A randomised controlled trial to compare drug dose reduction strategies in adults with rheumatoid arthritis and psoriatic arthritis for safer and more efficient drug use

A 3-month run-in period will be employed to ensure stability of low disease activity by requiring a DAS28-CRP < 3.2 in RA and MDA (>= 5 of 7 criteria) in PsA at screening (T-3) and baseline (T0). Eligible participants will be block randomised at T0 into five arms, USUAL CARE (control arm: continuation with treat-to-target b/tsDMARD therapy), TAPER1 (stopping b/tsDMARD only, not on csDMARDs), TAPER2 (RA stopping b/tsDMARD then MTX), TAPER3 (stopping b/tsDMARD then csDMARD) and TAPER4 (stopping csDMARD then b/tsDMARD); in a ~1:1:1:1:1 ratio for RA and ~1:1:0:2:2 ratio for PsA i.e. participants will have a ~4 in 5 chance of being assigned to slowly reduce, then stop their disease modifying anti-rheumatic drugs (DMARDs) over a 6- to 12-month period as guided by their level of disease activity and shared-decision making with their rheumatologist (TAPER). ~1 in 5 participants will be assigned to a ‘Usual Care (UC)’ control group. Usual Care participants will continue with their regular DMARDs as normal and will not be asked to reduce their dosages. Block balanced randomisation on disease group, current therapy profile and site will be employed to ensure similar numbers across subgroups. All DMARDs used in this study are already approved in Australia to treat Rheumatoid arthritis (RA) and/or Psoriatic arthritis (PsA) and will have been previously prescribed to participants as part of their routine care by a rheumatologist. Dose changes in the TAPER arms of the study are protocolised by a disease-activity guided DMARD down-titration alogorithm which aims to approximately halve the amount of drug at each down-titration step, where feasible (see below). Dose reductions and/or dose interval increases are specified based on the available literature and pragmatic considerations. Intervention Arms Arm 2: b/tsDMARD discontinuation after reduction (TAPER1) • Participants must be on a b/tsDMARD only (no concurrent csDMARDs) • Reduce b/tsDMARD by 50% at baseline, then if stable further 25% reduction at 3 months, then if stable, cease b/tsDMARD at 6 months. • Outcome data will be collected at -3, 0, 3, 6, 12, 18 and 24-month clinic visits. Arm 3: RA on b/tsDMARD + MTX (PBS required*) discontinuation after reduction (TAPER2) • Participants must be on a b/tsDMARD co-prescribed with MTX as per Australian Pharmaceutical Benefits Scheme (PBS) biologics eligibility criteria* (RA only). • Reduce b/tsDMARD by 50% at baseline, then if stable further 25% reduction at 3 months, then if stable, cease b/tsDMARD at 6 months, then if stable reduce MTX by 50% at 9 months, then if stable further 25% MTX reduction at 12 months, then if stable cease MTX at 15 months. • If the participant is taking >1 csDMARDs, all are down-titrated in parallel with MTX. • Outcome data will be collected at -3, 0, 3, 6, 9, 12, 15, 18, 24-month clinic visits. *Includes the following b/tsDMARDs: golimumab, abatacept, infliximab Arm 4: b/tsDMARD discontinuation after reduction then csDMARD discontinuation after reduction (TAPER3) • Participants must be on a b/tsDMARD and a csDMARD (not required as per PBS biologics eligibility criteria). • Reduce b/tsDMARD by 50% at baseline, then if stable further 25% reduction at 3 months, then if stable, cease b/tsDMARD at 6 months, then if stable reduce csDMARD by 50% at 9 months, then if stable further 25% csDMARD reduction at 12 months, then if stable cease csDMARD at 15 months. • If the participant is taking >1 csDMARDs, all are down-titrated in parallel. • Outcome data will be collected at -3, 0, 3, 6, 9, 12, 15, 18, 24-month clinic visits . Arm 5: csDMARD discontinuation after reduction then b/tsDMARD discontinuation after reduction (TAPER4) • Participants must be on a b/tsDMARD and a csDMARD (not required as per PBS biologics eligibility criteria). • Reduce csDMARD by 50% at baseline, then if stable further 25% reduction at 3 months, then if stable, cease csDMARD at 6 months, then if stable reduce b/tsDMARD by 50% at 9 months, then if stable further 25% b/tsDMARD reduction at 12 months, then if stable cease b/tsDMARD at 15 months. • If the participant is taking >1 csDMARDs, all are down-titrated in parallel. • Outcome data will be collected at -3, 0, 3, 6, 9, 12, 15, 18, 24-month clinic visits. For participants: • Medication use (including treatment switches and glucocorticoid use) and adverse events will be monitored at 3-monthly intervals (either at scheduled clinic visits or via phone call from the RN/O). • Patients are encouraged to contact the rheumatology clinic if they experience worsening symptoms and additional visits can be scheduled as per clinical need, including phone reviews or contact for flares. • All flares are monitored, reported and managed as per the Disease Flare Monitoring and Rescue Protocol. • Where feasible, ad hoc blood and/or synovial fluid (optional to site) samples may be collected for the biobank at any flare-related clinic visits. • ECGs and routine X-rays of the hands and feet will be taken at baseline (end of run-in, randomised participants only yet not required if patients had in the last 12 month) and 24 months. • All routine blood monitoring results will be documented. • The number and timing of scheduled clinic visits will vary based on treatment arm allocation. • A synovial biopsy procedure will be performed at self-selected sites after an additional synovial tissue collection consent from patients at baseline [T0], T6 or time of the first flare (whichever occurs first), and/or T18 (optional to patients). • Shared decision-making tools will be used at self-selected sites at screening visit [T-3] and T6. • Two CTCA scans will be performed at self-selected sites after an additional cardiovascular imaging consent from patients at baseline [T0] and T24. • Synovitis, enthesitis, tenosynovitis and perisynovitis measures by US will be evaluated at self-selected sites after an additional ultrasound imaging consent from patients at end of run-in baseline [T0], at the time of first flare (if applicable), and 24 months [T24]. DMARD down-titration protocol (for Arms 2 - 5) csDMARDs • Methotrexate, oral, RA and PsA, 10 - 30 mg weekly (100%), 5 - 15 mg weekly (50%), 2.5 - 7.5 mg weekly (25%), Stop • Methotrexate, oral, RA and PsA, 5 - 7.5 mg weekly (100%), 2.5 mg weekly (50%), Stop • Methotrexate, oral, RA and PsA, 2.5 mg weekly (100%), Stop • Methotrexate, SC, RA and PsA, 7.5 - 25 mg weekly (100%), 3.75 – 12.5 mg weekly (50%), 1.875 – 6.25 mg weekly (25%), Stop • Hydroxychloroquine, oral, RA, 400 mg daily (100%), 200 mg daily (50%), 200 mg every 2 days (25%), Stop • Hydroxychloroquine, oral, RA, 200 mg daily (100%), 200 mg every 2 days (50%), 200 mg every 4 days (25%), Stop • Sulfasalazine, oral, RA and PsA, 2 - 3 g daily (100%), 1 - 1.5 g daily (50%), 0.5 g daily (25%), Stop • Leflunomide, oral, RA and PsA, 20 mg daily (100%), 10 mg daily (50%), 10 mg every 2 days (25%), Stop • Leflunomide, oral, RA and PsA, 10 mg daily (100%), 10 mg every 2 days (50%), 10 mg every 4 days (25%), Stop • Azathioprine, oral, RA, 1–3 mg/kg daily (100%), 0.5–1.5 mg/kg daily (50%), 0.25–0.75 mg/kg daily (25%), Stop bDMARDs • Adalimumab, SC (subcutaneous), RA and PsA, 40 mg every 2 weeks (100%), 40 mg every 4 weeks (50%), 40 mg every 8 weeks (25%), Stop • Etanercept, SC, RA and PsA, 50 mg weekly (100%), 50 mg every 2 weeks (50%), 50 mg every 4 weeks (25%), Stop • Etanercept, SC, RA and PsA, 25 mg every 3 or 4 days (100%), 25 mg once a week (50%), 25 mg every 2 weeks (25%), Stop • Infliximab, IV (intravenous), RA, 3 mg/kg every 8 weeks (100%), 1.5 mg/kg every 8 weeks (50%), 0.75 mg/kg every 8 weeks (25%), Stop • Golimumab, SC, RA and PsA, 50 mg every 4 weeks (100%), 50 mg every 6 weeks (50%), 50 mg every 8 weeks (25%), Stop • Certolizumab, SC, RA and PsA, 200 mg every 2 weeks (100%), 200 mg every 4 weeks, 200 mg every 8 weeks (25%), Stop • Certolizumab, SC, RA and PsA, 400 mg every 4 weeks (100%), 200 mg every 4 weeks (50%), 200 mg every 8 weeks (25%), Stop • Abatacept, SC, RA and PsA, 125 mg weekly (100%), 125 mg every 2 weeks (50%), 125 mg every 4 weeks (25%), Stop • Abatacept, IV, RA and PsA, 500 – 1000 mg every 4 weeks (100%), 250 – 500 mg every 4 weeks (50%), 125 – 250 mg every 4 weeks (25%), Stop • Tocilizumab, SC, RA, 162 mg weekly (100%), 162 mg every 2 weeks (50%), 162 mg every 4 weeks (25%), Stop • Tocilizumab, IV, RA, 8 mg/kg every 4 weeks (100%), 4 mg/kg every 4 weeks (50%), 2 mg/kg every 4 weeks (25%), Stop • Secukinumab, SC, PsA, 150 mg every 4 weeks (100%), 150 mg every 6 weeks (50%), 150 mg every 8 weeks (25%), Stop • Secukinumab, SC, PsA, 300 mg every 4 weeks (100%), 150 mg every 4 weeks (50%), 150 mg every 8 weeks (25%), Stop • Ixekizumab, SC, PsA, 80 mg every 4 weeks (100%), 80 mg every 6 weeks (50%), 80 mg every 8 weeks (25%), Stop • Guselkumab, SC, PsA, 100 mg every 8 weeks (100%), 100 mg every 12 weeks (50%), 100 mg every 16 weeks (25%), Stop tsDMARDs • Baricitinib, oral, RA, 4 mg daily (100%), 2 mg daily (50%), 2 mg every 2 days (25%), Stop • Tofacitinib, oral, RA and PsA, 10 mg daily (100%), 5 mg daily (50%), 5 mg every 2 days (25%), Stop • Upadacitinib, oral, RA and PsA, 15 mg daily (100%), 15 mg every 2 days (50%), 15 mg every 4 days (25%), Stop