Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol

Abstract

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.

Atorvastatin is unlikely to prevent rheumatoid arthritis in high risk individuals: results from the prematurely stopped STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial

“…The unwillingness to participate in the current trial is in line with the experience in other completed (testing dexamethasone; rituximab) and ongoing (testing abatacept; hydroxychloroquine) RA prevention trials, some needing up to 5 years to achieve their recruitment aims 18–20 (ClinicalTrials.gov NCT02603146). It contrasts with the relative ease with which early RA trials recruit patients.…”

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

“…The Strategy for the Prevention of the Clinically Apparent Onset of RA (StopRA) study (40) in the US is randomizing individuals with ACPA levels ≥2 times normal to receive hydroxychloroquine versus placebo for 1 year; subjects are then followed up for an additional 2 years to assess the durability of response as well as to evaluate if treatment may result in a less aggressive form of IA/RA. Arthritis Prevention in the Preclinical Phase of RA with Abatacept (APPIPRA) in the UK and Europe is randomizing individuals with ACPA levels >3 times normal or ACPAs plus RF, and inflammatory joint symptoms/arthralgia, to receive abatacept subcutaneously weekly versus placebo for 1 year, with an additional 1 year of follow‐up (41). Other studies that have been launched include one using statins in autoantibody‐positive subjects (42), and one using glucocorticoids and methotrexate in individuals with arthralgia and no evidence of IA on examination but who have “subclinical” IA on magnetic resonance imaging (43).…”

How to enhance recruitment of individuals at risk of rheumatoid arthritis into trials aimed at prevention: understanding the barriers and facilitators

“… 27 Between November 2015 and January 2019, they were asked to participate in one of two prevention trials: the STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial, 10 and the Arthritis Prevention In the Pre-clinical Phase of RA with abatacept (APIPPRA) trial. 7 In case of being eligible for both trials, patients were first offered the STAPRA. Both trials were a multicentre, randomised, double-blind, placebo-controlled clinical trial to study the effect of temporary use of medication on RA prevention.…”

“…Several trials to test the efficacy of a pharmacological intervention aimed at primary prevention are ongoing or have recently been completed. 7–13 A common theme in these trials is that they experience severe difficulties with patient inclusion and need(ed) up to 5 years to achieve their recruitment aims, or failed to reach recruitment aims mainly due to an unwillingness to participate. Yet, successful completion of these trials is pivotal to advance in the field of primary prevention of RA.…”