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Trial registered on ANZCTR


Registration number
ACTRN12622000950763
Ethics application status
Approved
Date submitted
9/06/2022
Date registered
5/07/2022
Date last updated
3/04/2024
Date data sharing statement initially provided
5/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
BEAT CF: Pulmonary Exacerbations Treatment Platform - Backbone Antibiotics Domain
Scientific title
BEAT CF: Pulmonary Exacerbations Treatment Platform - Backbone Antibiotics Domain:
An evaluation of the comparative effectiveness of prescribing various standard of care, first-line Backbone Antibiotics in the management of pulmonary exacerbations requiring intensive therapy (PERIT) in children and adults with CF, with respect to their short-term improvement in lung function.
Secondary ID [1] 307269 0
Nil known
Universal Trial Number (UTN)
Trial acronym
BEAT CF DSA A - Backbone antibiotics
Linked study record
This record is a sub-study of ACTRN12621000638831 platform study master protocol.

Health condition
Health condition(s) or problem(s) studied:
Cystic Fibrosis 326525 0
Condition category
Condition code
Human Genetics and Inherited Disorders 323789 323789 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a Prescription for the Assigned antibiotic at the commencement of intensive therapy made by the Responsible Clinician or their authorised delegate.
For each of the 4 treatment options:
The Dose and Duration prescribed is not fixed, and will ultimately be at the discretion of the Responsible Clinician in adherence with local Cystic Fibrosis (CF) centre /hospital guidelines and policies. The protocol requires that the antibiotic has a planned duration of at least 7 days. No maximum duration of treatment is specified. Assigned antibiotics include:

1. Intravenous Piperacillin + tazobactam
As a guide, administration by intravenous (IV) infusion over 30 minutes or longer, or by continuous infusion over 24 hours.
Dose adjustment may be required in cases of impaired renal function (Creatinine Clearance of <40ml/min).

2. Intravenous Cefepime
As a guide, IV Cefepime should be given by IV push over several minutes, OR IV infusion over up to 30 minutes, OR continuous IV infusion over 24 minutes.
It may also be given by intramuscular (IM) injection.
Dose adjustment may be required in cases of impaired renal function (Creatinine Clearance of <50ml/min).

3. Intravenous Ceftazadime
As a guide, Administration by IV bolus over several minutes, or as an infusion over up to 30 minutes. Doses <1000mg may also be given by IM injection.
Dose adjustment may be required in cases of impaired renal function (Creatinine Clearance of <50ml/min).

4. Intravenous Ceftriaxone
As a guide, Administration by IV infusion over 30 minutes, or by push over 5-15 minutes.
It may also be given by IM injection.
May be required in cases of significant renal impairment (creatinine clearance of <10mL/minute).

Adherence to the assigned intervention will be monitored by the detailed information about intensive therapies that is captured in the BEAT CF database. This information will be transcribed from the hospital medical records into the BEAT CF database by dedicated BEAT CF site coordinators at each site.

Participants will only be randomised to one of these treatment arms for any single episode of a pulmonary exacerbation. If participants do not respond to the first treatment the clinician is free to decide which therapy the participant shall be switched to. There will be no subsequent randomsiation within a single pulmonary exacerbation episode.
Intervention code [1] 323705 0
Treatment: Other
Comparator / control treatment
1. First randomisation is to clinician's choice (Responsible Clinician’s Selected Intervention) or to a Random intervention (Randomly Assigned Intervention).
The comparator for this randomisation is the Clinician's choice treatment arm.

2. The second randomisation, for those assigned to the Random intervention in step 1, is randomisation to one of 4 interventions:
1. Intravenous Piperacillin + tazobactam
2. Intravenous Cefepime
3. Intravenous Ceftazadime
4. Intravenous Ceftriaxone
The the comparator for the second randomisation is each of the antibiotic arms. The assigned antibiotic is compared against each of the other antibiotic options.
Control group
Active

Outcomes
Primary outcome [1] 331557 0
The absolute change in the ppFEV1 measured by spirometry
Timepoint [1] 331557 0
Greater than 7 days but not more than 14 days after first dose of intensive therapy.
Secondary outcome [1] 410261 0
1. The relative change in the ppFEV1, measured by spirometry and defined as the proportional change (expressed as a percentage) in the ppFEV1 at day 7-10 from day 0.
Timepoint [1] 410261 0
Approximately 7 days from initiation of intensive therapy.
Secondary outcome [2] 410262 0
2. Absolute change in the FEV1pp measured by spirometry
Timepoint [2] 410262 0
Approximately 2 weeks, 4 weeks, 8 weeks, and 24 weeks after commencement of intensive therapy.
Secondary outcome [3] 410263 0
3. Relative change in the FEV1pp measured by spirometry
Timepoint [3] 410263 0
Approximately 2 weeks, 4 weeks, 8 weeks, and 24 weeks after commencement of intensive therapy.
Secondary outcome [4] 410264 0
4. Time taken for FEV1pp measured by spirometry to return to greater than or equal to 90% of the baseline FEV1pp measured by spirometry.
Timepoint [4] 410264 0
Approximately 1 week, 2 weeks, 4 weeks, 8 weeks, and 24 weeks after commencement of intensive therapy.
Secondary outcome [5] 410265 0
5. The absolute change in the severity of symptoms of respiratory infection as measured by the Chronic Respiratory Infection Symptom Score (CRISS)
Timepoint [5] 410265 0
Approximately 7 days, 14 days and 30 days after commencement of intensive therapy.
Secondary outcome [6] 410326 0
6. The time to next exacerbation measured as the time (in days) from commencement of intensive therapy to the next commencement of intensive therapy after a period of no intensive therapy of > 7 days. This will be determined by data for hospitalisations for lung exacerbations reported in the BEAT CF platform database.
Timepoint [6] 410326 0
Following a post BEAT CF enrolment hospitalisation for treatment of a lung exacerbation, and a period of no intensive therapy of greater than 7 days after discharge from that exacerbation.
Secondary outcome [7] 410327 0
7. Any interruption of planned therapy before 7 days (168hr) after commencement of intensive therapy, owing to intolerable effects presumed by the treating clinician to be attributable to therapy. Assessment will be made on data reported in the BEAT CF database.
Timepoint [7] 410327 0
Post enrolment in BEAT CF, during hospitalisation for a lung exacerbation: after commencement of intensive therapy in that hospitalisation, for up to 7 days from commencement of the intensive therapy
Secondary outcome [8] 410328 0
9. Health related quality of life, as scored by The Cystic fibrosis Quality of Life questionnaire, revised, (CFQR).
Timepoint [8] 410328 0
For participants over 6 years of age, every 12 weeks post enrolment in BEAT CF until the participant withdraws consent for continuing or the platform is closed.
Secondary outcome [9] 410329 0
10. A new detection of any strain of gram negative bacteria with in vitro resistance to any aminoglycoside, fluoroquinolone, antipseudomonal penicillin (including beta-lactam/beta-lactamase inhibitor combination), antipseudomonal cephalosporin, or carbapenem assessed by sputum culture or medical record review.
Timepoint [9] 410329 0
Any time post enrolment to BEAT CF and for the 2 years prior to enrolment to BEAT CF.
Secondary outcome [10] 410330 0
11. Any new onset of Clostridium difficile associated diarrhoea assessed by faecal sample post enrolment to BEAT CF, or by medical record review for the 1 year prior to BEAT CF enrolment.
Timepoint [10] 410330 0
Any time post enrolment to BEAT CF and for the 2 years prior to enrolment to BEAT CF.
Secondary outcome [11] 411287 0
8 Any interruption of planned therapy before 14 days (336hr) after commencement of intensive therapy, owing to intolerable effects presumed by the treating clinician to be attributable to therapy. Assessment will be made on data reported in the BEAT CF database.
Timepoint [11] 411287 0
Post enrolment in BEAT CF, during hospitalisation for a lung exacerbation: after commencement of intensive therapy in that hospitalisation, for up to 14 days (336hrs) from commencement of the intensive therapy

Eligibility
Key inclusion criteria
1. Be enrolled in the BEAT CF PEx Cohort (ACTRN12621000638831).
2. Documented informed consent to participate in the Backbone antibiotics Domain.
3. Are eligible for at least two Interventions in the Backbone Antibiotic Domain available at the clinical Site.
4. Must be able to reliably perform spirometry.
Minimum age
5 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. The person is unable to reliably perform spirometry (for example due to young age)
2. The person’s Responsible Clinician deems enrolment in the PEx Backbone Antibiotic Domain is not in their best interest.
A participant will be excluded from Assignment to a specific Intervention in the Backbone Antibiotics Domain if:
1. They have a known or suspected significant drug hypersensitivity to that antibiotic
2. They have another recognised contraindication to that antibiotic
3. The Intervention is deemed unacceptable by the Responsible Clinician e.g. because of a poor treatment response to that antibiotic (requiring a change in antibiotic treatment) in the preceding 12 months

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled 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)
Participants will be randomised 1:4 to either be Provisionally Assigned the Selected Regimen (“‘Clinician’s Choice”) or to be Provisionally Assigned a Randomly Assigned Regimen, for each Domain they are eligible for, and participating in. Prior to the Assignment being Revealed, it will be considered ‘Provisionally Assigned’.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Assignment to a Randomly Assigned Regimen will occur using response-adaptive randomisation (RAR). In RAR, the ratio of allocation to each Regimen varies over time in response to the accumulating data, such that the probability of Assignment to a Regimen is proportional to the posterior probability that, at the most recent Scheduled Analysis, it is the Best Regimen. When RAR is implemented, the initial allocation ratios will be equal across Regimens.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A Bayesian linear model will be used for the primary analysis. This model is used to estimate the mean change in ppFEV_1 from Day 0 (primary endpoint) for each regimen in each Stratum. These estimates can then be used to compare response to treatment for different Regimens or Interventions in each Stratum.
The Primary Endpoint aligns with the endpoint used in the recent STOP studies. The STOP Study Investigators used change in FEV1 as a proportion (percentage) of that predicted based on sex, age and height (ppFEV1), from the time of commencement of therapy (or admission) as the most appropriate measure of improved lung function. In that prospective study of North American adults with CF, the mean absolute change in ppFEV1 was 8.4 after 7 days of therapy, with a standard deviation of 11.3.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2022
Actual
7/09/2022
Date of last participant enrolment
Anticipated
30/04/2024
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
500
Accrual to date
17
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 22516 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 22517 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 22518 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [4] 22519 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [5] 22520 0
Perth Children's Hospital - Nedlands
Recruitment hospital [6] 22521 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [7] 22522 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [8] 22523 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [9] 22524 0
John Hunter Hospital - New Lambton
Recruitment hospital [10] 22525 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 37757 0
2145 - Westmead
Recruitment postcode(s) [2] 37758 0
2031 - Randwick
Recruitment postcode(s) [3] 37759 0
3052 - Parkville
Recruitment postcode(s) [4] 37760 0
5006 - North Adelaide
Recruitment postcode(s) [5] 37761 0
6009 - Nedlands
Recruitment postcode(s) [6] 37762 0
4101 - South Brisbane
Recruitment postcode(s) [7] 37763 0
2305 - New Lambton
Recruitment postcode(s) [8] 37764 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 311567 0
Government body
Name [1] 311567 0
Commonwealth of Australia as represented by the Department of Health
Country [1] 311567 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
Level 3, F23 Michael Spence Administration Building,
Corner of Eastern Avenue and City
Road, The University of Sydney,
NSW 2006 Australia
Country
Australia
Secondary sponsor category [1] 313050 0
None
Name [1] 313050 0
Address [1] 313050 0
Country [1] 313050 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311015 0
Child and Adolescent Health Services Human Research Ethics Committee
Ethics committee address [1] 311015 0
Ethics committee country [1] 311015 0
Australia
Date submitted for ethics approval [1] 311015 0
21/09/2021
Approval date [1] 311015 0
05/01/2022
Ethics approval number [1] 311015 0

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

Contacts
Principal investigator
Name 119702 0
Prof Thomas Snelling
Address 119702 0
University of Sydney Faculty of Medicine and Health School of Public Health Edward Ford Building Camperdown Campus NSW 2006
Country 119702 0
Australia
Phone 119702 0
+61 2 9563 6886
Fax 119702 0
Email 119702 0
tom.snelling@sydney.edu.au
Contact person for public queries
Name 119703 0
Thomas Snelling
Address 119703 0
University of Sydney Faculty of Medicine and Health School of Public Health Edward Ford Building Camperdown Campus NSW 2006
Country 119703 0
Australia
Phone 119703 0
+61 2 9563 6886
Fax 119703 0
Email 119703 0
tom.snelling@sydney.edu.au
Contact person for scientific queries
Name 119704 0
Thomas Snelling
Address 119704 0
University of Sydney Faculty of Medicine and Health School of Public Health Edward Ford Building Camperdown Campus NSW 2006
Country 119704 0
Australia
Phone 119704 0
+61 2 9563 6886
Fax 119704 0
Email 119704 0
tom.snelling@sydney.edu.au

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?

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.