injection site post-dose assessed at 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours will be measured and photographic evidence recorded
Timepoint [4] 350930 0
at 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours
Secondary outcome [5] 351140 0
Numbers of ultrasound-detected local changes 28 days post dose
Timepoint [5] 351140 0
28 days post injection

Eligibility
Key inclusion criteria
(a) Healthy male aged 18 - 65 years at the time of screening.
(b) BMI between 18.5kg/m2 and 26.0kg/m2.
(c) No history of chronic renal impairment or significant liver dysfunction.
(d) Participants who are considered likely to adhere to the trial guidelines for the duration of the trial.
(e) Sign and dated informed consent
Minimum age
18 Years
Maximum age
65 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
(a) Currently taking penicillin or use of penicillin-based antibiotics from screening to final study visit
(b) Known penicillin or soy allergy
(c) History of significant hip or gluteal surgery
(d) Use of any prescription medication or over-the-counter medication, herbal products, vitamins or minerals within 7 days prior to study drug administration until completion of the final follow up visit
(e) Participation in another clinical 3 months preceding the trial or planned participation in another clinical trial concurrently
(f) Histroy of tobacco use within 1 month of screening.

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)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Sample size was calculated based on a clinically significant and likely reduction in the primary outcome measure, namely the rate of absorption (Ka). This was set at around 40% for the following reasons: i) based on simulation data for children this would increase the median time above 0.02mg/L by around one week from 15 to 22 days and ii) animal studies comparing IM to SC dosing observed this difference (Ranheim et al44).
Power calculations were performed within NONMEM using a combination of local data in children and a published population PK model of IM benzylpenicillin in adults (Neely et al82) to perform Monte-Carlo mapped power implemented via Perl-Speaks-NONMEM. The simulations assumed a slower absorption with SC dosing using the crossover design and the planned sampling schedule. There was over 90% power with an alpha of 0.05 (significance level of 5%) to detect a difference of 40% with 11 participants. There was also around 80% power to detect a 30% difference with 14 participants.To account for possible loss to follow-up and unpaired data, a target of 15 participants was set.
For pharmacokinetic analysis: Log(e) plasma concentration-time datasets for benzylpenicillin will be analysed by nonlinear mixed effects modelling using NONMEM (v 7.2.0, ICON Development Solutions, Ellicott City, MD, US) with an Intel Visual FORTRAN 10.0 compiler. The Laplacian with interaction (LAPLACIAN with INTER) estimation method will be used. The minimum value of the objective function (OFV) and visual predictive checks will be used to choose suitable models during the model-building process. A significance level of P<0.01 was set for comparison of nested models.
Pain: Using a t-test with matched pairs, discrimination of 2 points with a SD of 1.7 should be attainable. Studies have shown that a reduction of pain by 30% is considered clinically significant. Therefore, to determine a difference in pain between the two routes, we considered a 30% difference to also be significant. We assumed a correlation between groups of 0.3; hence, n=15 results in power to discriminate of 94.6%; n=10 will result in power of 79.8% and n=12, 87.9%..
Adverse events and ultrasound-detected local changes at injection sites will be compared using Group T-tests to determine significant differrences.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
31/08/2018
Actual
2/09/2018
Date of last participant enrolment
Anticipated
2/09/2018
Actual
21/09/2018
Date of last data collection
Anticipated
6/01/2019
Actual
28/01/2019
Sample size
Target
15
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 11737 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 23773 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 300457 0
Other Collaborative groups
Name [1] 300457 0
Telethon Kids Institute
Country [1] 300457 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Telethon Kids Institute
Address
Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA6009
Country
Australia
Secondary sponsor category [1] 299928 0
None
Name [1] 299928 0
Address [1] 299928 0
Country [1] 299928 0
Other collaborator category [1] 280309 0
Individual
Name [1] 280309 0
Laurens Manning
Address [1] 280309 0
Medical School, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009
Country [1] 280309 0
Australia
Other collaborator category [2] 280310 0
Individual
Name [2] 280310 0
Sam Salman
Address [2] 280310 0
Medical School, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009
Country [2] 280310 0
Australia
Other collaborator category [3] 280311 0
Individual
Name [3] 280311 0
Kevin Batty
Address [3] 280311 0
School of Pharmacy and Biomedical Sciences, Curtin University, Kent Street, Bentley, WA6102
Country [3] 280311 0
Australia
Other collaborator category [4] 280312 0
Individual
Name [4] 280312 0
Rosemary Wyber
Address [4] 280312 0
The George Institute, Level 5, 1 King Street, Sydney, NSW2042
Country [4] 280312 0
Australia
Other collaborator category [5] 280313 0
Individual
Name [5] 280313 0
Robert Hand
Address [5] 280313 0
Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA6009
Country [5] 280313 0
Australia
Other collaborator category [6] 280314 0
Individual
Name [6] 280314 0
Jonathan Carapetis
Address [6] 280314 0
Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA6009
Country [6] 280314 0
Australia
Other collaborator category [7] 280315 0
Individual
Name [7] 280315 0
Robert Henderson
Address [7] 280315 0
Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009
Country [7] 280315 0
Australia
Other collaborator category [8] 280316 0
Individual
Name [8] 280316 0
Joseph Kado
Address [8] 280316 0
Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA6009
Country [8] 280316 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301260 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 301260 0
Ethics committee country [1] 301260 0
Australia
Date submitted for ethics approval [1] 301260 0
04/07/2018
Approval date [1] 301260 0
02/08/2018
Ethics approval number [1] 301260 0
2018-07-519

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 3011 3011 0 0
/AnzctrAttachments/375835-IMvsSC Protocol v1.1 20180731-clean.pdf (Protocol)
Attachments [2] 3012 3012 0 0
/AnzctrAttachments/375835-TKI_IMvsSC_Main PICF (v1.0, 30Jul18)_Final_Clean.pdf (Participant information/consent)
Attachments [3] 3013 3013 0 0
/AnzctrAttachments/375835-Signed HREC Approval.pdf (Ethics approval)

Contacts
Principal investigator
Name 86398 0
A/Prof Laurens Manning
Address 86398 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch, WA 6150
Country 86398 0
Australia
Phone 86398 0
+61861522222
Fax 86398 0
Email 86398 0
laurens.manning@uwa.edu.au
Contact person for public queries
Name 86399 0
Joseph Kado
Address 86399 0
Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA 6009
Country 86399 0
Australia
Phone 86399 0
+61863191454
Fax 86399 0
Email 86399 0
joseph.kado@telethonkids.org.au
Contact person for scientific queries
Name 86400 0
Laurens Manning
Address 86400 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch, WA 6150
Country 86400 0
Australia
Phone 86400 0
+61861522222
Fax 86400 0
Email 86400 0
laurens.manning@uwa.edu.au

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 laurens.manning@uwa.edu.au
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
No additional documents have been identified.