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Trial registered on ANZCTR


Registration number
ACTRN12621000135819
Ethics application status
Approved
Date submitted
14/12/2020
Date registered
10/02/2021
Date last updated
8/03/2022
Date data sharing statement initially provided
10/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Subcutaneous infusions of benzathine penicillin G (SCIP) in healthy adults
Scientific title
Safety, tolerability and pharmacokinetics of high dose, subcutaneous infusions of benzathine penicillin G (Bicillin® L-A) in healthy adults
Secondary ID [1] 303184 0
Nil
Universal Trial Number (UTN)
1111-1262-3340
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute rheumatic fever 320075 0
Rheumatic heart disease 320076 0
Treponema pallidum infection 320077 0
Streptococcus pyogenes infection 320078 0
Condition category
Condition code
Infection 318006 318006 0 0
Other infectious diseases
Infection 318007 318007 0 0
Sexually transmitted infections
Cardiovascular 318545 318545 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Administration of high dose (6.9mL, 13.8mL or 20.7mL [3.6MIU, 7.2MIU or 10.8MIU]) Bicillin® L-A by a single subcutaneous infusion up to 30 minutes.

Determination of the dosage participants will be receiving will be according to their enrollment number in the study and their weight group.

There will be 3 administration periods. In Cohort 1, 2 participants in each weight group (ideal and overweight BMI, 4 participants total) will receive a 6.9ml (3.6 MIU) dose of Bicillin® L-A by a single subcutaneous infusion up to 30 minutes.

In Cohort 2, five participants in each weight group (ideal and overweight BMI, 10 participants total) will receive a 13.8ml (7.2 MIU) dose of Bicillin® L-A by a single subcutaneous infusion up to 30 minutes.

In Cohort 3, five participants in each weight group (ideal and overweight BMI, 10 participants total) will receive a 20.7ml (10.8 MIU) dose of Bicillin® L-A by a single subcutaneous infusion up to 30 minutes.

Progression to the next Administration period is dependent upon no SAEs and will be determined by a Safety Monitoring Committee.
Intervention code [1] 319300 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 326000 0
The rate of absorption of high dose Bicillin® L-A, administered via subcutaneous infusion
Timepoint [1] 326000 0
Dried blood samples to ascertain primary outcome 1 will be taken at: baseline (prior to dosing), then t=2, 6, 12, and 24 hours after completion of the Bicillin ®L-A infusion, followed by day 2, 3, 5, 7, 14, 21, 28, and 42, 56, 70, 84, 98 and 112. Venous blood samples will be collected at 12 hours after completion of the Bicillin ®L-A infusion and 14 days after infusion completion.
Secondary outcome [1] 389820 0
To measure the pain experienced by participants following high dose Bicillin® L-A administered by subcutaneous infusion.

Pain scoring will be measured using the numeric rating scale (NRS), which is a valid method for recording pain in this setting. The NRS has been validated in adults for recording pain; the scoring system has 11 (0-10) different values anchored by terms describing pain severity extremes: 0=none, 1-3=mild, 4-6=moderate, and 7-10=severe. A score of 10 indicates the worst pain imaginable.
Timepoint [1] 389820 0
Pain scoring will be taken at: baseline, t=2, 6, 12, 24, 48, and 72 hours, then at day 5. After Day 5, further assessment of pain will occur only if injection-associated pain is recorded at the prior visit. Pain scoring will continue to be assessed until a participant reports a pain score of 0 for two consecutive assessments.
Secondary outcome [2] 389821 0
To measure the frequency and types of adverse events related to high dose Bicillin® L-A administered by subcutaneous infusion.

Adverse events will be collected by participant self-report, clinical observation during the confinement period and assessments undertaken three days after each dosing cohort by a Safety Monitoring Committee.
Timepoint [2] 389821 0
Adverse events will be assessed in the form of follow-up visits commencing 24 hours after completion of the Bicillin ®L-A infusion, followed by day 2, 3, 5, 7, 14, 21, 28, and 42, 56, 70, 84, 98 and 112. A follow up phone call will be made on day 126.
Secondary outcome [3] 389822 0
To measure Type and number of ultrasound-detected local changes following high dose Bicillin® L-A administered by subcutaneous infusion.

A Sonosite M-Turbo Ultrasound System (Sonosite) and Sonosite HFL38xp 6-13MHz 6 cm transducer (probe) will be used for to determine this outcome.
Timepoint [3] 389822 0
Ultrasound of the infusion area will occur at baseline prior to dosing and immediately after, and at day 28. Ultrasound will also occur every 28 days, up to day 112, if ultrasonographic changes persist.
Secondary outcome [4] 389823 0
To measure the time (in days) that penicillin concentrations remain above the minimum inhibitory concentration (0.02mg/mL) for Streptococcus pyogenes following high dose Bicillin® L-A administered by subcutaneous infusion.

Secondary outcome 4 will be assessed by dried blood spot samples and venous blood samples.
Timepoint [4] 389823 0
Dried blood samples to ascertain secondary outcome 4 will be taken at: baseline (prior to dosing), then t=2, 6, 12, and 24 hours after completion of the Bicillin ®L-A infusion, followed by day 2, 3, 5, 7, 14, 21, 28, and 42, 56, 70, 84, 98 and 112. Venous blood samples will be collected at 12 hours after completion of the Bicillin ®L-A infusion and 14 days after infusion completion.
Secondary outcome [5] 389824 0
To measure the time (in days) that penicillin concentrations remain above the minimum inhibitory concentration (0.018mg/mL) for Treponema pallidum following high dose Bicillin® L-A administered by subcutaneous infusion.

Secondary outcome 5 will be assessed by dried blood spot samples and venous blood samples.
Timepoint [5] 389824 0
Dried blood samples to ascertain secondary outcome 4 will be taken at: baseline (prior to dosing), then t=2, 6, 12, and 24 hours after completion of the Bicillin ®L-A infusion, followed by day 2, 3, 5, 7, 14, 21, 28, and 42, 56, 70, 84, 98 and 112. Venous blood samples will be collected at 12 hours after completion of the Bicillin ®L-A infusion and 14 days after infusion completion.

Eligibility
Key inclusion criteria
(a) Male and females aged 18 - 65 years at the time of screening.
(b) BMI between 20kg/m2 and 34.9kg/m2.
(c) No history of chronic renal impairment or significant liver dysfunction.
(d) No prior documented allergy to penicillin, cephalosporin antibiotics.
(e) Participants who are considered likely to adhere to the trial guidelines for the duration of the trial.
(f) Sign and dated informed consent in accordance with Good Clinical Practice (GCP)/Declaration of Helsinki.
(g) Participants must be in good state of health in the opinion of the investigator as indicated by a comprehensive clinical assessment (medical history and physical exam) and laboratory investigations (haematology, clinical chemistry, and urinalysis).
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
(a) Currently taking penicillins or use of any penicillin-based antibiotics from screening through to the final study visit. The use of probenecid, NSAIDs, or other medications which may significantly alter the Bicillin® L-A PK will also not be permitted within 14 days prior to study drug administration until completion of the final follow-up visit. Sporadic NSAID use (<5 occasions) in the 14 days prior to drug administration will be allowed, but the need for ongoing regular NSAIDS will render the person ineligible due to NSAIDS effects on proximal tubular penicillin excretion. Hormonal contraceptives for females and occasional paracetamol and ibuprofen use is permitted while on study.
(b) Known soy allergy.
(c) History of adverse drug reaction or hypersensitivity.
(d) History of seizure disorder
(e) Receipt of an investigational product within 3 months of Dosing.
(f) Planned participation in another clinical trial concurrently.
(g) Pregnant or breastfeeding females.
(h) Existing dermatological conditions that may affect skin integrity at the site of injection.
(i) Planned operation/absence from the study site during the duration of the study.
(j) History within the last 12 months of intramuscular, or subcutaneous injection of the abdominal wall, or history of surgery to the buttocks, abdomen or abdominal wall within the last 12 months.
(k) History of radiotherapy.
(l) 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, unless in the opinion of the Principal Investigator or delegate the medication will not compromise participant safety or interfere with study procedures or data validity.
(m) Participants who are smokers must abstain from using tobacco products during the confinement period.
(n) Laboratory tests that fail to meet the following thresholds: one repeat will be allowed at discretion of the investigator to confirm eligibility.
i. Haematology: complete blood count (Haemoglobin, total white cell count and platelet count) – parameters within gender-specific reference intervals from PathWest unless deemed not clinically significant by the investigator.
ii. Clinical chemistry within gender-specific reference intervals from PathWest unless deemed not clinically significant by the investigator: urea, glucose, creatinine, sodium, potassium, chloride and bicarbonate, lactate dehydrogenase, calcium, total protein, magnesium, phosphate, albumin, cholesterol, and uric acid. For renal function an eGFR >90ml/min/m2 will be considered normal using the CKD-EPI without albuminuria on dipstick].
iii. Liver function tests (only at screening): aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, gamma-glutamyl transferase [<1.5 x ULN (ALT, GGT; PathWest gender-specific reference ranges) will be considered not clinically significant].
iv. Negative HIV, Hepatitis B and C serology.
v. Negative pregnancy test at screening and check-in (females).

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)
Allocation is not concealed
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
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The sample is based on our recent knowledge of BPG pharmacology. The sample calculation for the comparison between ideal weight and overweight/obese participants is based on data from Kado et al. which demonstrates a difference of ~50% in the absorption characteristic (Ka1); based on this, a clinically meaningful difference between different body composition would require <10 participants in each group. The significance level is 5% (0.05). All dosed participants who contribute at least one penicillin concentration value will be included in the summary statistics and PK analysis.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
19/02/2021
Actual
19/03/2021
Date of last participant enrolment
Anticipated
31/03/2021
Actual
17/05/2021
Date of last data collection
Anticipated
23/08/2021
Actual
23/09/2021
Sample size
Target
24
Accrual to date
Final
24
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 18198 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 32255 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 307424 0
Charities/Societies/Foundations
Name [1] 307424 0
Cure Kids New Zealand
Country [1] 307424 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Telethon Kids Institute
Address
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 308092 0
Commercial sector/Industry
Name [1] 308092 0
Linear Clinical Research
Address [1] 308092 0
1 Hospital Avenue, B-Block, 1st Floor, Nedlands WA 6009
Country [1] 308092 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307506 0
Bellberry Limited
Ethics committee address [1] 307506 0
123 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 307506 0
Australia
Date submitted for ethics approval [1] 307506 0
23/12/2020
Approval date [1] 307506 0
23/02/2021
Ethics approval number [1] 307506 0
2020-12-1348

Summary
Brief summary
The associated morbidity from rheumatic heart disease (RHD) is the leading driver of cardiovascular inequality for Indigenous Australians. Across the Tasman, its precursor acute rheumatic fever (ARF) and RHD almost exclusively affect Maori and Pacific children and young adults living in socio-economically deprived areas of the North Island of New Zealand.

For 70 years, the only proven way to prevent ARF progression has been benzathine penicillin G (BPG), given as a monthly intramuscular (IM) injection. The effectiveness of this approach is limited by pain and the frequency of injection which leads to sub- optimal adherence in these vulnerable groups.

There is an urgent need to improve penicillin formulations for all children living with ARF/RHD. Based on a randomised cross-over trial conducted by our team, we hypothesise that BPG could be repurposed as an ‘implant’ if given as a high-dose subcutaneous (SC) infusion of penicillin (SCIP). By providing sustained penicillin concentrations for >3 months, this approach would fulfil the ideal product characteristics for the next generation of long-acting penicillins. This 3-year multiphase program begins with a phase 1 study, assessing the safety, tolerability and pharmacokinetics of SCIP in healthy adults (SCIP-I). If SCIP appears tolerable and provides sustained penicillin concentrations, we will perform an observational study of SCIP in children living with ARF (SCIP-II). Concurrently, we will implement mixed-methods studies to identify acceptability, barriers and benefits of SCIP RHD, both from consumer and health care provider perspectives (SCIP-IIa).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 107478 0
A/Prof Laurens Manning
Address 107478 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country 107478 0
Australia
Phone 107478 0
+61 0863191457
Fax 107478 0
Email 107478 0
[email protected]
Contact person for public queries
Name 107479 0
Joseph Kado
Address 107479 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country 107479 0
Australia
Phone 107479 0
+61 863191454
Fax 107479 0
Email 107479 0
[email protected]
Contact person for scientific queries
Name 107480 0
Joseph Kado
Address 107480 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country 107480 0
Australia
Phone 107480 0
+61 863191454
Fax 107480 0
Email 107480 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?
De-identified individual participant data (and relevant data dictionary) that underlie the results reported for this study (text, tables, figures and appendices).
When will data be available (start and end dates)?
Immediately following publication of the study results. 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
EmbaseSubcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.2023https://dx.doi.org/10.1128/aac.00962-23
N.B. These documents automatically identified may not have been verified by the study sponsor.