ANZCTR - Registration

Registration number

ACTRN12621001695897

Ethics application status

Approved

Date submitted

4/03/2021

Date registered

10/12/2021

Date last updated

30/11/2023

Date data sharing statement initially provided

10/12/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

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

Scientific title

A multi-centre, open-label, parallel-group randomised controlled trial of disease-modifying anti-rheumatic drug (DMARD) dose maintenance (USUAL CARE) vs DMARD discontinuation after reduction (STOP) in adult patients with rheumatoid arthritis and psoriatic arthritis on stable biologic or targeted synthetic (b/ts) DMARD therapy +/- conventional synthetic (cs)DMARD/s, who are in sustained low disease activity at baseline

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

PROSPECT (PRedicting disease-mOdifying anti-rheumatic drug doSe reduction response in rheumatoid and Psoriatic arthritis with EConomic evaluaTion)

Linked study record

Participating in this study also involves participation in a biobank and registry study called the Australian Arthritis and Autoimmune Biobank Collaborative (A3BC; 2019/PID11585; 2019/ETH10386; ACTRN12621001564842). The A3BC works with the clinical trial team to provide supporting infrastructure for the capture of trial data and biospecimen collection/processing/storage services.

Health condition

Health condition(s) or problem(s) studied:

Rheumatoid arthritis

Psoriatic arthritis

Condition category

Condition code

Inflammatory and Immune System

Rheumatoid arthritis

Inflammatory and Immune System

Other inflammatory or immune system disorders

Musculoskeletal

Other muscular and skeletal disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

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 at screening (T-3) and baseline (T0). Ineligible participants will be discontinued on the study. Eligible participants will be block randomised at T0 into five arms, USUAL CARE (control arm: continuation with treat-to-target b/tsDMARD therapy), STOP1 (stopping b/tsDMARD only, not on csDMARDs), STOP2 (RA stopping b/tsDMARD then MTX), STOP3 (stopping b/tsDMARD then csDMARD) and STOP4 (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 (STOP). ~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 STOP 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, for example, fixed-dose auto-injectors and some tablets cannot be easily half-dosed, and fixed-dose auto-injectors with 4-weekly maintenance dosing intervals are down-titrated by dose interval increases of 2 weeks, rather than interval doubling, to fit within the study length constraints. Low dose oral methotrexate (2.5 – 7.5 mg weekly) is stopped in 1 to 2 steps.

Intervention Arms

Arm 2: b/tsDMARD discontinuation after reduction (STOP1)
• 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 + methotrexate (MTX; PBS required*) discontinuation after reduction (STOP2)
• 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 and reduce MTX by 50%, then if stable further 25% MTX reduction at 9 months, then if stable cease MTX at 12 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, 18, 24-month clinic visits.
*Includes the following b/tsDMARDs: golimumab, abatacept, infliximab

Arm 4: b/tsDMARD discontinuation after reduction then csDMARD discontinutation after reduction (STOP3)
• 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 and reduce csDMARD by 50%, then if stable further 25% csDMARD reduction at 9 months, then if stable cease csDMARD at 12 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, 18, 24-month clinic visits.

Arm 5: csDMARD discontinuation after reduction then b/tsDMARD discontinutation after reduction (STOP4)
• 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 and reduce b/tsDMARD by 50%, then if stable further 25% b/tsDMARD reduction at 9 months, then if stable cease b/tsDMARD at 12 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, 18, 24-month clinic visits.

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

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

Participating in this study also involves participation in a biobank and registry study called the Australian Arthritis and Autoimmune Biobank Collaborative (A3BC; 2019/PID11585; 2019/ETH10386; ACTRN12621001564842). Collected samples and data are subject to the retention and use conditions specified on the A3BC Consent Form, which participants will complete in parallel with their PROSPECT study consent.

Participant adherence and compliance will be assessed in several ways. Participants will complete the 5-item Compliance Questionnaire for Rheumatology (CQR5) at two timepoints throughout the study, and will be provided with a journal to keep track of any study drug changes, for example, pause due to infection. Ongoing compliance will be assessed at each follow-up clinic or phone review by the study rheumatologist and/or research nurse/officer. Linked PBS dispensing data will be available at the end of the study for retrospective analyses of adherence using the “proportion of days covered” method. Biobanked blood samples will also be available for therapeutic drug monitoring substudies.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Arm 1: b/tsDMARD continuation USUAL CARE (UC)
• Participants must be on a b/tsDMARD (with or without concurrent csDMARDs).
• Treating rheumatologists are advised to continue with existing treat-to-target therapy and adjust as needed per best practice guidelines with the aim to maintain at least low disease activity.
• Outcome data will be collected at -3, 0, 3, 6, 12, 18 and 24 month clinic visits.

Control group

Active

Outcomes

Primary outcome [1]

Proportion persistent low/minimal disease activity (non-inferiority analysis) assessed by maintenance of low/minimal disease activity state determined by the proportion of participants who remain in the inferiority margin for Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28CRP) (<=20% change from baseline) in RA & Minimal Disease Activity (MDA) in PsA. Failure is determined by persistent loss of low/minimal disease activity for 3 consecutive months.

Timepoint [1]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt.

Primary outcome [2]

Cost per QALY (Superiority analysis) assessed using EQ-5D-5L (primary outcome) and healthcare utilisation costs assessed by questionnaire (designed specifically for this study) and data linkage.

Timepoint [2]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt.

Secondary outcome [1]

Time to flare assessed as days between end of run-in baseline and any confirmed flare during the study. RA flare defined when the DAS28CRP has increased by >1.2 from end of run-in, or has increased >0.6 from end of run-in and is >=3.2. PsA flare defined by loss of MDA (<5/7 MDA criteria are met).

Timepoint [1]

Assessed for duration of study period from end of run-in baseline to 24 month endpoint

Secondary outcome [2]

Proportion who switch to other biologic/biosimilar assessed by case report form

Timepoint [2]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [3]

Mean number of serious adverse events assessed by Adverse Event Report form review (validated using Common Terminology Criteria for Adverse Events; CTCAE)

Timepoint [3]

End of study

Secondary outcome [4]

Proportion who withdraw due to adverse events assessed by the study withdrawal log

Timepoint [4]

End of study

Secondary outcome [5]

Direct medical care costs assessed by questionnaire/diary (designed specifically for this study) and data linkage to Medicare Benefits Schedule, Pharmaceutical Benefits Scheme and hospitalisation data

Timepoint [5]

Questionnaire/diary data collected 6-monthly throughout the study. Linkage data will be sought for up to 1 year preceding trial entry and 4 years after, depending on pending data linkage custodian approvals.

Secondary outcome [6]

Indirect disease/ treatment costs by questionnaire/diary (designed specifically for this study)

Timepoint [6]

Collected 6-monthly throughout the study

Secondary outcome [7]

Mean doses of DMARD and non-DMARD therapies assessed by case report form

Timepoint [7]

Collected 3-monthly throughout the study

Secondary outcome [8]

Proportion of participants with minimal radiographic progression assessed by Modified Sharp-van der Heijde score (mSvdH) > 0.5

Timepoint [8]

End of run-in baseline and 24 months

Secondary outcome [9]

Proportion of participants who experience disease flares assessed using RA Flare Questionnaire (RA-FQ)

Timepoint [9]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [10]

Proportion of participants who experience disease flares assessed using PsA Flare Questionnaire

Timepoint [10]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [11]

Proportion of participants who experience disease flares assessed using Simplified Disease Activity Index for RA (SDAI)

Timepoint [11]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [12]

Proportion of participants who experience disease flares assessed using Clinical Disease Activity Index (CDAI)

Timepoint [12]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [13]

Proportion of participants who experience disease flares assessed using DAS28CRP

Timepoint [13]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [14]

Proportion of participants who experience disease flares assessed using Disease Activity Index for Psoriatic Arthritis (DAPSA)

Timepoint [14]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [15]

Proportion of participants who experience disease flares assessed using MDA

Timepoint [15]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [16]

Proportion of participants who experience disease flares assessed using Psoriatic Arthritis Disease Activity Score (PASDAS)

Timepoint [16]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [17]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using RA Flare Questionnaire (RA-FQ)

Timepoint [17]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [18]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using PsA Flare Questionnaire

Timepoint [18]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [19]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using SDAI

Timepoint [19]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [20]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using CDAI

Timepoint [20]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [21]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using DAS28CRP

Timepoint [21]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [22]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using DAPSA

Timepoint [22]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [23]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using MDA

Timepoint [23]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [24]

Proportion having prolonged disease flares (>=4 days) requiring change in therapy assessed using PASDAS

Timepoint [24]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [25]

Mean change in disease activity assessed by SDAI

Timepoint [25]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [26]

Mean change in disease activity assessed by CDAI

Timepoint [26]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [27]

Mean change in disease activity assessed by DAS28CRP

Timepoint [27]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [28]

Mean change in disease activity assessed by DAPSA

Timepoint [28]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [29]

Mean change in disease activity assessed by MDA

Timepoint [29]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [30]

Mean change in disease activity assessed by PASDAS

Timepoint [30]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [31]

Mean change in quality of life assessed by Health Assessment Questionnaire Disability Index (HAQ-DI)

Timepoint [31]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [32]

Mean change in quality of life assessed by PROMIS29

Timepoint [32]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [33]

Mean change in quality of life assessed by Assessment of Quality of Life 8D (AQoL-8D)

Timepoint [33]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [34]

Mean change in quality of life assessed by EQ-5D-5L

Timepoint [34]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [35]

Mean change in physical function assessed by Health Assessment Questionnaire Disability Index (HAQ-DI)

Timepoint [35]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [36]

Mean change in physical function assessed by PROMIS29

Timepoint [36]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [37]

Mean change in physical function assessed by Assessment of Quality of Life 8D (AQoL-8D)

Timepoint [37]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [38]

Mean change in physical function assessed by EQ-5D-5L

Timepoint [38]

End of run-in baseline compared with:
UC: After 12 months treat-to-target therapy, and
STOP:
- Successful down-titration (i.e. no major flares requiring dose reversions): After 12 months of no csDMARD and/or no b/tsDMARD
- Unsuccessful/incomplete down-titration (i.e. dose reversions required): After 12 months of initial down-titration attempt

Secondary outcome [39]

Change in comorbidity burden assessed by case report form using Charlson Comorbidity Index, Elixhauser’s Comorbidity measure, Functional comorbidity index, Multimorbidity index (MMI) and Rheumatic Disease Comorbidity Index

Timepoint [39]

End of run-in baseline compared with 24 months

Eligibility

Key inclusion criteria

- Age >=18 years
- RA diagnosed according to the ACR/EULAR 2010 diagnostic criteria or PsA diagnosed according to the CASPAR diagnostic criteria
- Stable on biologic therapy (b/tsDMARDs*) ± concurrent csDMARDs** for >=6 months duration
- First started any b/tsDMARDs >=2 years ago (not early disease)
- RA only: DAS28CRP REM or LDA <3.2 at start (T-3) and end of 3-month run-in period (T0)
- PsA only: VLDA (7 of 7 MDA criteria) or MDA (>=5 of 7 MDA criteria) at start (T-3) and end of 3-month run-in period (T0)
- If on oral steroids the dose must be stable and <=5mg prednisone daily equivalent

*RA: includes abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, golimumab, infliximab, tocilizumab, tofacitinib, upadacitinib
*PsA: includes adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, ixekizumab, secukinumab, tofacitinib, upadacitinib
**includes methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

No

Key exclusion criteria

All exclusion

- Patients with concurrent medical conditions that in the opinion of the treating rheumatologist are likely to impact the patient’s safety or interfere with the evaluation of the study outcome (e.g. short life expectancy or planned major surgery).
- Patients who are unable/unwilling to provide informed consent for both the clinical trial, and A3BC Biobank-Registry participation for the full duration of the trial.
- Patients with insufficient English language understanding and communication skills (and without access to an interpreter) sufficient to provide informed consent and/or understand and participate in study processes.
- Patients who are on >5mg daily prednisone equivalent glucocorticoids or who have had any parenteral or intra-articular glucocorticoids in the last 6 months.
- Patients who are primarily on immunomodulating agents for other health conditions, for example b/tsDMARDs for Crohn’s disease.
- Patients who are taking any excluded DMARDs: rituximab, ustekinumab, guselkumab, penicillamine, ciclosporin, apremilast.
- Female patients who are pregnant or breastfeeding or planning a pregnancy during the study period.
- Patients who had an investigational new drug within the last 12 weeks.
- Patients with a history of neurological/psychological illness or condition such as to interfere with the patient’s ability to understand the requirements of the study.

Study design

Statistical methods / analysis

Primary Outcome Analyses

• The primary noninferiority per protocol analysis is the cumulative incidence of participants with RA and PsA who meet the failure endpoint in the down-titration arms compared to usual care and do not exceed a noninferiority margin of 20% using a Fishers exact using a per protocol population which is usually conservative in noninferiority studies.
• The co-primary superiority analysis will compare cost per QALY to test the hypothesis that the down-titration arms will be cost saving using a superiority ITT analysis. This is (CostUsualCare – CostDrug Discontinuation) / (QALY UsualCare - QALYDrug Discontinuation) using an ITT population. A per protocol analysis will also be performed. This will determine incremental cost-effectiveness ratio (ICER) (ratio costs / quality-adjusted life-years [QALY]) of intervention versus usual care. QALY evaluation is measured on the EQ-5D. The cost–utility and EQ-5D analysis will be conducted according to the intent-to-treat.

Secondary Analyses

• Comparisons of the mean disease activity and the mean time averaged disease activity between the intervention arms and usual care arm at end of follow-up.
• Comparisons of the co-morbidity burden between the intervention arms and usual care arm at baseline and end of follow-up using commonly used indices in rheumatic diseases.
• Time to failure endpoint using Cox proportional-hazard models and Kaplan Meier survival curves.
• Linear mixed model of equivalence of the slope of the RA DAS28 and PsA PASDAS disease activity scores from baseline to end of study (up to 24 months) based on repeated DAS28 and PASDAS measures.
• Structural damage progression using the modified van der Heijde-modified Sharp score (mSvdH)
• Maintenance of functional status using patient-reported outcomes.
• A comparison of the proportion of patients using NSAIDs, glucocorticoids or cs/bDMARDs between the down-titration arms and usual care.
• A superiority analysis comparing the proportion of patients with adverse events between the down-titration arms and usual care, focused on mild vs. moderate-severe infection and treatment thereof.

Exploratory Analyses (full substudy protocols to be submitted in future)

• Exploring multi-omic predictors of successful drug discontinuation
• Health Economics analysis: incremental cost per additional QALY gained for each treatment arm over usual care
• Relationship between drug concentration and disease activity in patients with rheumatoid arthritis
• Cardiovascular Disease (CVD) biomarkers: comparing differences which may predict positive or negative CVD outcomes associated with DMARD down-titration
• Influence of health literacy on patient outcomes
• Shared decision-making using patient decision aids
• Health equity: assessing differences in PROGRESS-Plus health equity characteristics between recruited and non-recruited patients
• Multi-factorial medication adherence assessment

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/12/2022

Actual

12/12/2022

Date of last participant enrolment

Anticipated

1/12/2024

Actual

Date of last data collection

Anticipated

1/03/2027

Actual

Sample size

Target

324

Accrual to date

25

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,WA,VIC

Recruitment hospital [1]

Royal North Shore Hospital - St Leonards

Recruitment hospital [2]

St George Hospital - Kogarah

Recruitment hospital [3]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [4]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [5]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [6]

The Queen Elizabeth Hospital - Woodville

Recruitment hospital [7]

Flinders Medical Centre - Bedford Park

Recruitment hospital [8]

Royal Perth Hospital - Perth

Recruitment hospital [9]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [10]

Austin Health - Heidelberg Repatriation Hospital - Heidelberg West

Recruitment postcode(s) [1]

2065 - St Leonards

Recruitment postcode(s) [2]

2217 - Kogarah

Recruitment postcode(s) [3]

2050 - Camperdown

Recruitment postcode(s) [4]

4102 - Woolloongabba

Recruitment postcode(s) [5]

5000 - Adelaide

Recruitment postcode(s) [6]

5011 - Woodville

Recruitment postcode(s) [7]

5042 - Bedford Park

Recruitment postcode(s) [8]

6000 - Perth

Recruitment postcode(s) [9]

6150 - Murdoch

Recruitment postcode(s) [10]

3081 - Heidelberg West

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Australian Government, Department of Health, National Health and Medical Research Council, Medical Research Future Fund (MRFF)

Country [1]

Australia

Primary sponsor type

University

Name

University of Sydney

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern Sydney Local Health District Human Research Ethics Committee

Ethics committee address [1]

NSLHD Research Office
Level 13 Kolling Building
Royal North Shore Hospital
Reserve Road, St Leonards, NSW, 2065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

27/10/2021

Approval date [1]

09/12/2021

Ethics approval number [1]

2021/ETH11902

Summary

Brief summary

Overview: This trial aims to determine whether the high-cost, highly specialised biologic, biosimilar and targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs), used to treat Australians living with severe rheumatoid arthritis (RA) and psoriatic arthritis (PsA), can be safely reduced without compromising efficacy. The trial will concurrently address patient and clinician concerns regarding drug safety, efficacy and health system sustainability, with potential to lead to less harms and substantial individual and societal savings. The project will generate new knowledge on RA and PsA low disease activity state and/ or remission in the short to medium term while optimising long-term return on investment by following participants longitudinally as a clinical registry/biobank cohort. Clinical and biomarker predictors of successful (or failure) of down-titration strategies will be evaluated.

Design: A multi-centre, open-label, non-inferiority, parallel-group randomised controlled trial of disease-modifying antirheumatic drug (DMARD) +/- conventional synthetic (cs)DMARD dose continuation (USUAL CARE) vs discontinuation after tapering (STOP) in adults with rheumatoid arthritis and psoriatic arthritis in sustained low disease activity at baseline. Comprehensive clinical, self-reported and administrative data and biospecimens will be collected throughout the study.

Trial website

Public notes

Contacts

Principal investigator

Name

Prof Lyn March

Address

Department of Rheumatology
Level 7C, Acute Services Building, Royal North Shore Hospital
Reserve Rd, St Leonards, NSW, 2065

Country

Australia

Phone

+61 2 9463 1765

Email

[email protected]

Contact person for public queries

Name

Lyn March

Address

Department of Rheumatology
Level 7C, Acute Services Building, Royal North Shore Hospital
Reserve Rd, St Leonards, NSW, 2065

Country

Australia

Phone

+61 2 9463 1765

Email

[email protected]

Contact person for scientific queries

Name

Lyn March

Address

Department of Rheumatology
Level 7C, Acute Services Building, Royal North Shore Hospital
Reserve Rd, St Leonards, NSW, 2065

Country

Australia

Phone

+61 2 9463 1765

Email

[email protected]

Trial Review

Documents added manually

Documents added automatically