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. Able to complete essential study procedures and communicate with study staff, with the support of family, carers or interpreters if necessary.
2. Clinical confirmation of PMR diagnosis.
3. ALL of: (i) PMR diagnosed; (ii) previous steroid-responsive bilateral ache in trapezius, shoulder region or upper arms; (iii) previous CRP>5mg/L, or ESR/plasma viscosity above local reference range, occurring together with PMR symptoms.
4. At least 4 points from a possible 6 (fulfilling the PMR classification criteria(35)):
   • 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) both within reference range at screening: 2 points.
   • No documented hand or foot synovitis during active PMR: 1 point.
5. Currently receiving oral prednisolone and willing to attempt taper as per study protocol.
6. At least one previous relapse during steroid therapy: recurrence of steroid-responsive PMR symptoms (aching in hip and/or shoulder areas, as defined above).

Exclusion criteria Patients must not have ANY of the following:

1. Contra-indication to tapering prednisolone dose, or to methotrexate based on local guidelines as in clinical practice.
2. Pregnancy or lactation.
3. A medical condition other than PMR that 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.
4. Current/prior diagnosis of GCA, substantiated by evidence of GCA on previous temporal artery biopsy or vascular imaging.
5. Current/prior diagnosis of rheumatoid arthritis, substantiated by high ACPA titres (57) or by typical radiographic erosions in hands or feet (58).
6. Other medical condition that in the opinion of the Investigator is severe enough to seriously compromise evaluation of the primary or key secondary endpoints, including severe, enduring mental illness.
7. Treatment with any DMARD or biologic agent within 6 weeks of randomisation.
8. Terminal illness.

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 conduced on the intention to treat (ITT) population. Primary analysis will be conduced 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.