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Trial registered on ANZCTR


Registration number
ACTRN12622001063707
Ethics application status
Approved
Date submitted
26/07/2022
Date registered
1/08/2022
Date last updated
20/01/2023
Date data sharing statement initially provided
1/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
BEAT CF: Pulmonary Exacerbations Treatment Platform - Adjunct Antibiotics Domain
Scientific title
BEAT CF: Pulmonary Exacerbations Treatment Platform - Adjunct Antibiotics Domain:
An evaluation of the comparative effectiveness of prescribing various standard of care, adjunct 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] 307647 0
Nil known
Universal Trial Number (UTN)
Trial acronym
BEAT CF DSA B - Adjunct 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 327151 0
Condition category
Condition code
Human Genetics and Inherited Disorders 324288 324288 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a Prescription for the Assigned antibiotic (or no Adjunct Antibiotic) at the commencement of intensive therapy made by the Responsible Clinician or their authorised delegate.
For each of the 2 treatment options involving adjunct antibiotics:
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 Tobramycin
As a guide, intravenous (IV) injection over several minutes, OR an IV infusion over up to 1 hour. It may also be given by intramuscular (IM) injection.

2. Inhaled Tobramycin
As a guide, Several formulations are used for inhalational therapy. Generally ampoules for nebulisation are used in preference to capsules for inhalation for PERIT.
500mg/5mL vial - (Tobra-Day); 300mg/5mL ampoule Tobramycin solution for inhalation (various brands), and 28mg capsules for inhalation (Tobi® Podhaler) which is PBS-subsidised for children greater than or equal to 6years old only.

3. No adjunct antibiotic

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 assigned arm the clinician is free to decide which therapy the participant shall be switched to. There will be no subsequent randomsiations to adjunct antibiotics within a single pulmonary exacerbation episode.
Intervention code [1] 324102 0
Treatment: Drugs
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 3 interventions:
1. Intravenous tobramycin
2. Inhaled tobramycin
3. No adjunct antibiotic
The comparator for the second randomisation is each of the other arms in this domain. The assigned antibiotic is compared against each of the other options.

The comparator for each arm is each of the other arms in this domain. The assigned antibiotic is compared to the other antibiotic option, and against the no adjunct antibiotic option.
Control group
Active

Outcomes
Primary outcome [1] 332113 0
The absolute change in the ppFEV1 measured by spirometry
Timepoint [1] 332113 0
Greater than 7 days but not more than 14 days after first dose of intensive therapy.
Secondary outcome [1] 412276 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] 412276 0
Approximately 7 days from initiation of intensive therapy.
Secondary outcome [2] 412277 0
2. Absolute change in the FEV1pp measured by spirometry
Timepoint [2] 412277 0
Approximately 2 weeks, 4 weeks, 8 weeks, and 24 weeks after commencement of intensive therapy.
Secondary outcome [3] 412278 0
3. Relative change in the FEV1pp measured by spirometry
Timepoint [3] 412278 0
Approximately 2 weeks, 4 weeks, 8 weeks, and 24 weeks after commencement of intensive therapy.
Secondary outcome [4] 412280 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] 412280 0
Approximately 1 week, 2 weeks, 4 weeks, 8 weeks, and 24 weeks after commencement of intensive therapy.
Secondary outcome [5] 412282 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] 412282 0
Approximately 7 days, 14 days and 30 days after commencement of intensive therapy.
Secondary outcome [6] 412283 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] 412283 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] 412284 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] 412284 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] 412285 0
9. Health related quality of life, as scored by The Cystic fibrosis Quality of Life questionnaire, revised, (CFQR).
Timepoint [8] 412285 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] 412286 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] 412286 0
Any time post enrolment to BEAT CF and for the 2 years prior to enrolment to BEAT CF.
Secondary outcome [10] 412287 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] 412287 0
Any time post enrolment to BEAT CF and for the 2 years prior to enrolment to BEAT CF.
Secondary outcome [11] 412288 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] 412288 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 Adjunct antibiotic Domain.
3. Are eligible for at least two Interventions in the Adjunct Antibiotic Domain available at the clinical Site (including no Adjunct Antibiotic).
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 Adjunct Antibiotic Domain is not in their best interest.

A participant will be excluded from Assignment to a specific Intervention in the Adjunct Antibiotic Domain if:
1. They have a known or suspected significant drug hypersensitivity to tobramycin or other aminoglycosides
2. Recognised contraindication to IV tobramycin, including known renal, auditory or vestibular impairment which, in the opinion of the Responsible Clinician, precludes its use.
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 ppFEV1 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
5/09/2022
Actual
7/09/2022
Date of last participant enrolment
Anticipated
30/04/2024
Actual
Date of last data collection
Anticipated
31/05/2024
Actual
Sample size
Target
5000
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 22864 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 22865 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 22866 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [4] 22867 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [5] 22868 0
Mater Private Hospital - South Brisbane
Recruitment hospital [6] 22869 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [7] 22870 0
Perth Children's Hospital - Nedlands
Recruitment hospital [8] 22871 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [9] 22872 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [10] 22873 0
John Hunter Hospital - New Lambton
Recruitment hospital [11] 22874 0
John Hunter Children's Hospital - New Lambton
Recruitment postcode(s) [1] 38172 0
2031 - Randwick
Recruitment postcode(s) [2] 38173 0
2050 - Camperdown
Recruitment postcode(s) [3] 38171 0
2145 - Westmead
Recruitment postcode(s) [4] 38178 0
2305 - New Lambton
Recruitment postcode(s) [5] 38177 0
3052 - Parkville
Recruitment postcode(s) [6] 38174 0
4101 - South Brisbane
Recruitment postcode(s) [7] 38175 0
5006 - North Adelaide
Recruitment postcode(s) [8] 38176 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 311908 0
Government body
Name [1] 311908 0
Commonwealth of Australia as represented by the Department of Health
Country [1] 311908 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] 313393 0
None
Name [1] 313393 0
Address [1] 313393 0
Country [1] 313393 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311344 0
Child and Adolescent Health Services Human Research Ethics Committee
Ethics committee address [1] 311344 0
Office 5E, Perth Children’s Hospital 15 Hospital Avenue, Nedlands WA 6009
Ethics committee country [1] 311344 0
Australia
Date submitted for ethics approval [1] 311344 0
21/09/2021
Approval date [1] 311344 0
05/01/2022
Ethics approval number [1] 311344 0

Summary
Brief summary
BEAT CF is a national, multi-site project which aims to learn and implement , which of the antibiotics commonly used to treat lung infections are best.

There is no single standard of care for managing CF pulmonary exacerbations. Standard care comprises a range of interventions and varies across and within CF treatment centres and may evolve over the course of the PEx Treatment Platform.
At the time of initiation of the PEx Treatment Platform Protocol, management of pulmonary exacerbations generally involves the use of one or more intravenous (IV) antibiotic therapies.

Most Australian clinicians manage pulmonary exacerbations with an antipseudomonal beta-lactam or carbapenem, combined with a non-beta lactam antibiotic - most typically the aminoglycoside tobramycin given intravenously (IV). Tobramycin can also be given via inhalation. Inhaled tobramycin is widely used for outpatient management, it is rarely used as part of inpatient management of PEx.

This particular domain to the BEAT CF PEx treatment platform aims to find out if there is any gain in providing tobramycin in addition to ‘backbone’ antibiotic therapy. Also, it will assess there is any difference in giving tobramycin by the IV or inhaled route, and whether no tobramycin is non-inferior to the IV or inhaled tobramycin.

Some clinicians reserve the use of IV aminoglycoside for patients known to be colonised with Pseudomonas aeruginosa. Some, but not all, clinicians use the results of microbiology and in vitro susceptibilities to guide antibiotic selection. Many centres provide additional antibiotic cover targeted to specific pathogens, but only if identified on sputum microbiology, e.g. for Stenotrophomonas maltophilia or Staphylococcus aureus.

The duration of IV antibiotic therapy is typically 14 days, and generally ranges from 10 days to 21 days. A recent RCT found evidence that 10 days was non-inferior to 14 days of IV antibiotics therapy in those with a rapid treatment response, and found no evidence that 21 days was superior to 14 days of IV antibiotics in those without a rapid treatment response.

The primary objectives, outcomes and endpoints for the PEx Cohort were informed by a systematic review of the literature and involvement of key clinical and consumer stakeholders.
Trial website
www.beatcf.org.au
Trial related presentations / publications
Public notes
BEAT CF is a modular and hierarchical project. At the highest level of the hierarchy is the BEAT CF PEx Cohort. This domain specific appendix is one of the lower levels of the hierarchy. Lower levels build upon, and provide detail and specificity to, the higher level. Lower level documents (e.g. Domain specific appendices) must be read in conjunction with the higher level documents (PEx Core Protocol and PEx Treatment Platform).

Contacts
Principal investigator
Name 120786 0
Prof Thomas Snelling
Address 120786 0
University of Sydney Faculty of Medicine and Health School of Public Health Edward Ford Building Camperdown Campus NSW 2006
Country 120786 0
Australia
Phone 120786 0
+61 2 9563 6886
Fax 120786 0
Email 120786 0
tom.snelling@sydney.edu.au
Contact person for public queries
Name 120787 0
Prof Thomas Snelling
Address 120787 0
University of Sydney Faculty of Medicine and Health School of Public Health Edward Ford Building Camperdown Campus NSW 2006
Country 120787 0
Australia
Phone 120787 0
+61 2 9563 6886
Fax 120787 0
Email 120787 0
tom.snelling@sydney.edu.au
Contact person for scientific queries
Name 120788 0
Prof Thomas Snelling
Address 120788 0
University of Sydney Faculty of Medicine and Health School of Public Health Edward Ford Building Camperdown Campus NSW 2006
Country 120788 0
Australia
Phone 120788 0
+61 2 9563 6886
Fax 120788 0
Email 120788 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.