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Trial registered on ANZCTR


Registration number
ACTRN12623000577617
Ethics application status
Approved
Date submitted
15/05/2023
Date registered
25/05/2023
Date last updated
25/05/2023
Date data sharing statement initially provided
25/05/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A study to investigate the pharmacokinetics of subcutaneous administration of cefazolin and meropenem
Scientific title
Safety, tolerability and pharmacokinetics of subcutaneous meropenem and cefazolin as an alternative to intravenous delivery in adults
Secondary ID [1] 309662 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Subcutaneous antibiotic administration 330088 0
Condition category
Condition code
Infection 326913 326913 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cross-over, self-controlled trial. Pharmacokinetic data will be collected for both subcutaneous and intravenous administration for each participant.

For patients already receiving meropenem (1g dose) or cefazolin (2g dose) as part of their infection management plan (either once, twice or 3 times daily), the intervention is delivering one dose of the patient’s prescribed antibiotic via a subcutaneous catheter rather than the intravenous route.

The antibiotic will be administered intravenously in accordance with packaging and local guidelines. A venous blood sample (3mLs of blood in a lithium heparin tube) will be collected immediately prior to infusion (T0), then 0.5, 1, 2, 4, and 8 hours post-initiation of infusion for patients on three times daily (i.e. 8 hourly) dosing regimens, with additional samples at 12 hours for patients on twice daily (i.e. 12 hourly) dosing, and at 18 and 24 hours for patients on daily dosing.

The patient’s next dose will be administered via the subcutaneous route, according to the following:
- The charted dose of antibiotic will be prepared to a 50mL volume with normal saline
- A flexible subcutaneous needle will be inserted
- The dose will be delivered over 30 minutes via gravity feed.
- The needle will be removed after the dose is delivered

Venous blood samples will be taken at the same time points as for the IV dose (T0, then 0.5, 1, 2, 4 and 8 hours post initiation of infusion in patients on three times daily (i.e. 8 hourly) dosing regimens, with additional samples at 12 hours for patients on twice daily (i.e. 12 hourly) dosing, and at 18 and 24 hours for patients on daily dosing.

After the single subcutaneous dose, patients will revert to the intravenous route for their next scheduled dose.
Intervention code [1] 326096 0
Treatment: Other
Comparator / control treatment
Cross over self-controlled trial with PK data collected for both SC and IV administration in each participant.
Control group
Active

Outcomes
Primary outcome [1] 334750 0
The primary outcome is equivalent bioavailability of subcutaneous administration compared to that of intravenous; assessed using venous blood sampling to measure the concentration of antibiotic as specified timepoints after administration by both routes.
Timepoint [1] 334750 0
0, 0.5, 1. 2, 4, 8 hours post dose of cefazolin or meropenem if three times daily (8 hourly) dosing.
Additional timepoint of 12 hours post dose if twice daily (12 hourly) dosing
Additional timepoints of 18 and 24 hours if once daily dosing.
Secondary outcome [1] 421951 0
Tolerability of subcutaneous administration. This will be assessed as a composite outcome based on the numerical (0-10) rating scores for pain, erythema and oedema.
Timepoint [1] 421951 0
0.5, 1, 2, 4, 8, 12 and 24 hours post subcutaneous administration.

Eligibility
Key inclusion criteria
18 years of age or over.
Inpatient who is clinically stable, defined as not having been in ICU or having had an emergency response call in the 24 hours prior to enrolment.
Ability to provide informed consent.
Patient must be receiving = 1g of meropenem or = 2g cefazolin daily.
Anticipated to require IV cefazolin or meropenem for at least 48 hours after enrolment.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
•Patients not clinically stable, as defined by being in ICU, having had a MET call in the 24 hours before screening for enrolment.
•Children <18 years
•Patients whose treating team predict will cease meropenem within 48 hours.
•Patients receiving >1g meropenem, or >2g cefazolin per dosing interval.
•Patients also taking medications predicted to interfere with meropenem or cefazolin pharmacokinetics (valproic acid, probenecid)
•Patients unable to give informed consent themselves.

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
Not Applicable
Type of endpoint/s
Bio-equivalence
Statistical methods / analysis
A population approach will be taken for the pharmacokinetic analysis with all concentrations of meropenem/cefazolin modelled using non-linear mixed effects modelling. Modelling will be performed 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 estimates method with interaction will be used with the minimum value of the objective function value, goodness-of-fit plots and predictive checks used to select suitable compartmental models during model-building. 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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/06/2023
Actual
Date of last participant enrolment
Anticipated
1/08/2023
Actual
Date of last data collection
Anticipated
4/08/2023
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 24736 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 40358 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 313855 0
Hospital
Name [1] 313855 0
South Metropolitan Health Service (in kind support)
Country [1] 313855 0
Australia
Primary sponsor type
Individual
Name
Laurens Manning
Address
Harry Perkins Institute for Medical Research (south)
Fiona Stanley Hospital Campus
5 Robin Warren Drive
Murdoch
WA 6150
Country
Australia
Secondary sponsor category [1] 315685 0
University
Name [1] 315685 0
University of Queensland (in kind support)
Address [1] 315685 0
Brisbane,
Queensland 4072
Country [1] 315685 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313002 0
South Metropolitan Health Service HREC
Ethics committee address [1] 313002 0
Fiona Stanley Hospital,
11 Robin Warren Drive,
Murdoch
WA 6150
Ethics committee country [1] 313002 0
Australia
Date submitted for ethics approval [1] 313002 0
13/02/2023
Approval date [1] 313002 0
24/03/2023
Ethics approval number [1] 313002 0

Summary
Brief summary
There is a small, but emerging body of knowledge demonstrating the safety and efficacy of subcutaneous (SC) infusion of antibiotics. This practice, popularised in France has been successfully implemented at Fiona Stanley Hospital both for in-patients as well as with the Infectious Diseases Ambulatory Care (IDAC) service delivering ceftriaxone, ertapenem and teicoplanin by this route to select patients.

In this prospective, single arm cross over study, we aim to extend this experience to SC meropenem and cefazolin which are 2 commonly used antibiotics for severe infections in hospitalised patients.

Patients already receiving either meropenem or cefazolin (usually given three times daily) will be followed closely following administration of IV dosing, followed by the same dose administered as a SC infusion.

Detailed safety and tolerability assessments will be accompanied by collection of blood to measure antibiotic concentrations to confirm antibiotic exposure is not compromised.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126646 0
A/Prof Laurens Manning
Address 126646 0
Level 1, Harry Perkins Institute for Medical Research (South)
Fiona Stanley Campus
5 Robin Warren Drive
Murdoch
Western Australia 6150
Country 126646 0
Australia
Phone 126646 0
+61 8 6151 1146
Fax 126646 0
Email 126646 0
[email protected]
Contact person for public queries
Name 126647 0
Fionnuala Murray
Address 126647 0
Level 2, Harry Perkins Institute for Medical Research (South)
Fiona Stanley Campus
5 Robin Warren Drive
Murdoch
WA 6150
Country 126647 0
Australia
Phone 126647 0
+61 861511146
Fax 126647 0
Email 126647 0
[email protected]
Contact person for scientific queries
Name 126648 0
Fionnuala Murray
Address 126648 0
Level 2, Harry Perkins Institute for Medical Research (South)
Fiona Stanley Campus
5 Robin Warren Drive
Murdoch
WA 6150
Country 126648 0
Australia
Phone 126648 0
+61 861511146
Fax 126648 0
Email 126648 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
19167Study protocol  [email protected]



Results publications and other study-related documents

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