Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000692538
Ethics application status
Approved
Date submitted
17/05/2024
Date registered
30/05/2024
Date last updated
8/09/2024
Date data sharing statement initially provided
30/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety, tolerability and pharmacokinetics of 2g subcutaneous ceftriaxone as an alternative to intravenous administration
Scientific title
Safety, tolerability and pharmacokinetics of 2g subcutaneous ceftriaxone as an alternative to intravenous administration in adult inpatients
Secondary ID [1] 312174 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infection 333828 0
Condition category
Condition code
Infection 330501 330501 0 0
Other infectious diseases
Infection 330502 330502 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
For patients already receiving ceftriaxone 2g as part of their infection management plan the intervention is delivering one dose of the patient’s prescribed antibiotic via the subcutaneous (SC: intervention arm) rather than the intravenous (IV: control arm) route. Both the intravenous and subcutaneous doses will be administered by a registered nurse.
The antibiotic will be administered intravenously accordance with packaging and local guidelines. A dry blood spot blood sample will be collected immediately prior to infusion (T0), then 0.75-1, 2-3, 4-5, 8 hours (or as late as possible on the day) and 12 hours post-initiation (but before the next dose for those on twice daily dosing) of infusion for patients on twice daily dosing. For the majority of patients on once daily dosing regimens, an additional sample at 24 hours post initiation of infusion will be collected (which will also be the pre-dose sample timepoint for the SC administration.
The patient’s next dose will be administered via the SC route, adopting the existing protocol for ertapenem, 1g ceftriaxone and teicoplanin:
- The charted dose of antibiotic will be prepared to a 50mL volume with normal saline
- A flexible subcutaneous needle (23G) will be inserted
- The dose will be delivered over 30 minutes via gravity feed or infusion pump
- The needle will be removed after the SC dose is delivered.
- Dry blood spots will be collected at the same time points as for the IV dose (prior to the infusion (T0), then 0.75-1, 2-3, 4-5, 8 hours (or as late as possible on the day) and 12 hours post-initiation (but before the next dose) of infusion for patients on twice daily dosing. For patients on once daily dosing regimens, an additional sample at 24 hours post initiation of infusion will be collected.
- After the single SC dose, patients will revert to the IV route for their next scheduled dose.
Administration of antibiotics, and collection of dried blood samples will be documented in the patient's electronic medical records to ensure adherence.
Intervention code [1] 328617 0
Treatment: Drugs
Comparator / control treatment
For intravenous administration (control arm), the following steps will be followed:
- 2g of Ceftriaxone will be diluted with 50ml of normal saline and will be infused over at least 30 minutes.
Control group
Active

Outcomes
Primary outcome [1] 338271 0
The primary endpoint will be the safety and tolerability of subcutaneous administration of ceftriaxone 2g, based on objective clinical evaluation of adverse events and subjective numerical rating scores for pain, erythema and oedema.
This will be assessed as a composite outcome.
Timepoint [1] 338271 0
The tolerability and safety of subcutaneous infusion will be assessed immediately after the infusion and then at each scheduled sampling time point (i.e. at approximately 1 hour, 2 hours, 4 hours, 8 hours, and 12 hours after the subcutaneous administration).
Secondary outcome [1] 435235 0
Comparative bioavailability of SC vs IV administration
Timepoint [1] 435235 0
This will be calculated after sample collection and processing has been completed for the pre-determined number of patients (24 participants in total). For both SC and IV administration, a dry blood spot blood sample will be collected immediately prior to infusion (T0), then 0.75-1, 2-3, 4-5, 8 hours (or as late as possible on the day) and 12 hours post-initiation (but before the next dose for those on twice daily dosing) of infusion for patients on twice daily dosing. For the majority of patients on once daily dosing regimens, an additional sample at 24 hours post initiation of infusion will be collected (which will also be the pre-dose sample timepoint for the SC administration.

Eligibility
Key inclusion criteria
Must meet all of:
- Age 18 years and older.
- Inpatient at Fiona Stanley Hospital
- Capacity to provide informed consent.
- Prescribed ceftriaxone 2g as part of their infection management plan.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will not be eligible for participation if any of the following criteria are met:
- Patients deemed to be clinically unstable (defined as requiring High-level dependency care (HDU)/Intensive care (ICU) or having had a medical emergency team (MET) call within the preceding 24 hours)
- Patients with a history of cognitive impairment, intellectual disability or a mental illness that leads to the inability to provide informed consent
- Children < 18 years.
- History of anaphylaxis or serious adverse reaction to cephalosporins in past.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 4
Type of endpoint/s
Safety
Statistical methods / analysis
NONMEM (version 7.2.0, ICON Development Solutions, Ellicott City, MD, USA) with an Intel Visual FORTRAN 10.0 compiler will be used for nonlinear mixed-effects modelling of all predicted plasma concentrations of ceftriaxone measured from DBS concentrations using a previously validated method. The first-order conditional estimates method with interaction will be used, with the minimum value of the objective function value (OFV), goodness-of-fit plots, and predictive checks used to arrive at suitable models during the model-building process.
The models will be used to obtain population estimates of conventional PK parameters including ka (rate of absorption for SC doses), VC (central volume of distribution), CL (clearance), VP and Q (peripheral volumes of distribution(s) and their respective inter-compartmental clearance(s)). A significance level of P<0.05 will be set for comparison of nested models and allometric scaling will be employed a priori, with volume terms multiplied by (weight/70)1.0 and clearance terms by (weight/70)0.75.
An additional parameter will be included to estimate the bioavailability of SC administration compared to IV doses (where, by definition, bioavailability is 1). While the potential influence of other covariates (in particular renal function and also age, other measures of size, co-morbidities etc.) will be assessed in the model, identifying covariate relationships is not the aim of the study and, given the cross-over design, will not influence the estimate of SC bioavailability. Model evaluation will include a non-parametric bootstrap to evaluate model parameter precision as well as goodness of fit plots and visual predictive checks to assess for any bias.
The key targets were i) to have power to detect a 10% lower bioavailability of SC vs. IV dosing and ii) to be able to demonstrate equivalent bioavailability between the two routes of administration. This was defined to be a lower 90% CI of the estimate of SC bioavailability no less than 0.8 and derived from FDA/EMA guidance for bioequivalence where the 90% CI should fall between 0.8-1.25 for assessed parameters. We assumed comparable data from a study of SC vs IV ertapenem for the rate of SC absorption and population variability of relative bioavailability of SC vs IV. In the first step the sample size required to detect a 10% lower bioavailability with SC dosing, noting IV dosing has a bioavailability of 1. A Monte Carlo Mapped Power simulation was performed using Perl speaks NONMEM (PsN).
>20 patients would have >95% power to detect a 10% difference in bioavailability. Secondly, based on our experience with widespread administration of SC ertapenem and SC ceftriaxone (1g dosing) as well as our unpublished trial of SC meropenem and cefazolin, we expect the pain scores to be low. As such, a modest sample size of at least 20 participants should confirm the tolerability of SC ceftriaxone delivered as a 2g dose. To account for drop-out during the various infusions, we aim to recruit a total of 24 participants.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/06/2024
Actual
26/06/2024
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
28/02/2025
Actual
Sample size
Target
24
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 26553 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 42593 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 316541 0
Hospital
Name [1] 316541 0
Fiona Stanley Hospital
Country [1] 316541 0
Australia
Funding source category [2] 316600 0
University
Name [2] 316600 0
Curtin University
Country [2] 316600 0
Australia
Primary sponsor type
Hospital
Name
Fiona Stanley Hospital
Address
Country
Australia
Secondary sponsor category [1] 318722 0
None
Name [1] 318722 0
Address [1] 318722 0
Country [1] 318722 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315334 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 315334 0
Ethics committee country [1] 315334 0
Australia
Date submitted for ethics approval [1] 315334 0
26/03/2024
Approval date [1] 315334 0
04/04/2024
Ethics approval number [1] 315334 0

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

Contacts
Principal investigator
Name 134374 0
A/Prof Laurens Manning
Address 134374 0
Fiona Stanley Hospital, 11 Robbin Warren Drive, Murdoch, Western Australia , 6150
Country 134374 0
Australia
Phone 134374 0
+61 8 6151 1146
Fax 134374 0
Email 134374 0
[email protected]
Contact person for public queries
Name 134375 0
Henco Nel
Address 134375 0
Fiona Stanley Hospital, 11 Robbin Warren Drive, Murdoch, Western Australia , 6150
Country 134375 0
Australia
Phone 134375 0
+61 8 6151 1145
Fax 134375 0
Email 134375 0
[email protected]
Contact person for scientific queries
Name 134376 0
Henco Nel
Address 134376 0
Fiona Stanley Hospital, 11 Robbin Warren Drive, Murdoch, Western Australia , 6150
Country 134376 0
Australia
Phone 134376 0
+61 086152 2222
Fax 134376 0
Email 134376 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


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
22428Study protocol    387829-(Uploaded-17-05-2024-16-50-30)-Study-related document.docx
22430Informed consent form    387829-(Uploaded-17-05-2024-16-51-02)-Study-related document.docx



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.