Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623001342606
Ethics application status
Approved
Date submitted
24/08/2023
Date registered
19/12/2023
Date last updated
19/12/2023
Date data sharing statement initially provided
19/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Steroid-Reducing Options for ReLapsING PolyMyalgia Rheumatica (STERLING PMR)Australian-specific protocol
Scientific title
Steroid-Reducing Options for ReLapsING PMR (The STERLING-PMR study) Australian-specific protocol for a multi-centre, Phase III, parallel-group, open-label, randomised controlled trial to compare the clinical and cost-effectiveness of adding immunosuppression to steroid-tapering treatment for patients with relapsing PMR, versus steroid-tapering alone
Secondary ID [1] 310548 0
ISRCTN17828080
Secondary ID [2] 311204 0
EUDRA-CT 2023-000130-15
Universal Trial Number (UTN)
Trial acronym
STERLING PMR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
polymyalgia rheumatica 331242 0
Condition category
Condition code
Musculoskeletal 328000 328000 0 0
Other muscular and skeletal disorders
Inflammatory and Immune System 328123 328123 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention administered in this study is disease-modifying antirheumatic drugs (DMARDs) for 18 months.
DMARDS; Methotrexate will be started at 15mg weekly; this can be reduced to 10mg weekly if the higher dose is not tolerated. Maximum dose in 25 mg.
If 10mg weekly MTX is not tolerated, or if MTX is ineffective, MTX may be switched to leflunomide (LEF) starting at 10mg daily. The starting dose will be increased to 20mg daily if tolerated, or reduced to 10mg every 2 days if not tolerated. The minimum LEF dose will be 10mg twice weekly. If this minimal LEF dose is not tolerated, DMARD will be stopped.
MTX will be co-prescribed with folic acid according to local practice; the folic acid dose will be at least 5mg weekly, and may be prescribed up to six days per week (folic acid is not generally given on the same day as MTX). 18 month of treatment.

Where possible within the conduct of this trial, local systems and processes to reduce the risk of DMARD dosing errors should be followed. For example, participants must be instructed on the importance of adhering to the once-weekly dosing. Therefore, when initiating MTX, it is usually recommended to discuss and agree with the participant a specified day of the week that they will take their MTX. Where the participant is supported in the management of their condition by a family member of carer, with the consent of the participant the family member or carer must also be involved in these discussions.

Participants will be advised to maintain a record of their DMARD doses in addition to their steroid doses and provided with a personal diary for this if required. Details of DMARD compliance will be collected by the site research team during telephone and face-to-face assessments.
Blood monitoring of methotrexate will follow local recommendations. As a guide the British Society for Rheumatology DMARD monitoring guidelines recommend FBC, U+E and LFT approximately 8ml taken each draw:
• every two weeks until on stable dose for six weeks
• then monthly for three months and
• quarterly thereafter
The site team will issue sufficient laboratory request forms to cover the duration of each prescription and will check the results of the monitoring blood tests before each new prescription of MTX is issued. Providing the results of the prior test do not fall within the limits and are acceptable according to local physician discretion, windows either side of these blood monitoring dates will be allowed.

Monitoring of leflunomide via blood tests and blood pressure measurements will follow local recommendations. As a guide the British Society for Rheumatology DMARD monitoring guidelines recommend FBC, U+E, LFT and a blood pressure measurement:
• every two weeks until on stable dose for six weeks
• monthly for three months and
• quarterly thereafter

MTX must be stopped before LEF is commenced (they should not be taken together in this trial). MTX polyglutamates may be retained in tissues for some weeks after MTX cessation, and therefore a wash-out period of at least 2 weeks is recommended before starting LEF; this may be extended to 8 weeks where required.

Prednisolone / dose as needed/ up to 18 months
for Prednisolone tapering will depend on participants start dose and will be participant specific there is not set taper. The taper will be tapered at the discursion of the treating physician

The trial will include a 12-month internal pilot phase to evaluate the feasibility of recruitment and therefore delivery of the trial.
A 12-month internal feasibility phase will determine the likelihood of achieving i) opening of centres, ii) planned recruitment rate, and iii) achieving the recruitment target of 200 participants (50 from Australia, 150 form UK sites). An internal review will also be conducted after 8 months, corresponding to one-third of the total recruitment phase.. At the end of the internal pilot phase, if Amend (amber) criteria are met, then a recovery plan detailing remedial actions will be submitted to the funder. If this is approved, the trial will proceed with caution.
Intervention code [1] 326852 0
Treatment: Drugs
Comparator / control treatment
The control group is standard of care Prednisolone dose as required. The dose and frequency of the prednisolone taper in the control group will be at the discretion of the treating physician for 18 months. Tapering will depend on participants start dose and will be participant specific as determined by treating physician.

Participants will be advised to maintain a record of their steroid doses and provided with a personal diary for this if required. Details of steroid compliance will be collected by the site research team during telephone and face-to-face assessments.
Control group
Active

Outcomes
Primary outcome [1] 335862 0
The primary outcome measure is mean participant reported cumulative prednisolone dose between randomisation and 18 months post-randomisation, reported by participants via a monthly questionnaire
Timepoint [1] 335862 0
18 months form randomisation
Secondary outcome [1] 425918 0
PMR Symptom Severity – Mean PMR-IS Symptom domain score, Mean PMR-IS Symptom function score, Mean PMR-IS Psychological/Emotional well-being domain score, Mean PMR-IS Steroid side effect domain score – all at each of the timepoints
Timepoint [1] 425918 0
Weeks 12, 24, 36, 48, 60, 72, 80 post randomisation
Secondary outcome [2] 427772 0
Health-related Quality of Life – Mean EQ-5D-5L Utility
Timepoint [2] 427772 0
Weeks 12, 24, 36, 48, 60, 72, 80 post randomisation
Secondary outcome [3] 427773 0
PMR Disease Activity (Mean PMR Activity Score (PMR-AS)
Timepoint [3] 427773 0
at weeks 4, 24 and 8 following randomisation

Eligibility
Key inclusion criteria
Participants meeting ALL the following criteria will be considered for enrolment into the study

1. Age 18 years or more at the time the consent form is signed
2. ALL of:
(i) documented diagnosis of PMR, confirmed by the local investigator.
(ii) previous steroid-responsive bilateral ache in the region of the trapezius, shoulder or upper arms.
(iii) previous C-reactive protein (CRP) greater than 5mg/L, or erythrocyte sedimentation rate (ESR)/plasma viscosity above local laboratory reference range, at either diagnosis or at time of a flare of PMR.
3. At least 4 points from a possible 6:
• Previous stiffness in association with other features of PMR: 2 points.
• Previous aching of hip area (groin, buttock, lateral hip or upper thigh) in association with other features of PMR:1 point.
• Rheumatoid factor (RF) and anti-citrullinated peptide antibody (ACPA/anti-CCP) both within local laboratory reference range at or during the 1 year prior to the screening visit: 2 points.
• No rheumatologist-documented hand or foot synovitis during active PMR symptoms: 1 point.
4. Currently taking steroid treatment for PMR and willing to attempt dose reduction (tapering).
5. At least one previous relapse during steroid therapy, defined as steroid-responsive recurrence of PMR symptoms (aching in hip and/or shoulder areas).
6. Consent to participate.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded from this study for ANY of the following reasons:
1. Contraindication to tapering steroid dose, or to methotrexate therapy.
2. Women who are currently pregnant, lactating or planning to become pregnant in the next 2 years
3. Women of child-bearing potential (WCBP) or men unwilling to use an effective birth control measure whilst receiving treatment (either methotrexate or leflunomide)
Women of child-bearing potential (WCBP) or men unwilling to use an effective birth control measure and for an appropriate period after the last dose of protocol treatment:(Six months in the case of methotrexate, applicable for both male participants and women of child-bearing potential (WCBP)). In the case of male participants, the contraceptive measures can be taken by either themselves or their female partners.
4. A medical condition other than PMR that has required >2 courses of systemic glucocorticoid treatment lasting 5 days or more, or any course lasting 30 days or more, during the year prior to randomization.
5. Giant cell arteritis (previous or current) in the opinion of the local investigator.
6. Rheumatoid arthritis, psoriatic arthritis or spondyloarthritis (previous or current) in the opinion of the local investigator
7. At the baseline visit active infection of sufficient severity to be a contra-indication to commencing methotrexate, in the opinion of the local investigator.
8. Participant taking concurrent trimethoprim-sulfamethoxazole at the time of the baseline assessments
9. Active gastric ulcer at the baseline visit in the opinion of the local investigator
10. Known prior history of a significant immunodeficiency syndrome, defined as an immunodeficiency severe enough to cause recurrent infections of frequency or severity that in the opinion of the investigator would preclude DMARD treatment
11. Known prior history of hereditary galactose intolerance, hereditary total lactase deficiency or hereditary disorder of glucose-galactose malabsorption
12. Current treatment with folate antagonists including trimethoprim-sulfamethoxazole
13. Other medical condition that in the opinion of the local investigator is severe enough to seriously compromise evaluation of the primary or key secondary endpoints
14. Treatment with any immunosuppressive therapy (conventional synthetic, targeted synthetic or biological DMARD) within 3 months prior to randomisation.
15. Treatment with any investigational drug in the last 4 months prior to the start of protocol treatment.
16. Unable to complete essential study procedures and communicate with study staff independently.
17. Participants must NOT fulfil any of the following within 6 weeks prior to baseline: Haemoglobin <10.0 g/dL; total white cell count <3.5 x109/L; absolute neutrophil count <1.5 x109/L; platelet count <100 x109; ALT (alanine aminotransferase) or AST > 2 x upper limit of reference range for the laboratory conducting the test, eGFR (estimated glomerular filtration rate) <30ml/min
18. Evidence of respiratory disease on chest radiograph (performed during screening or within the 6 months prior to screening) of sufficient severity to be a contra-indication to commencing methotrexate, in the opinion of the local investigator.


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)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
In UK primary care (Clinical Practice Research Datalink), patients with relapsing PMR had a mean cumulative prednisolone dose of 5g over 18 months (coefficient of variation (CV) 0.78) .Lai L. Risk of diabetes mellitus associated with use of oral glucocorticoids in patients with polymyalgia rheumatica and giant cell arteritis: University of Leeds; 2020

A clinically relevant reduction is benchmarked against the reduction likely to substantively reduce the risk of fracture or infection. Extrapolating from observational data, an average reduction in cumulative prednisolone dose of 1.5g (a reduction in mean daily dose of 2.7mg over 18 months) would be predicted to significantly reduce hip and vertebral fracture risk van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and fracture risk: relationship to daily and cumulative doses. Rheumatology (Oxford). 2000;39(12):1383-9. This corresponds to a 30% reduction in cumulative dose. Our PPI group helped inform this target effect size: discussions around trade-offs revealed that most would not consider a DMARD worth it unless it could substitute for more than 2.5mg daily prednisolone over an 18-month period.

Assuming a log-normal distribution, 200 participants will provide 90% power to detect a target 30% reduction in cumulative prednisolone dose, assuming a CV of 0.78, 2-sided independent t-test for fold change (H0: mean fold change=1), 5% significance and 20% attritionCaporali R, Cimmino MA, Ferraccioli G, Gerli R, Klersy C, Salvarani C, et al. Prednisone plus Methotrexate for Polymyalgia Rheumatica. Annals of Internal Medicine. 2004;141(7):493-500 . The trial will retain at least 80% power if the CV is as large as 0.94. As part of this Australia is recruiting 50 participants there for 25% of the total number for the study.
The primary analysis on log (cumulative prednisolone-equivalent dose reported over 18 months) will use multivariable linear regression, with covariates for the minimisation factors; age at randomisation will be retained as a continuous covariate, under transformation as necessary. Adjusted mean fold difference in cumulative prednisolone dose will be presented with 95% confidence interval (CI) and significance. Summaries on mean fold difference and absolute difference in cumulative prednisolone dose will be presented.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
8/01/2024
Actual
Date of last participant enrolment
Anticipated
2/02/2024
Actual
Date of last data collection
Anticipated
25/12/2026
Actual
Sample size
Target
200
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,WA,VIC
Recruitment hospital [1] 25445 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [2] 25446 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 25447 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 41189 0
5011 - Woodville
Recruitment postcode(s) [2] 41190 0
3084 - Heidelberg
Recruitment postcode(s) [3] 41191 0
6150 - Murdoch
Recruitment postcode(s) [4] 41192 0
5011 - Woodville Park
Recruitment postcode(s) [5] 41193 0
6150 - Bateman
Recruitment postcode(s) [6] 41194 0
3081 - Heidelberg West
Recruitment outside Australia
Country [1] 25726 0
United Kingdom
State/province [1] 25726 0
Leeds

Funding & Sponsors
Funding source category [1] 314662 0
Government body
Name [1] 314662 0
national health medical research council
Country [1] 314662 0
Australia
Primary sponsor type
University
Name
the University of Adelaide
Address
230 North Tce AUSTRALIA SA 5005.
Country
Australia
Secondary sponsor category [1] 316626 0
Government body
Name [1] 316626 0
Central Adelaide Local Health Network
Address [1] 316626 0
1 Port Rd, Adelaide SA 5000
Country [1] 316626 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313681 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 313681 0
Ethics committee country [1] 313681 0
Australia
Date submitted for ethics approval [1] 313681 0
19/07/2023
Approval date [1] 313681 0
16/08/2023
Ethics approval number [1] 313681 0
:2023/HRE00162

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

Contacts
Principal investigator
Name 128990 0
Prof Catherine Hill
Address 128990 0
The Queen Elizabeth Hospital, level 5C, 28 Woodville road, Woodville south, South Australia, 5011
Country 128990 0
Australia
Phone 128990 0
+61 08 8222 6688
Fax 128990 0
+61 08 8133 4030
Email 128990 0
[email protected]
Contact person for public queries
Name 128991 0
Carlee Ruediger
Address 128991 0
The Queen Elizabeth Hospital, level 5C, 28 Woodville road, Woodville south,, South Australia 5011
Country 128991 0
Australia
Phone 128991 0
+61 08 8222 7369
Fax 128991 0
+61 08 8133 4030
Email 128991 0
[email protected]
Contact person for scientific queries
Name 128992 0
Carlee Ruediger
Address 128992 0
The Queen Elizabeth Hospital, level 5C, 28 Woodville road, Woodville south, South Australia 5011
Country 128992 0
Australia
Phone 128992 0
+61 08 8222 7369
Fax 128992 0
+61 08 8133 4030
Email 128992 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual data will be shared, participants will be given a identification number through out the study


What supporting documents are/will be available?




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.