Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000696594
Ethics application status
Approved
Date submitted
12/05/2024
Date registered
31/05/2024
Date last updated
31/05/2024
Date data sharing statement initially provided
31/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Reducing the frequency of outpatient review in people with cystic fibrosis on high-efficacy modulator therapy – a non-inferiority, randomised controlled trial (REFORM).
Scientific title
The effect of reducing the frequency of outpatient review in people with cystic fibrosis on high-efficacy modulator therapy – a non-inferiority, randomised controlled trial (REFORM).
Secondary ID [1] 312087 0
None
Universal Trial Number (UTN)
Trial acronym
REFORM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cystic Fibrosis 333710 0
Condition category
Condition code
Respiratory 330391 330391 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a multicentre, randomized, non-inferiority trial. It is not blinded.

This pragmatic trial investigating the safety and acceptability of reducing the frequency of outpatient reviews will leverage off normal clinical practice.

Participants will be randomised to standard interval (3 monthly) vs. extended interval (6 monthly - intervention group) outpatient review. Patients in the intervention group (i.e. extended interval) will receive 6 monthly review for 2 years from time of enrolment. The enrolment, 12 month and 24 month appointments will be in-person appointments with in-laboratory spirometry. Other appointments can be in-person or via telehealth at the discretion of the Cystic Fibrosis (CF) service and participant (per usual practice in CF clinics). All clinic visits will occur as per standard practice otherwise. Participants will be asked to complete an online survey every 3 months independent of the arm they are enrolled in (please see below).

During outpatient review, data will be collected per usual clinical practice including: lung function (in-laboratory or home spirometry), symptoms, exacerbations, hospitalisations, weight, sputum microbiology and medications. The data will be entered into the Australian Cystic Fibrosis Data Registry (ACFDR) as per usual practice. No additional data will be collected at clinic visits.

Participants will receive a brief electronic survey via REDCap every 3 months to assess whether they have had any pulmonary exacerbations, additional clinic appointments or medication changes.

Participants will complete a patient satisfaction questionnaire and the Cystic Fibrosis questionnaire-revised respiratory domain questionnaire at baseline, 12 and 24 months in REDCap.

As per usual practice, if participants are experiencing increased symptoms or have other concerns between routine appointments, they will contact the nurses at their CF service and receive additional appointments if necessary. This will not be a protocol violation and we are collecting information about additional appointments.
Data regarding the number of routine and additional attendances (including outpatient and inpatient attendances) will be collected.

The study will be administered by the study investigators which include members of the CF clinic team at each site and 1 CF coordinator (member of the CF team) at each site. The coordinator will monitor clinic attendance and any unplanned clinic visits.
Intervention code [1] 328563 0
Treatment: Other
Comparator / control treatment
Participants will be randomised to standard interval (3 monthly - control/comparator group) vs. extended interval (6 monthly - Intervention group) outpatient review.
Control group
Active

Outcomes
Primary outcome [1] 338205 0
Change in lung function (percent predicted forced expiratory volume in 1 second, ppFEV1) between groups at 24 months post randomization
Timepoint [1] 338205 0
At recruitment compared to 24 months post randomization
Secondary outcome [1] 434961 0
Pulmonary exacerbations: total number
Timepoint [1] 434961 0
24 months after randomization
Secondary outcome [2] 434962 0
Respiratory Symptom Survey (CFQR- respiratory domain) at baseline, 12 and 24 months.
Timepoint [2] 434962 0
Compare both groups at baseline, 12 and 24 months after randomization
Secondary outcome [3] 434963 0
Number of additional visits to CF clinic
Timepoint [3] 434963 0
Compare number of additional (unplanned) CF clinic appointments for both groups every 3 months and at 24 months post randomization.
Secondary outcome [4] 434964 0
Any changes to medications
Timepoint [4] 434964 0
Compare any changes in medication use every 3 months and at 24 months after randomization.
Secondary outcome [5] 434965 0
Patient Satisfaction
Timepoint [5] 434965 0
Compare both groups at 12 and 24 months after randomization (baseline).
Secondary outcome [6] 435290 0
Pulmonary exacerbations: time to first exacerbation
Timepoint [6] 435290 0
Compare both groups at 24 months from randomisation.

Eligibility
Key inclusion criteria

1. Adult (18 years and older) participants with cystic fibrosis
2. Taking Highly Effective Modulator Therapy (HEMT) for 3 months or longer
3. Willing to provide informed consent and willing to participate and comply with study requirements.
4. Enrolled to the Australian Cystic Fibrosis Data Registry
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Exacerbation within the last 28 days
2. History of hospitalization for CF respiratory exacerbation in the past 12 months
3. ppFEV1 < 40% (on HEMT)
4. Antibiotic treatment for non-tuberculous mycobacterial disease within the past 28 days
5. Changes to chronic therapies (for example nebulized therapies, azithromycin) within the past 28 days
6. Use of an investigational product within the past 28 days
7. New growth of Pseudomonas, Mycobacterium abscessus and Burkholderia cepacia complex within the past 90 days
8. Transition from paediatric to adult care within the last 12 months
9. Women who are pregnant
10. Prior lung transplant
11. Unstable extrapulmonary cystic-fibrosis-related disease
12. Other comorbidities which in the opinion of the investigator would make participation unsafe

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)
Allocation not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The participant will be randomized at the enrolment visit after they have met the eligibility criteria and provided informed consent and performed spirometry. Computer-generated randomisation will be on a 1 to 1 ratio with random permuted blocks, stratified by participating site and by ppFEV1 group (ppFEV1 <70, ppFEV1 >=70) and will occur within an independent randomisation tool within the Australian CF Data Registry (ACFDR).
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
SAMPLE SIZE ESTIMATION

The type I error for the primary hypothesis was based on a one-sided 0·025 alpha-level test, reporting a two- sided 95% CI. A sample size of 313 participants enrolled with 10% drop out would result in 282 participants included in the primary analysis. Assuming an SD for the 24-month change in ppFEV1 equal to 7.75 (derived from ACFDR data*), 282 participants provides 90% power to detect non-inferiority with a margin of –3% assuming no effect of discontinuation.

* Calculations are based on the FEV1pp measured in the Alfred CF service in 2022 and 2023.
If you select people with an FEV1pp>40%, stable on Trikafta (treated for >=1 month) and then on stable treatment for 6-12 months, there were 146 subjects with paired results. The baseline mean FEV1 is 71.84, SD 19.4, at 6-12 months of treatment mean FEV1 73.3, SD 19.7.
If the outcome is the change in FEV1pp over 12 months. The difference between baseline FEV1pp and 6-12 months FEV1pp on Trikafta with current usual care gives a mean difference of 1.461, SD 7.75; 95%CI 0.194 to 2.73.

STATISTICAL ANALYSIS PLAN

Descriptive data will be expressed as mean ± SD, unless otherwise stated. Unpaired t-tests or Mann-Whitney U tests will be used for between group comparisons of change in ppFEV1, depending on normality of data distribution. A non-inferiority margin of -3% for the difference between groups in the 24 month change in ppFEV1 has been established a priori from previously published data (1). This will be assessed on the per-protocol population.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
26/06/2024
Actual
Date of last participant enrolment
Anticipated
26/05/2025
Actual
Date of last data collection
Anticipated
26/05/2027
Actual
Sample size
Target
313
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 26531 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 26532 0
Westmead Hospital - Westmead
Recruitment hospital [3] 26533 0
John Hunter Hospital - New Lambton
Recruitment hospital [4] 26534 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 42572 0
2050 - Camperdown
Recruitment postcode(s) [2] 42573 0
2145 - Westmead
Recruitment postcode(s) [3] 42574 0
2305 - New Lambton
Recruitment postcode(s) [4] 42575 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 316443 0
Self funded/Unfunded
Name [1] 316443 0
Country [1] 316443 0
Primary sponsor type
Government body
Name
Sydney Local Health District
Address
Country
Australia
Secondary sponsor category [1] 318613 0
Government body
Name [1] 318613 0
Western Sydney Local Health District
Address [1] 318613 0
Country [1] 318613 0
Australia
Secondary sponsor category [2] 318660 0
Government body
Name [2] 318660 0
Hunter New England Local Health District
Address [2] 318660 0
Country [2] 318660 0
Australia
Secondary sponsor category [3] 318661 0
Government body
Name [3] 318661 0
Alfred Health (Primary Health Network within Victoria)
Address [3] 318661 0
Country [3] 318661 0
Australia
Other collaborator category [1] 283030 0
Other
Name [1] 283030 0
Australian Cystic Fibrosis Data Registry (ACFDR)
Address [1] 283030 0
Country [1] 283030 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315235 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 315235 0
https://www.slhd.nsw.gov.au/rpa/research/
Ethics committee country [1] 315235 0
Australia
Date submitted for ethics approval [1] 315235 0
27/03/2024
Approval date [1] 315235 0
23/04/2024
Ethics approval number [1] 315235 0

Summary
Brief summary
The aims of this study are to investigate the safety and acceptability of reducing the frequency of outpatient clinic visits from 3 months (standard of care) to 6 months (intervention group) in people with cystic fibrosis (pwCF) on high-efficacy modulator (HEMT). We hypothesise that 6 monthly routine clinic visits will be non-inferior to 3 monthly visits (current standard of care).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134082 0
Dr Sheila Sivam
Address 134082 0
Royal Prince Alfred Hospital Level 11 Dept of Respiratory and Sleep Medicine Missenden Road Camperdown NSW 2050
Country 134082 0
Australia
Phone 134082 0
+612 95158167
Fax 134082 0
Email 134082 0
sheila.sivam@sydney.edu.au
Contact person for public queries
Name 134083 0
Sheila Sivam
Address 134083 0
Royal Prince Alfred Hospital Level 11 Dept of Respiratory and Sleep Medicine Missenden Road Camperdown NSW 2050
Country 134083 0
Australia
Phone 134083 0
+612 95158167
Fax 134083 0
Email 134083 0
slhd-rpa-cftrials@health.nsw.gov.au
Contact person for scientific queries
Name 134084 0
Sheila Sivam
Address 134084 0
Royal Prince Alfred Hospital Level 11 Dept of Respiratory and Sleep Medicine Missenden Road Camperdown NSW 2050
Country 134084 0
Australia
Phone 134084 0
+612 95158167
Fax 134084 0
Email 134084 0
sheila.sivam@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.