Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000614897p
Ethics application status
Submitted, not yet approved
Date submitted
26/03/2021
Date registered
21/05/2021
Date last updated
21/05/2021
Date data sharing statement initially provided
21/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Comparison of two tapering regimens in the management of glucocorticoid withdrawal - the PRED-STOP trial
Scientific title
Randomised controlled trial of the effect of two tapering regimens for withdrawal of glucocorticoids on pituitary-adrenal function recovery in patients taking supraphysiological glucocorticoid therapy
Secondary ID [1] 303800 0
None
Universal Trial Number (UTN)
Trial acronym
PRED-STOP trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
asthma 321198 0
glucocorticoid-responsive dermatological conditions 321199 0
rheumatoid arthritis 321200 0
polymyalgia rheumatica 321201 0
pituitary-adrenal axis suppression 321692 0
Condition category
Condition code
Metabolic and Endocrine 318986 318986 0 0
Other metabolic disorders
Inflammatory and Immune System 319094 319094 0 0
Other inflammatory or immune system disorders
Respiratory 319095 319095 0 0
Asthma
Skin 319096 319096 0 0
Dermatological conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Comparison of two different tapering regimens for withdrawal of glucocorticoids in patients where the clinician is aiming to cease the medication.
12 week Intervention:
Hydrocortisone 20 mg once daily for 4 weeks, followed by 10 mg once daily for 8 weeks
Oral tablet
Adherence monitored with tablet count at week 4 and week 12 visits
Intervention code [1] 320058 0
Treatment: Drugs
Comparator / control treatment
Comparator is a slow wean of prednisolone
12 week Intervention
Prednisolone 5 mg once daily for 4 weeks, followed by:
Prednisolone 4 mg once daily for 2 weeks
Prednisolone 3 mg once daily for 2 weeks
Prednisolone 2 mg once daily for 2 weeks
Prednisolone 1 mg once daily for 2 weeks
Oral tablet
Adherence monitored with tablet count at week 4 and week 12 visits
Control group
Active

Outcomes
Primary outcome [1] 326911 0
Percent of participants with normal pituitary-adrenal function
• defined as passing short Synacthen test (SST) (60 minute cortisol >500 nmol/L)
Timepoint [1] 326911 0
12 weeks post commencement of study drug
Secondary outcome [1] 393099 0
• Time (weeks) from commencement of study drug to passing short Synacthen test (60 minute cortisol >500 nmol/L)
Timepoint [1] 393099 0
up to 1 year (52 weeks) from commencement of study drug
pituitary-adrenal function will be assessed every 8 weeks from week 12 to week 52, up until the point where the participant passes the short Synacthen test
ie week 20, week 28, week 36, week 44, week 52.
If participant passes at week 28, the next assessment is at study exit, week 52.
Secondary outcome [2] 393100 0
• Quality of life and fatigue
Addison's disease specific Quality of Life score (AddiQoL)
Chalder Fatigue Scale
Timepoint [2] 393100 0
12 weeks and 52 weeks post commencement of study drug
Secondary outcome [3] 393101 0
• Percent of participants with normal pituitary-adrenal function defined as passing a short Synacthen test (SST) (60 minute cortisol >500 nmol/L)
Timepoint [3] 393101 0
1 year post commencement of study drug

Eligibility
Key inclusion criteria
• Age 18 years or over
• Able to give written informed consent
• Medical condition which has required supraphysiological glucocorticoid therapy:
o Prednisolone dose (or equivalent) greater than or equal to 5 mg daily for 6 or more weeks
o Dexamethasone greater than or equal to 0.5 mg daily for 6 or more weeks
• Pre-dose morning cortisol <200 nmol/L
• Managing clinician has clinical intent to cease glucocorticoids completely
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Condition requiring lifelong chronic glucocorticoid use
• Known pathological pituitary or adrenal dysfunction
• Active malignancy
• Pregnancy

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)
central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical power:
• Estimated that 90% of participants on hydrocortisone regimen would have normal pituitary adrenal function by 12 weeks.
• To detect a 25% reduction in the proportion of participants passing the SST at 12 weeks, the study would need 53 in each group to achieve alpha of 0.05 and power of 0.8.
• Therefore, target enrolment 120 participants – 60 in each group

Data analysis:
Data from the randomised controlled trial will be analysed both by intention to treat and per protocol completion.
Between group comparison for continuous variables will be carried out by unpaired Student t test or Mann Whitney U test if the data fail parametric assumptions.
Between group comparisons for categorical variables will be carried out using the Fisher’s exact test.
Repeated measures data will be analysed by a two-way repeated measures analysis of variance (ANOVA) after log transformation for data not satisfying parametric assumptions.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/06/2021
Actual
Date of last participant enrolment
Anticipated
31/10/2023
Actual
Date of last data collection
Anticipated
31/10/2024
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 18975 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 33482 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 308152 0
Government body
Name [1] 308152 0
Metro South Study, Education and Research Trust Account
Country [1] 308152 0
Australia
Primary sponsor type
Individual
Name
A/Prof W Inder - Investigator initiated
Address
Department of Diabetes and Endocrinology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country
Australia
Secondary sponsor category [1] 308919 0
None
Name [1] 308919 0
Address [1] 308919 0
Country [1] 308919 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 308135 0
Metro South HREC
Ethics committee address [1] 308135 0
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Ethics committee country [1] 308135 0
Australia
Date submitted for ethics approval [1] 308135 0
12/03/2021
Approval date [1] 308135 0
Ethics approval number [1] 308135 0

Summary
Brief summary
Background:
Glucocorticoids such as prednisolone are commonly prescribed for inflammatory and autoimmune conditions, with estimated long-term use in 1-3% of adults in the general population. Long-term glucocorticoid therapy is associated with significant adverse effects such as weight gain, osteoporosis, diabetes, hypertension and cardiovascular disease. Chronic high doses suppress the function of the pituitary-adrenal system and impair endogenous cortisol production, which may lead to adrenal insufficiency. An estimated 48-63% of patients receiving long-term glucocorticoids develop adrenal insufficiency. Recovery can occur approximately four weeks after stopping glucocorticoids, but may take up to one year or more. Few studies have described specific tapering regimens and associated outcomes and there is no standardised method to withdraw glucocorticoids. Whether continuing prednisolone in smaller doses or converting to hydrocortisone is superior in outcome is unknown.
Hypothesis:
That a glucocorticoid tapering regimen using the short-acting glucocorticoid hydrocortisone is superior to a standard gradual dose reduction in prednisolone.
Trial website
Not yet established
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 109662 0
A/Prof Warrick Inder
Address 109662 0
Department of Diabetes and Endocrinology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 109662 0
Australia
Phone 109662 0
+61 7 3176 9563
Fax 109662 0
+61 7 3176 2973
Email 109662 0
warrick.inder@health.qld.gov.au
Contact person for public queries
Name 109663 0
A/Prof Warrick Inder
Address 109663 0
Department of Diabetes and Endocrinology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 109663 0
Australia
Phone 109663 0
+61 7 3176 9563
Fax 109663 0
+61 7 3176 2973
Email 109663 0
warrick.inder@health.qld.gov.au
Contact person for scientific queries
Name 109664 0
A/Prof Warrick Inder
Address 109664 0
Department of Diabetes and Endocrinology
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba QLD 4102
Country 109664 0
Australia
Phone 109664 0
+61 7 3176 9563
Fax 109664 0
+61 7 3176 2973
Email 109664 0
warrick.inder@health.qld.gov.au

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 of the individual participant data collected during the trial, after de-identification
When will data be available (start and end dates)?
Immediately following publication, no end date
Available to whom?
Anyone who wishes to access it
Available for what types of analyses?
Any purpose
How or where can data be obtained?
By emailing the principal investigator A/Prof Warrick Inder
warrick.inder@health.qld.gov.au


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.