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Trial registered on ANZCTR


Registration number
ACTRN12622000916741
Ethics application status
Approved
Date submitted
21/06/2022
Date registered
27/06/2022
Date last updated
8/03/2024
Date data sharing statement initially provided
27/06/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
SCIP RHD: Are SubCutaneous Infusions of benzathine Penicillin G (BPG) longer lasting and more acceptable than intramuscular BPG in children with Rheumatic Heart Disease?
Scientific title
Safety, tolerability and acceptability of high dose, subcutaneous infusions of benzathine penicillin G (Bicillin® L-A) in children and young adults with rheumatic fever
Secondary ID [1] 307398 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
rheumatic fever 326729 0
rheumatic heart disease 326730 0
Condition category
Condition code
Cardiovascular 323965 323965 0 0
Other cardiovascular diseases
Infection 323966 323966 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase II trial to test the safety, tolerability, acceptance, and pharmaco-equivalence of high dose subcutaneous Bicillin® L-A in children and young adults living with rheumatic fever and regularly receiving intramuscular benzathine penicillin G (BPG) injections.

28 days after the participants last BPG intramuscular injection (i.e. when the next BPG intramuscular injection would be scheduled to be administered) trained staff will instead administer one high dose (20.7mL/10.8MIU) subcutaneous infusion of Bicillin® L-A over a 20-30 minute period. The administration will be supervised and participants will be monitored for two hours following the abdominal infusion. Participants will forego their usual monthly BPG injection for 70 days post dosing at which point they will be resumed.
Intervention code [1] 323834 0
Treatment: Drugs
Intervention code [2] 323835 0
Prevention
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331759 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.
Timepoint [1] 331759 0
Dried blood samples to ascertain the outcome will be taken at: baseline (prior to dosing), 48 hours after completion of the Bicillin ®L-A infusion, followed by day 28, 42, 56 and 70 following the subcutaneous infusion.

Venous blood will be taken prior to dosing (baseline)
Primary outcome [2] 331760 0
To measure the pain experienced by participants following high dose Bicillin® L-A administered by subcutaneous infusion.
Timepoint [2] 331760 0
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 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.

Pain scoring will be taken at: baseline, 24 hours, 48 hours and 72 hours post dosing, then at 28 days post dosing. After day 28, 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.
Primary outcome [3] 331761 0
To demonstrate acceptability of high dose subcutaneous Bicillin® L-A in children/young adults with rheumatic fever currently receiving regular intramuscular BPG injections.
Timepoint [3] 331761 0
All participants will have one-on-one face-to-face semi-structured interviews designed for this study to understand lived experiences of receiving regular BPG intramuscular injections in comparison to subcutaneous infusion, Interviews will occur on the day of the infusion and days 28 and 70 post dosing. Interviews will be audio recorded, hand written notes will also be taken of key discussion points.
Secondary outcome [1] 411042 0
To measure the frequency and types of adverse events related to high dose Bicillin® L-A administered by subcutaneous infusion.
Timepoint [1] 411042 0
Adverse events will be assessed on the day of infusion (2 hours post infusion) and in the form of in-person follow-up visits commencing 24 hours after completion of the Bicillin ®L-A infusion, followed by days 2, 42, 56, and 70 post dosing. Follow-up phone calls will be made 24 and 72 hours after the infusion.

Adverse events will be collected by participant self-report, clinical observation during the confinement period and on follow-up days post dosing. Participants will be inspected by a trained study team member for evidence of skin erythema. Skindex-16 (a validated measurement of skin disease) will be used at all time points. Any adverse events will be reported to an internal data safety monitoring committee.

Secondary outcome [2] 411116 0
Semi-structured individual face-to-face interviews designed for this study will be used to explore perceptions, attitudes and training of health workers delivering the Bicillin ®L-A subcutaneous infusion and how this could impact the patient experience.
Timepoint [2] 411116 0
After all participants have received their Bicillin ®L-A subcutaneous infusion.
Secondary outcome [3] 411117 0
Focus group (maximum of 6 per group) face-to-face interviews designed for this study will be used to explore perceptions, attitudes and training of health workers delivering regular BPG and how this could impact the patient experience.
Timepoint [3] 411117 0
After all participants have received their Bicillin ®L-A subcutaneous infusion.

Eligibility
Key inclusion criteria
Aged 6 years of age or older with a prior diagnosis of rheumatic fever or rheumatic heart disease.
Currently on secondary prophylaxis.
No prior documented allergy to penicillin, cephalosporin antibiotics.
Normally reside in New Zealand.
Minimum age
6 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
History of adverse drug reaction or hypersensitivity.
Planned absence from their usual place of residence during the study trial.
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.
Pregnancy.
Scarring or superficial changes on the abdomen.
Dermatological conditions that affect the abdomen

Study design
Purpose of the study
Prevention
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
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2022
Actual
1/11/2022
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
1/04/2025
Actual
Sample size
Target
65
Accrual to date
47
Final
Recruitment outside Australia
Country [1] 24845 0
New Zealand
State/province [1] 24845 0
Wellington and Waikato

Funding & Sponsors
Funding source category [1] 311674 0
Charities/Societies/Foundations
Name [1] 311674 0
CureKids
Country [1] 311674 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
23A Mein Street
Newtown
Wellington 6021
Country
New Zealand
Secondary sponsor category [1] 313128 0
Charities/Societies/Foundations
Name [1] 313128 0
Telethon Kids Institute
Address [1] 313128 0
Northern Entrance, Perth Children's Hospital, 15 Hospital Ave, Nedlands WA 6009
Country [1] 313128 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311130 0
Southern Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 311130 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 311130 0
New Zealand
Date submitted for ethics approval [1] 311130 0
Approval date [1] 311130 0
31/01/2022
Ethics approval number [1] 311130 0
11094

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

There is an urgent need to improve penicillin formulations for all children living with ARF/RHD. Based on previous work we hypothesise that penicillin can be delivered as an ‘implant’ if given as a high-dose subcutaneous (SC) infusion, which will allow for sustained penicillin concentrations (>3 months). This approach would fulfil the ideal product characteristics for the next generation of long acting penicillin. Our Phase I trial showed that SCIP was tolerable and provided sustained penicillin concentrations in healthy adults. We therefore are now moving to Phase II, which will involve children and young adults who are currently receiving monthly BPG injections for their ARF/RHD. Alongside demonstrating safety, tolerability and minimum inhibitory concentrations of Bicillin ®L-A delivered by subcutaneous infusion; we will implement mixed-methods study to identify acceptability, barriers and benefits, both from consumer and health care provider perspectives.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120046 0
Dr Julie Bennett
Address 120046 0
University of Otago
23A Mein Street
Newtown
Wellington 6021
Country 120046 0
New Zealand
Phone 120046 0
+64 21321993
Fax 120046 0
Email 120046 0
[email protected]
Contact person for public queries
Name 120047 0
Julie Bennett
Address 120047 0
University of Otago
23A Mein Street
Newtown
Wellington 6021
Country 120047 0
New Zealand
Phone 120047 0
+64 21321993
Fax 120047 0
Email 120047 0
[email protected]
Contact person for scientific queries
Name 120048 0
Julie Bennett
Address 120048 0
University of Otago
23A Mein Street
Newtown
Wellington 6021
Country 120048 0
New Zealand
Phone 120048 0
+64 21321993
Fax 120048 0
Email 120048 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be made publicly available.


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
EmbaseQualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies.2023https://dx.doi.org/10.1371/journal.pone.0285037
Dimensions AI“Hurts less, lasts longer”; a qualitative study on experiences of young people receiving high-dose subcutaneous injections of benzathine penicillin G to prevent rheumatic heart disease in New Zealand2024https://doi.org/10.1371/journal.pone.0302493
N.B. These documents automatically identified may not have been verified by the study sponsor.