STERLING

Phase III

Multi-centre, Phase III, parallel-group, open-label, randomised controlled trial with internal pilot

Patients with polymyalgia rheumatica (PMR) who are (1) receiving oral prednisolone (steroid) treatment and (2) who have previously experienced at least one relapse of PMR.

Patients must fulfil ALL of the following:

1. Age 18 years or more at the time the consent form is signed
2. ALL of:
   1. documented¹ diagnosis of PMR, confirmed by the local investigator.
   2. previous steroid-responsive bilateral ache in the region of the trapezius, shoulder or upper arms, as reported by the patient to the secondary care site research team
   3. 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, as reported by the patient to the secondary care site research team: 2 points.
   • Previous aching of hip area (groin, buttock, lateral hip or upper thigh) in association with other features of PMR, as reported by the patient to the secondary care site research team: 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), as reported by the patient to the secondary care site research team.
5. At least one previous relapse during steroid therapy, defined as steroid-responsive recurrence of PMR symptoms (aching in hip and/or shoulder areas), as reported by the patient to the secondary care site research team.
6. Consent to participate (written, informed consent or witnessed verbal informed consent).

¹ Acceptable documentation may include but not be limited to referral documentation from the GP practice, GP records containing diagnostic code (e.g. Read code, SNOMED code), or letter from an appropriately trained and qualified physician documenting the diagnosis

Exclusion criteria Patients must not have ANY of the following:

1. Contraindication to tapering steroid dose, or to methotrexate therapy, in the judgement of the local investigator²
2. Currently pregnant or lactating
3. Women of child-bearing potential (WCBP) or men unwilling to use an effective birth control measure (Appendix 2) whilst receiving treatment and for an appropriate period after the last dose of protocol treatment (as indicated in the relevant SmPC). 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 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 or 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

² Contraindication to MTX includes comorbidities such as severe respiratory disease or chronic infections (31): investigators must use their clinical judgement, based on local practice and/or national clinical practice guidelines for methotrexate prescribing in rheumatology contexts.

200

20

4 study visits over 18 months (screening, baseline, 6 months, 18 months)

18 months

The last study visit will be for 18 months
Consent will be sought for 10 years’ continued follow up via routinely-collected clinical data via electronic healthcare records and national datasets (HES, ONS).

Recruitment period:
1st Jan 2023 to 31st Dec 2025
This includes a one-year internal feasibility phase.

Prednisolone dose taken by patients, reported by monthly questionnaire

From monthly questionnaires:

• Pain NRS
• Stiffness NRS
• Function HAQ-DI
• Fatigue FACIT-F
• Relevant SF-36 subscales
• Keele PMR PROM

PMR disease activity PMR-AS assessed at 0, 8, 18 months

Date of prednisolone cessation if reported by patient in monthly questionnaires

Date of prednisolone cessation and remission of PMR symptoms if reported by patient in monthly questionnaires

Total prednisolone dose prescribed by GP during trial period: collected from GP records at end of trial

Patient-reported relapse: if an increase in PMR symptoms was sufficiently severe to require alteration of the steroid dosing plan

Adverse events related to PMR or to trial treatment, reported directly by patients or by study site
Steroid Impact PROM (Bristol)

SF-36-PCS (key secondary)
SF-36-MCS
EQ-5D-5L

WPAI

As per local guidelines

Clinical diagnosis confirmed by hospital site

Resource use questionnaire (3-monthly)

Health economic modelling

FBC, U+E, LFT
Rheumatoid factor and anti-CCP antibody titres

Blood pressure
Inflammatory markers
PMR disease activity
Clinical remission or non-remission status
Glycaemic status
Metabolic status
Adrenal insufficiency
Bone density Blood pressure
ESR, CRP
PMR-AS (composite score)
Clinician’s judgement of PMR remission
HbA1c
Urate
9am cortisol (if pred<=5mg) DEXA

Chest radiograph (screening)
DEXA (screening, 18mo)

Laboratory Involvement All laboratory tests including ESR will use the local hospital laboratories. No central laboratories will be involved.
Optionally an extra blood sample may be collected and stored for research sub-studies, to be analysed after the end of the study.

All patients will continue to receive usual care (a tapering course of prednisolone under the care of their GP).
Patients will be randomised 1:1 to disease-modifying antirheumatic drug (DMARD) therapy plus usual care, or usual care alone.
For those randomised to the DMARD arm, DMARD will be prescribed and blood monitoring tests arranged by the hospital site throughout the trial.
DMARD will be methotrexate first line; this will be switched to leflunomide in case of lack of tolerance or inefficacy.
Patients who successfully stop prednisolone during the 18-month follow-up period may if they wish stop DMARD after 6-12 months of steroid-free remission.

Methotrexate (MTX) will be given orally, starting at 15mg weekly and escalating to 20mg weekly if tolerated, reduced to minimum 10mg weekly if not tolerated.
Folic acid will be co-prescribed with MTX to reduce toxicity as per usual practice.
Leflunomide (LEF) will be given orally, starting at 10mg daily and escalating to 20mg daily if tolerated, reduced to 10mg every other day if not tolerated.
Prescribing and blood test monitoring for MTX or LEF, at frequencies determined by local practice, will be undertaken by the hospital site throughout the trial.

Primary analysis will be conducted on the intention to treat (ITT) population. Primary analysis will be conducted on log(cumulative prednisolone dose over 18 months) using multivariable linear regression.

Sample size calculation Subject to assumptions about coefficient of variation, attrition and 5% significance level, 200 participants will provide a 90% power to detect a target 30% reduction in cumulative prednisolone dose.