Trial design We present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. Methods The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study. Conclusions There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the “at risk” state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. Trial registration Current Controlled Trials, ID: ISRCTN46017566 . Registered on 4 July 2014. Electronic supplementary material The online version of this article (10.1186/s13063-019-3403-7) contains supplementary material, which is available to authorized users.

Trial design: We present a study protocol for a multi-centre, randomised, double blind, parallel group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class costimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. Methods: The study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants aged 18 or over who report inflammatory sounding joint pain (clinically suspicious arthralgia) and who are found to be positive for serum autoantibodies associated with RA were eligible for enrolment. All study subjects were randomised to receive weekly injections of investigational medicinal product (IMP), either abatacept or placebo treatment over a 52-week period. Participants were then followed up for a further 52 weeks. The primary endpoint was defined as the time to development of ≥ 3 swollen joints, or to the fulfilment of the 2010 ACR/EULAR classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study. Conclusions: There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment, the challenges associated with defining the “at risk” state, and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. Trial registration: Current Controlled Trials, ID: ISRCTN46017566. Registered on 04 July 2014.

BackgroundWhile genetic and epidemiological factors have been used traditionally to evaluate the risk of developing rheumatoid arthritis (RA), the definition of higher risk states has been refined in more recent years through inclusion of serum autoantibodies and symptom complexes, such as inflammatory joint pain. Data from at risk cohorts have reported rates of progression to RA in excess of 50% over 24 months. These combined features have provided a framework for the design of interception studies, aimed at delaying or preventing RA.ObjectivesWe evaluated the feasibility, efficacy and acceptability of T-cell co-stimulation modulation with abatacept in individuals at risk of developing RA in the Arthritis Prevention In the Pre-clinical Phase of RA with Abatacept (APIPPRA) study.MethodsAPIPPRA is a Phase IIB randomised, double blind, placebo-controlled trial recruiting ACPA+RF+or ACPAhi(≥3 x ULN) RF-individuals with arthralgia. Consenting participants were randomised, stratified by gender, smoking status and country, to receive 52 weekly subcutaneous injections of placebo or 125mg abatacept, and followed up for a further 52 weeks after stopping treatment. Exclusion criteria included previous episodes of clinical synovitis, prior corticosteroids or DMARDs. The primary endpoint was the time to development of either clinical synovitis in ≥3 joints, or RA according to ACR/EULAR 2010 criteria, whichever was met first, where joint involvement required swelling. Joint synovitis was confirmed by ultrasonography. The study was powered to detect a 50% reduction in progression in those receiving abatacept. Secondary endpoints included multiple disease activity assessments, the time to commencing DMARDs and/or corticosteroids, X-ray and ultrasound scores, as well as safety data. The main ITT analysis was repeated in a per-protocol population of participants who did not take forbidden medication, and who, in the first year or up to a primary event, had 90% adherence to treatment.ResultsBetween December 2014 and January 2019, 280 individuals were evaluated for eligibility across 31 study sites, 28 in the UK and 3 in the Netherlands. Two hundred and thirteen were randomised, 103 to placebo and 110 to abatacept. Mean age was 49 and 77% were female. Ninety-three percent of individuals were ACPAhi. Ultrasonography at baseline suggested modest levels of active sub-clinical synovitis (73% of participants with power Doppler score of 0). In total, there were 65 primary outcome events. After stopping treatment at 52 weeks there were 30 events (29%) in the placebo arm and 7 (6%) in the abatacept arm. By the end of the study there were 38 (37%) and 27 (25%) events, respectively, resulting in differences in mean arthritis-free survival time between arms of 99.2 days (95% CI 37.5 – 160.9;p-value=0.002), in favour of abatacept. The respective log-rank test for difference in the survival distribution wasp=0.044, reflecting a large effect in the first year and convergence over the second year (see Figure 1). The per protocol analysis showed similar results. The cumulative proportion of arthritis-free participants at 52 weeks was 0.692 (SE 0.047) in the placebo arm and 0.928 (SE 0.026) for the abatacept arm, and 0.585 (SE 0.054) for placebo and 0.704 (SE 0.048) for abatacept at 104 weeks.Post hocanalysis revealed that individuals with an extended autoantibody profile at baseline were more likely to remain arthritis-free following abatacept therapy. Those treated with abatacept had lower tender joint counts and pain scores during the treatment period, when compared to placebo. There were 4 serious adverse events in the abatacept group and 10 in the placebo group, including two deaths, one in each arm, none deemed attributable to study drug.Figure 1.ConclusionTherapeutic intervention during the RA at risk phase is feasible, with acceptable safety profiles. T cell co-stimulation modulation with abatacept for 52 weeks showed a reduction in the development of RA over two years. There were no new safety signals.AcknowledgementsThe APIPPRA trial is an Investigator Sponsored Research (ISR) study funded by Bristol Myers Squibb, and jointly sponsored by Guy’s and St Thomas’ NHS Foundation NHS Trust and King’s College London in the UK and Leiden University Medical Center in the Netherlands. Bristol Myers Squibb played no role in data acquisition or analysis.Disclosure of InterestsAndrew Cope Speakers bureau: BMS, Abbvie, Galapagos, Consultant of: BMS, GSK, Abbvie, Grant/research support from: BMS, Janssen, UCB, Marianna Jasenecova: None declared, Joana Vasconcelos: None declared, Andrew Filer Grant/research support from: Roche, UCB, Nascient, Mestag, GSK, Janssen, Karim Raza Grant/research support from: BMS, Sumera Qureshi: None declared, Maria-Antonietta D’Agostino: None declared, Iain McInnes Consultant of: BMS, Grant/research support from: BMS, John Isaacs Speakers bureau: AbbVie, BMS, Gilead, Roche, Consultant of: AbbVie, BMS, Gilead, Roche, Grant/research support from: GSK, Janssen and Pfizer, Arthur Pratt Consultant of: Inflection Biosciences, Grant/research support from: GSK, Pfizer, Galapagos, Benjamin Fisher Consultant of: Novartis, Roche, BMS, Galapagos, Servier, UCB, Janssen, Grant/research support from: Janssen, Galapagos, Servier, Celgene, Christopher D Buckley: None declared, Paul Emery Consultant of: BMS, Grant/research support from: BMS, Pauline Ho: None declared, Maya H Buch: None declared, Coziana Ciurtin: None declared, Thomas Huizinga Speakers bureau: BMS, Consultant of: BMS, Grant/research support from: BMS, Dirkjan van Schaardenburg Speakers bureau: BMS, Caroline Murphy: None declared, Toby Prevost: None declared.

Background: Individuals with joint pain and carrying serum autoantibodies associated with rheumatoid arthritis (RA) are at high risk of developing RA. While there are currently no evidence-based guidelines to inform therapy decisions for such subjects, there are therapies licensed for the treatment of established RA that target pathways implicated in the earliest phase of the disease. Accordingly, we set out to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first in class costimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis. Methods and Design The APIPPRA study was designed as a randomised, double blind, parallel group placebo-controlled clinical trial, aiming to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants aged 18 or over who report inflammatory sounding joint pain (clinically suspicious arthralgia) and who are found to be positive for serum autoantibodies associated with RA, will be randomised to receive weekly injections of investigational medicinal product (IMP), either abatacept or placebo treatment over a 52-week period. All study subjects consent to a further 52 weeks of follow up to monitor for the primary endpoint, the time to development of ≥ 3 swollen joints, or to the fulfillment of the 2010 ACR/EULAR classification criteria for RA using swollen but not tender joints, whichever endpoint is met first. In either case, swollen joints are confirmed by ultrasonography. Discussion There is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. Here, we propose to explore the effects of immunomodulatory therapy at the very earliest detectable phase of disease using an intervention that is already licensed for use in established RA. We discuss the rationale behind choice and duration of treatment, the challenges associated with defining the “at risk” state, and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA. Trial registration Current Controlled Trials, ID: ISRCTN46017566. Registered on 04 July 2014