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Trial registered on ANZCTR


Registration number
ACTRN12623000976684
Ethics application status
Approved
Date submitted
9/08/2023
Date registered
7/09/2023
Date last updated
7/09/2023
Date data sharing statement initially provided
7/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Ceftolozane/Tazobactam Continuous Intravenous Infusion given in an Outpatient Setting to treat Infective Exacerbations of Cystic Fibrosis and Bronchiectasis
Scientific title
The feasibility of ceftolozane/tazobactam Continuous Infusion for Exacerbations of Cystic Fibrosis and Bronchiectasis Treated in an outpatient parenteral antibiotic therapy (OPAT) Setting
Secondary ID [1] 310146 0
CTN registry ID: CT-2023-CTN-00033-1-v1
Universal Trial Number (UTN)
U1111-1295-4030
Trial acronym
CERTAIN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Bronchiectasis 330717 0
Cystic Fibrosis 330718 0
Condition category
Condition code
Human Genetics and Inherited Disorders 327555 327555 0 0
Cystic fibrosis
Respiratory 328005 328005 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive 9g/day ceftolozone+tazobactam in a 24-hour intravenous infusion on an outpatient parental antibiotic programme (OPAT) in place of standard of care antibiotics for infective exacerbation of cystic fibrosis (CF) / bronchiectasis, where infection with pseudomonas aeruginosa or burkholderia cepacia complex organisms is known to be present. Participants will receive 10-14 days of treatment at their physician's discretion based on clinical response to treatment. Ceftolozone+tazobactam will be administered in a 240mL Nipro Surefuser device at a rate of 10mLs per hour. Any deviation from the participant receiving ceftolozone+tazobactam as prescribed will be reported to the treating team and research team as per routine clinical care. At day 0-3, 5-7 and 10-14 blood testing, sputum testing, lung function testing, administration of CF- and bronchiectasis-specific questionnaires and adverse event reporting will be carried out. Clinical review at day 28-42 will be carried out to assess for recrudesce of symptoms and further need for antibiotics.
Intervention code [1] 326545 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335406 0
The feasibility of the use of ceftolozane/tazobactam given via continuous infusion in an OPAT setting for the treatment of acute exacerbations of CF and bronchiectasis, in patients known to be colonised with pseudomonas aeruginosa or burkholderia cepacia complex.

Feasibility will be determined as a composite of clinical response (as assessed by disease-specific questionnaires - see below, serum inflammatory marker monitoring and spirometry in the case of patients with cystic fibrosis), adverse events and report of relapse of respiratory infection at 3 months.

Adverse events will be monitored and described. Possible symptomatic AE's include: nausea, diarrhoea, headache, vomiting, constipation, insomnia, rash and fever. Possible laboratory abnormalities include: liver function test derangement and acute kidney injury. These will be monitored by regular blood tests during and after the course of ceftolozane/tazobactam. AE's will be assessed by direct questioning of participants at the time of research visits, by clinical examination, monitoring of laboratory results and and by participants self-reporting symptoms of concern to the research team any time during or after their course of ceftolozone/tazobactam

Disease specific questionnaires used will be: Quality of Life Questionnaire-Bronchiectasis (QOL-B; Quittner et al 2015); Cystic Fibrosis Questionnaire Revised (CFQ-R; Quittner et al 2009), St George’s Respiratory Questionnaire (SGRQ; Wilson et al 1997).

Relapse of respiratory infection at 3 months will be defined by requirement for further oral or intravenous IV antibiotics following cessation of ceftolozane/tazobactam.
Timepoint [1] 335406 0
Questionnaires, inflammatory markers, spirometry in the case of participants with cystic fibrosis and adverse events will be assessed at: Day 0-1 post commencement of intervention, Day 5-7 post commencement of intervention, Day 10-14 post commencement of intervention and Day 28-42 post commencement of intervention. Relapse of respiratory infection will be assessed 3 months post-commencement of intervention.
Secondary outcome [1] 424408 0
Composite outcome of clinical response to ceftolozane-tazobactam via continuous infusion in an OPAT setting for infective exacerbations of CF and non-CF bronchiectasis. Determinants of the composite outcome will be: disease-specific questionnaires, serum inflammatory marker monitoring, spirometry in the case of patients with cystic fibrosis, and relapse of infection 3 months following completion of ceftolozane-tazobactam course. Disease specific questionnaires used will be: Quality of Life Questionnaire-Bronchiectasis (QOL-B; Quittner et al 2015); Cystic Fibrosis Questionnaire Revised (CFQ-R; Quittner et al 2009), St George’s Respiratory Questionnaire (SGRQ; Wilson et al 1997).
Timepoint [1] 424408 0
Day 0-1 post commencement of intervention,
Day 5-7 post commencement of intervention,
Day 10-14 post commencement of intervention,
Day 28-42 post commencement of intervention,
3 months post completion of intervention
Secondary outcome [2] 424409 0
Safety and tolerability of continuous infusion ceftolozane/tazobactam. Ceftolozone/tazobactam has a very similar AE profile to other broad spectrum intravenous antibiotics, e.g. piperacillin/tazobactam and meropenem. Possible symptomatic AE's include: nausea, diarrhoea, headache, vomiting, constipation, insomnia, rash and fever. These will be assessed direct questioning of participants at the time of research visits, by clinical examination and and by participants self-reporting symptoms of concern to the research team any time during or after their course of ceftolozone/tazobactam. Possible laboratory abnormalities include: liver function test derangement and acute kidney injury. These will be monitored by regular blood tests during and after the course of ceftolozane/tazobactam.
Timepoint [2] 424409 0
Clinical AE's will be monitored from day 0 to day 90 post commencement of intervention.
Laboratory AE's will be assessed at Day 0-1 post commencement of intervention, Day 5-7 post commencement of intervention, Day 10-14 post commencement of intervention and Day 28-42 post commencement of intervention. Relapse of respiratory infection will be assessed 3 months post-commencement of intervention.
Secondary outcome [3] 424410 0
To describe relative bacterial load over the course of ceftolozane/tazobactam treatment as assessed by quantitative PCR (qPCR) on sputa.
Timepoint [3] 424410 0
Day 0-1 post commencement of intervention,
Day 5-7 post commencement of intervention,
Day 10-14 post commencement of intervention,
Day 28-42 post commencement of intervention,
Secondary outcome [4] 424411 0
To describe in vitro antimicrobial susceptibility of airway pathogens present in sputum samples to ceftolozane/tazobactam and other anti-pseudomonal/anti-Burkholderia antibiotics over the course of ceftolozane/tazobactam treatment. This will be determined by a composite outcome of antimicrobial susceptibility testing, whole-genome sequencing (WGS), culturomic sequencing, and bioinformatic analysis.
Timepoint [4] 424411 0
Day 0-1 post commencement of intervention,
Day 5-7 post commencement of intervention,
Day 10-14 post commencement of intervention,
Day 28-42 post commencement of intervention,

Eligibility
Key inclusion criteria
•Age > 18 years
•Diagnosis of CF or bronchiectasis
•Colonised with pseudomonas aeruginosa or burkholderia cepacia species, with documented isolation of either organism in sputum in the preceding 6 months in the case of non-CF patients, and 2 years in the case of CF patients.
•Current infectious exacerbation requiring treatment with intravenous antibiotics, suitable to be managed on OPAT
•Productive of sputum
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
•Unable to consent
•Current pregnancy (as confirmed by urine beta-HCG) or partner who is currently pregnant
•Current breastfeeding
•Not appropriate for OPAT (as determined by treating clinician)
•Estimated CrCl < 50mL/min
•History of hypersensitivity reaction to piperacillin/tazobactam or members of the cephalosporin class of antibiotics
•Unable to expectorate

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
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
N = 30. As this is an exploratory feasibility study, no power calculations are deemed necessary. It is expected that the estimated study number of 30 subjects will account for some expected attrition, and will result in a valid conclusion in relation to the feasibility and utility of ceftolozane/tazobactam in treating acute exacerbations of CF and bronchiectasis in an OPAT setting.

Statistical analysis will be performed using SPSS software, R, or GraphPad Prism. Paired Student’s t-tests will be used to compare WGS, culturomics, and quantitative PCR results to traditional pathology laboratory culture techniques. Two-sided testing will be performed with correlation between continuous variables examined using multiple regression analysis techniques. The analysis of variance will be used to fit the model, with goodness-of-fit statistics performed. A p-value 0.05 will be interpreted as statistically significant. Parameters will be reported as mean ± standard deviation for descriptive statistics and ±standard error of the mean for evaluative statistics.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/10/2023
Actual
Date of last participant enrolment
Anticipated
2/10/2024
Actual
Date of last data collection
Anticipated
2/01/2025
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 25207 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [2] 25208 0
The Prince Charles Hospital - Chermside
Recruitment hospital [3] 25209 0
Mater Hospital Brisbane - South Brisbane
Recruitment postcode(s) [1] 40877 0
4575 - Birtinya
Recruitment postcode(s) [2] 40878 0
4032 - Chermside
Recruitment postcode(s) [3] 40879 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 314306 0
Commercial sector/Industry
Name [1] 314306 0
Merck, Sharp & Dohme (Australia) Pty Ltd
Country [1] 314306 0
Australia
Primary sponsor type
Hospital
Name
Sunshine Coast Hospital and Health Service
Address
6 Doherty St
Birtinya
QLD 4575
Country
Australia
Secondary sponsor category [1] 316259 0
None
Name [1] 316259 0
Address [1] 316259 0
Country [1] 316259 0
Other collaborator category [1] 282760 0
Other Collaborative groups
Name [1] 282760 0
Sunshine Coast Health Institute
Address [1] 282760 0
6 Doherty Street
Birtinya
QLD 4575
Country [1] 282760 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313418 0
Metro North HREC B
Ethics committee address [1] 313418 0
Research OfficeBuilding 14Rode RoadCHERMSIDE QLD 4032
Ethics committee country [1] 313418 0
Australia
Date submitted for ethics approval [1] 313418 0
03/01/2023
Approval date [1] 313418 0
16/02/2023
Ethics approval number [1] 313418 0
90934

Summary
Brief summary
For patients with CF and non-CF bronchiectasis, chronic airway infection with Gram-negative organisms such as Pseudomonas aeruginosa and Burkholderia cepacia complex species (BCC) is highly challenging to treat and associated with significant morbidity and mortality. These organisms are naturally resistant towards many antibiotic classes, limiting the available arsenal of effective antibiotics for their treatment and eradication. Therefore, there is a pressing need for new antimicrobial therapy options for infective exacerbations associated with these organisms.
There are clear logistical and financial benefits for acute infective exacerbations of CF and non-CF bronchiectasis to be managed on OPAT programs. Many acute infective exacerbations can be safely managed in this way, and a substantial body of evidence supports non-inferiority of OPAT compared with inpatient care. From a logistical perspective, feasibility of OPAT programs is greatly improved by antibiotics being infused over a 24-hour period rather than via bolus several times per day. Unfortunately, many mainstay anti-pseudomonal and anti-Burkholderia antibiotics (including meropenem, imipenem and ceftazidime) are not stable for 24 hours at room/body temperature therefore are unsuitable for use on OPAT.
This study aims to assess viability of ceftolozane/tazobactam (C/T) administered via OPAT in adult patients with exacerbations of CF or non-CF bronchiectasis. Secondary aims are to describe clinical outcomes of patients receiving C/T, tolerability of C/T, relative sputum bacterial load throughout treatment and assess development of resistance to C/T and other antibiotics. We aim to recruit 30 patients, colonized with either pseudomonas aeruginosa or burkholderia cepacia complex, with a current infectious exacerbation requiring intravenous antibiotic treatment. We propose to administer C/T via infusion for 10-14 days with review at day 0-3, 5-7 and 10-14. Blood testing, sputum testing, lung function testing, administration of CF- and bronchiectasis-specific questionnaires and adverse event reporting will be carried out at these times. Serum levels of C/T will be monitored using a validated assay. Clinical review at day 28-42 will be carried out to assess for recrudescence of symptoms and further need for antibiotics and a follow-up phone call will be made at 3 months to assess whether any further antibiotics were needed for new/recrudescent symptoms of infection.
We expect to find that C/T is safe, well-tolerated and effective in treating infective exacerbations of bronchiectasis in OPAT settings. We expect to find that bacterial density in sputum samples reduces over the course of treatment, and that development of antimicrobial resistance is minimal.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128090 0
Dr Julia Bashford
Address 128090 0
Sunshine Coast University Hospital6 Doherty StBirtinyaQLD4575
Country 128090 0
Australia
Phone 128090 0
+61752020000
Fax 128090 0
Email 128090 0
[email protected]
Contact person for public queries
Name 128091 0
Dr Julia Bashford
Address 128091 0
Sunshine Coast University Hospital6 Doherty StBirtinyaQLD4575
Country 128091 0
Australia
Phone 128091 0
+61752020000
Fax 128091 0
Email 128091 0
[email protected]
Contact person for scientific queries
Name 128092 0
Dr Julia Bashford
Address 128092 0
Sunshine Coast University Hospital6 Doherty StBirtinyaQLD4575
Country 128092 0
Australia
Phone 128092 0
+61752020000
Fax 128092 0
Email 128092 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?
All de-identified line-by-line data
When will data be available (start and end dates)?
Immediately following publication, no end date determined
Available to whom?
Researchers who provide a sound proposal
Available for what types of analyses?
IPD meta-analysis
How or where can data be obtained?
Contact PI via email [email protected]


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.