Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000684426
Ethics application status
Approved
Date submitted
5/06/2025
Date registered
27/06/2025
Date last updated
27/06/2025
Date data sharing statement initially provided
27/06/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to compare safety, tolerability, and how the body processes a powdered penicillin injection (Extencilline®) given into the muscle or under the skin in healthy adults
Scientific title
Pharmacokinetics, Safety, Tolerability and Acceptability of Intramuscular Versus Subcutaneous Administration of a Powdered Formulation of Benzathine Penicillin G (Extencilline®) in Healthy Adults
Secondary ID [1] 314571 0
Nil known
Universal Trial Number (UTN)
U1111-1316-2304
Trial acronym
Powdered IM versus SC Penicillin (PIMSCIP)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Group A streptococcal infections 337735 0
Syphilis 337673 0
Rheumatic heart disease 337674 0
acute rheumatic fever 337734 0
Condition category
Condition code
Infection 334008 334008 0 0
Sexually transmitted infections
Inflammatory and Immune System 334163 334163 0 0
Autoimmune diseases
Infection 334162 334162 0 0
Other infectious diseases
Cardiovascular 334009 334009 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an unblinded, prospective study applying sequential administration of powdered BPG (Extencilline®), delivered first as an IM injection (2.4 MU), then via SCIP (Subcutaneous Infusion of BPG) with a pre-defined wash-out period between doses. All participants will receive 2.4 MU powdered BPG (Extencilline®) as a first dose at baseline, followed by an 8-week washout period, given prior pharmacokinetic data showed majority of participants did not have a detectable plasma penicillin concentration beyond 6 weeks. After the washout period, the first five participants will receive 2.4 MU as SCIP. Once tolerability of the lower dose as SCIP has been confirmed, the next five participants will receive 7.2 MU as SCIP, followed by a further five participants at 10.8 MU as SCIP. This non-randomized sequential design allows for controlled dose escalation and safety monitoring during the administration of Extencilline® via the SC route. These doses have been selected to allow assessment across the full range of treatment doses used for the treatment of early syphilis (2.4 MU) and late latent or unknown duration syphilis (7.2MU) and higher doses to allow assessment of tolerability which could be applicable to patients receiving secondary prophylaxis for RHD (up to 10.8 MU).

The SCIP intervention will be administered as a single-dose infusion by medically trained, GCP-certified staff (e.g., registered nurses) under investigator supervision. Ultrasound guidance may be employed to optimize site selection and cannula placement. As dosing is only once and clinic-administered, conventional adherence concerns do not apply. Adherence will be ensured via direct observation, with pharmacokinetic sampling and plasma penicillin assays providing objective confirmation of dose delivery and systemic absorption.
Intervention code [1] 331194 0
Treatment: Drugs
Comparator / control treatment
Active Control Treatment: Intramuscular (IM) administration of benzathine penicillin G (Extencilline®)
Name of treatment: Benzathine penicillin G (Extencilline®)

Formulation: Powdered formulation reconstituted for injection

Dose: 2.4 million units (MU)

Route of administration: Deep intramuscular injection into the dorsogluteal region

Frequency: Single administration during the first dosing period

Mode of administration: Manual injection using standard aseptic technique, according to protocol-specific SOPs

Preparation: Reconstituted as per manufacturer instructions using water for injection; lidocaine may be added to reduce pain

Verification of administration: Ultrasound imaging used to confirm intramuscular placement

Observation: Participants are monitored post-injection for tolerability and adverse events; pain scores and blood samples are collected at scheduled intervals
Control group
Active

Outcomes
Primary outcome [1] 341669 0
The key rate of absorption (ka) of powdered BPG (Extencilline®) administered SCIP and IM
Timepoint [1] 341669 0
Up to 42 days post-injection for each administration route (IM and SCIP). Frequency of assessment: Pharmacokinetic blood sampling will be conducted at multiple predefined timepoints to capture the absorption profile of benzathine penicillin G (BPG; Extencilline®) following each administration route. Specifically: - For IM BPG administered on Day 0, venous blood samples will be collected on Days 0, 1, 2, 3, 7, 14, 21, 42, and 56 - For SCIP BPG administered on Day 56, venous blood samples will be collected on Days 56, 57, 58, 59, 63, 70, 77, 84, 98, 112, and 128. These timepoints were selected to enable robust population pharmacokinetic modeling across both early and extended post-dose periods. Primary timepoint specification: The primary outcome is the estimated absorption rate constant (ka) of powdered BPG (Extencilline®) administered via both IM and SCIP routes, assessed using nonlinear mixed-effects modeling (NONMEM) of serial plasma penicillin concentrations. Although ka is estimated across all post-dose sampling timepoints, the primary analysis timepoint for the SCIP arm is Day 98, which represents the final core sampling timepoint for all participants prior to long-term follow-up (Days 112 and 128 are optional depending on detectability of penicillin levels). For the IM arm, the corresponding final scheduled sampling point is Day 42. The final model will integrate all timepoints to estimate ka, but Day 98 (SCIP) and Day 42 (IM) serve as the primary endpoints for completion of the scheduled pharmacokinetic sampling.
Secondary outcome [1] 448269 0
Qualitative experience of receiving SC BPG, in relation to IM administration, assessed using mixed methods (surveys and semi-structured interviews)
Timepoint [1] 448269 0
Immediately post-injection (Day 0 for IM; Day 56 for SCIP), and At 6 hours, Day 7, and Day 21 post-injection for both IM and SCIP.
Secondary outcome [2] 448266 0
Measurement of plasma penicillin concentration time above the target concentration for efficacy (18ng/mL) for Treponema pallidum following administration of 2.4 MU, 7.2 MU and 10.8 MU of powdered BPG (Extencilline®) for IM and SCIP, normalised to a dose of 7.2MU
Timepoint [2] 448266 0
For each administration route (IM and SCIP), secondary pharmacokinetic outcomes—including duration of therapeutic penicillin concentrations, area under the concentration–time curve (AUC), and time above the minimum inhibitory concentration (T>MIC)—will be assessed using venous plasma samples collected across the following periods: IM administration: Participants will receive a single intramuscular dose of BPG (Extencilline®) on Day 0, with pharmacokinetic sampling on Days 0, 1, 2, 3, 7, 14, 21, 42, and 56. On Day 0, blood will be drawn twice (pre-dose and 6 hours post-dose). On all subsequent days, a single sample will be collected. Notably, the pre-SCIP dose sample on Day 56 serves as the final PK sample for the IM phase, capturing the terminal elimination phase SCIP administration: Participants will receive a single subcutaneous infusion of BPG on Day 56, with pharmacokinetic sampling on Days 56, 57, 58, 59, 63, 70, 77, 84, 98, 112, and 128. Similarly, on Day 56, two samples will be taken (pre-dose and 6 hours post-dose); all other timepoints involve single samples. This sampling schedule is designed to capture both the early absorption/distribution phase and the extended elimination phase of BPG, providing sufficient data to evaluate pharmacokinetic parameters across all dose cohorts and administration routes. While daily sampling is not conducted, the selected timepoints allow robust modeling of BPG kinetics with appropriate resolution of the absorption rate and duration of therapeutic exposure.
Secondary outcome [3] 448270 0
Adverse events following SCIP and IM administration of powdered BPG (Extencilline®)
Timepoint [3] 448270 0
From Day 0 to Day 42 following IM administration, and From Day 56 to Day 98 following SCIP administration
Secondary outcome [4] 448267 0
Secondary-derived PK parameters including Cmax, Tmax, AUC and concentrations at 42 days following administration of 2.4 MU, 7.2 MU and 10.8 MU of powdered BPG (Extencilline®)
Timepoint [4] 448267 0
Up to 42 days post-dose for each administration (IM and SCIP). Timepoints include Day 0 (pre-dose), 6h, 24h, 48h, 72h, Day 7, 14, 21, 28, and Day 42. Applies to all dose cohorts: 2.4 MU, 7.2 MU, and 10.8 MU.
Secondary outcome [5] 448268 0
Pain scores associated with receiving powdered BPG (Extencilline®) administered IM and SCIP
Timepoint [5] 448268 0
Immediately post-injection (Day 0 and Day 56 for IM and SCIP, respectively), and At Days 1, 2, 3, 7, 14, 21 post-injection (and additional timepoints if pain persists).

Eligibility
Key inclusion criteria
Participants who meet all the inclusion criteria are eligible to be a participant in the trial:
1. Males or non-pregnant and non-lactating females aged 18 - 65 years at the time of screening.
2. Women of child-bearing potential must agree to use contraception for the duration of study participation and follow up. Consistent use of a barrier method of contraception is acceptable.
3. BMI between 18.5kg/m2 and 26.0 kg/m2. The upper BMI limit of 26 kg/m² was chosen to reduce variability in pharmacokinetics arising from altered absorption in individuals with higher adiposity, which may impact both SC and IM BPG delivery as evidenced in our previous studies.
4. Participants who are considered likely to adhere to the trial guidelines for the duration of the trial.
5. Able to provide informed consent in accordance with Good Clinical Practice (GCP).
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Participants who meet any of these criteria are not eligible for participation in the trial:
1. Currently taking penicillins or use of any penicillin-based antibiotics from screening through to the subsequent dosing visits. The use of probenecid, and non-steroidal anti-inflammatory drugs, or other medications which may significantly alter BPG PK will also not be permitted within 14 days prior to study drug administration until completion of the final follow-up visit, with the exception of occasional paracetamol and ibuprofen use.
2. Concurrent participation in another clinical trial.
3. Planned operation/absence during the follow-up duration of the study.
4. Known or prior documented penicillin allergy.
5. Known or documented immediate hypersensitivity (anaphylaxis) to another beta-lactam antibiotic agent (cephalosporins, monobactam, carbapenems).
6. Known allergy to soy or peanuts (An excipient of powdered BPG).
7. Known or prior documented allergy to lidocaine (local anaesthetic agent).
8. Presence of significant abnormalities in complete blood count, as assessed by the investigator or designee.
9. Presence of significant abnormal renal function, as assessed by the investigator or designee.
10. Presence of significant liver dysfunction, as assessed by the investigator or designee.
11. Existing dermatological conditions or other abnormalities (e.g., extensive scarring from significant hip/gluteal surgery/radiotherapy) that may affect skin and subcutaneous tissue integrity at the site of injection, especially abdomen, buttocks or loins.
12. Use of any prescription medication or over-the-counter medication (except for oral paracetamol up to 4g/24 hours; oral, parenteral or implanted hormonal contraception in women of child bearing potential), herbal products, vitamins or minerals, within 7 days prior to study drug administration until completion of the final follow-up visit, unless in the opinion of the PI or delegate the medication will not compromise participant safety or interfere with study procedures or data validity.
13. Participants who are unable or unwilling to avoid nicotine use during confinement periods.
14. History of alcohol or drug abuse in the past 12 months prior to screening, or participants who are positive for Urine drug screen (UDS) and alcohol breath test (ABT) at screening or prior to dosing (Repeat testing as per the investigator (or designee) discretion).
15. Blood pressure and heart rate are outside the ranges 90-140 mmHg systolic, 40-90 mmHg diastolic, heart rate 40-100 beats/min.
16. Participants who have received any study drug within 30 days or 5 half-lives, whichever is longer prior to screening.
17. Any other reason which in the opinion of the Principal Investigator would compromise participant safety, or interfere with study procedures or data validity.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Sample size: The crossover study design minimizes between-patient variability with route of delivery as the key driver of observed variability between dosing occasions. Based on our models of SCIP and SC administration to date, the most important PK parameter which influences observed penicillin is absorption constant (Ka2). This is because of ‘flip-flop’ kinetics where the absorption constant is >100 fold longer than the clearance from the central compartment.

Based on similar studies of SCIP using a different preparation of BPG (Bicillin® L-A, Pfizer), our estimate is that Ka will be increased by a factor of 50-100%. Previous data do not suggest the key absorption parameter is dose dependent. Simulations (which account for estimates of residual variability in the model) demonstrate adequate power (>90%; a=0.05) to detect a minimum difference of 50% if 15 participants are recruited. With our published approaches to modelling BPG, we believe it is optimal to base sample size calculation on the parameter which has the biggest impact on overall PK profiles.
Analysis plan: Loge plasma concentration-time datasets for penicillin 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 first-order conditional with interaction (FOCE 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 will be set for comparison of nested models. Allometric scaling for size will be employed a priori, with an exponential of 1 for volume (V) and ¾ for clearance (CL) terms. Residual variability (RV) will be estimated as additive error for log-transformed data.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/07/2025
Actual
Date of last participant enrolment
Anticipated
17/10/2025
Actual
Date of last data collection
Anticipated
28/02/2026
Actual
Sample size
Target
15
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 319121 0
Charities/Societies/Foundations
Name [1] 319121 0
Gates Foundation (BMGF ref INV-077092)
Country [1] 319121 0
United States of America
Primary sponsor type
Charities/Societies/Foundations
Name
The Kids Research Institute Australia
Address
Country
Australia
Secondary sponsor category [1] 321582 0
None
Name [1] 321582 0
Address [1] 321582 0
Country [1] 321582 0
Other collaborator category [1] 283540 0
University
Name [1] 283540 0
Curtin University
Address [1] 283540 0
Country [1] 283540 0
Australia
Other collaborator category [2] 283538 0
University
Name [2] 283538 0
University of western Australia
Address [2] 283538 0
Country [2] 283538 0
Australia
Other collaborator category [3] 283539 0
Other Collaborative groups
Name [3] 283539 0
Linear Clinical Research
Address [3] 283539 0
Country [3] 283539 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317713 0
Bellberry Human Research Ethics Committee D
Ethics committee address [1] 317713 0
Ethics committee country [1] 317713 0
Australia
Date submitted for ethics approval [1] 317713 0
23/04/2025
Approval date [1] 317713 0
30/05/2025
Ethics approval number [1] 317713 0
HREC2025-04-592

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 141906 0
A/Prof Laurens Manning
Address 141906 0
The Kids Research Institute Australia, 15 Hospital Avenue, Nedlands, WA 6009
Country 141906 0
Australia
Phone 141906 0
+61 400783194
Fax 141906 0
Email 141906 0
[email protected]
Contact person for public queries
Name 141907 0
Elizabeth Eadie-Mirams
Address 141907 0
The Kids Research Institute Australia. 15 Hospital Avenue, Nedlands, WA 6009
Country 141907 0
Australia
Phone 141907 0
+61 424589101
Fax 141907 0
Email 141907 0
[email protected]
Contact person for scientific queries
Name 141908 0
Eshetie Birru
Address 141908 0
The Kids research Institute Australia. 15 Hospital Avenue, Nedlands, WA 6009
Country 141908 0
Australia
Phone 141908 0
+61 452542116
Fax 141908 0
Email 141908 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: Individual participant data will not be shared due to ethical constraints and the limited size and sensitive nature of the dataset, including qualitative interviews



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.