None listed
Conditions
Brief summary
Steroid-Reducing Options for ReLapsING PMR (STERLING-PMR): a pragmatic, randomised trial to compare the clinical and cost-effectiveness of adding immunomodulation to steroid-tapering treatment for patients with relapsing PMR, versus steroid-tapering alone. This is a Multi-centre, Phase III, parallel-group, open-label, randomised controlled trial with internal pilot. Internal Pilot: 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 (41). An internal review will also be conducted after 8 months, corresponding to one-third of the total recruitment phase (42). 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 This study aims to determine the clinical and cost-effectiveness of adding a disease-modifying anti-rheumatic drugs (DMARDs) to prednisolone-tapering treatment in relapsed PMR patients. The primary objective to test whether adding a DMARD to usual-care prednisolone reduces patient-reported cumulative steroid dose requirements over 18 months, compared with usual-care alone; within a pragmatic RCT design. The secondary objectives will be assessment of PMR symptom severity and disease activity; time to stopping steroids and to steroid-free remission; cumulative steroid dose; AE; quality of life; work participation; diagnosis of adrenal insufficiency or GCA; and the impact of increased referrals on Rheumatology service capacity.
Interventions
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 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.
Sponsors
the University of Adelaide
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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.
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.
Outcome results
None listed