Peripheral Spondyloarthritis Clinical Trial
Official title:
SPondyloArthritis: Inducing Drug-free Remission by Early TNF-Alpha bloCkade Under Guidance of Single Cell RNA Sequencing and Epigenetic Profiling. "The SPARTACUS Trial"
The SPARTACUS study will explore the therapeutic efficacy of 2 different treatment strategies for patients suffering from peripheral Spondyloarthritis (pSpA), classified according to the "Assessment in SpondyloArthritis international Society" (ASAS) classification criteria; it will be set up as a 48-week, prospective, randomized, active-comparator controlled, double-blind, double-dummy, clinical trial with a two-fold clinical objective: - To compare a standard step-up approach using conventional synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs), such as methotrexate and/or sulphasalazine (the "csDMARD Step-Up"-strategy), with an early remission-induction treatment strategy that immediately introduces biological DMARDs (bDMARDs) as the first step in the treatment algorithm; in this group the Tumor Necrosis Factor inhibitor (TNFi) golimumab will be utilised (the "TNFi Induction"-strategy). - To define the window of opportunity within which temporary treatment with bDMARDs might be more effective, by stratifying patients according to symptom duration: patients with shorter symptom duration (<3 months) versus those with more longstanding disease (between 3-12 months of symptom duration). The double-blind phase of the study will compare the 2 treatment strategies with regard to the proportion of patients that achieve a status of (sustained) clinical remission. Differences between patients with very early disease (<3 months symptom duration) versus those with symptom duration between 3 and 12 months, will be evaluated. In patients that reach sustained clinical remission, all study treatments (both in the "csDMARD Step-up"-group and the "TNFi Induction"-group) will be stopped, and long-term, clinical follow-up of these patients will allow to explore the possibility of "drug-free remission"; also with regard to this objective, the difference in symptom duration will be evaluated.
SPARTACUS will have several achievable goals: 1. To show superiority of early treatment of pSpA patients with bDMARDs as compared to standard of care. In current practice, TNFi, the predominant bDMARDs in SpA, are only reimbursed in a restricted number of indications: they can be prescribed for axial disease (axSpA) and for the specific pSpA-entity, psoriatic arthritis (PsA); however, even in PsA, they are only reimbursed for longstanding, erosive disease, when patients have already failed (multiple) csDMARD(s). In patients with pSpA without psoriasis, rheumatologists can only prescribe csDMARDs, because TNFi are still off-label despite the overall good efficacy observed in several proof-of-concept studies, incl. one phase 3 trial (Ability-2). For this subgroup of patients, the unmet need is therefore still unacceptably high. Moreover, the patients included in Ability-2 reflected the current step-up treatment paradigm: patients already had longstanding disease (symptom duration of approx. 7 years) and had used (and failed) conventional treatment options before trial entry (99% prior use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), 69% prior csDMARD use). In this population, a statistically significant difference between adalimumab and placebo was observed, but clinical remission rates remained somehow disappointing with only 33% of patients reaching the predefined remission outcome after 3 years of continuous adalimumab use. Until recently, no data were available regarding the treatment of early pSpA with bDMARDs. To address this knowledge gap, we designed a proof-of concept study to explore the therapeutic potential of TNFi in patients with pSpA with very short symptom duration, the CRESPA-trial. In this study, all patients had a symptom duration of less than 12 weeks: they were randomized to receive either immediate TNFi therapy (golimumab) or placebo. In summary, the results of this trial demonstrated that after 24 weeks of treatment, complete clinical remission could be achieved in 75% of golimumab-treated patients versus only 20% in patients treated with placebo (thus refuting the perception that a large majority of pSpA patients would go in spontaneous clinical remission). Due to the placebo-controlled design, the CRESPA trial did not provide any data on the percentage of patients that would have achieved clinical remission while on standard-of-care "csDMARD Step-up" treatment. The design of the SPARTACUS head-to-head trial will allow us to evaluate superiority of the new approach to current practice. 2. To delineate the window of opportunity for intensive treatment of pSpA: a transient time frame in which a disease is more susceptible to treatment. In the proof-of-concept CRESPA trial, all included patients had a symptom duration of less than 12 weeks. In these patients very high clinical remission rates were observed when patients were immediately treated with a TNFi. Interestingly, when the bDMARD treatment was interrupted after reaching sustained remission, 53% of patients remained in drug-free remission at long-term follow-up, providing preliminary evidence for the "window of opportunity" hypothesis: by effectively tackling pSpA (with bDMARDs) in a very early phase of the disease, drug-free remission might be an achievable goal in a significant number of patients. However, the CRESPA-trial does not allow to generalize the findings to pSpA patients with longer symptom duration. Moreover, the above-mentioned extension of the Ability-2 study would suggest that patients with a symptom duration of multiple years would have lower remission rates and would need chronic, life-long bDMARD treatment. The SPARTACUS trial will still focus on early treatment of pSpA (symptom duration <12 months), but the stratification of patients according to symptom duration (<3 months (identical to the CRESPA trial) versus between 3 and 12 months) will allow us to explore the exact time frame in which a window of opportunity is applicable. The goal is to demonstrate that drug-free remission is a feasible outcome when an early intensive treatment strategy is adopted and to delineate the window of opportunity (in terms of symptom duration) in which such a remission-induction strategy is successful, leading to significant health economic benefits. 3. To unravel new biomarkers of therapy response using cutting-edge single cell technology. In the CRESPA trial, we observed that despite the fact that 53% of patients were able to achieve drug-free remission, a significant proportion nevertheless relapsed. In this small proof-of-concept study, we were not able to detect significant predictors or remission or relapse. Also, 18% of patients did not achieve sustained clinical remission, but nevertheless experienced a significant improvement of signs and symptoms; in these patients long-term treatment was necessary. These results indicate that clinical response to TNFi is heterogeneous and underscores the need for biomarkers that can identify at baseline different pathogenic subsets that are associated with the (lack of) response to a TNFi. The recent introduction of new procedures such as ultrasound-guided synovial biopsy sampling in our early arthritis clinic has permitted to access synovial samples of virtually all peripheral joints (incl. wrists and small finger joints). By using innovative and unbiased tools recently developed in the area of single-cell analyses (RNA-sequencing and epigenetic profiling), we will obtain profound insights into the cellular heterogeneity of these unique patient samples. 4. To determine health-economic and societal impact of early, intensive bDMARD treatment of patients with recent-onset pSpA (compared to the currently reimbursed csDMARD Step-up strategy). A unique feature of SPARTACUS is that clinical trial and biomarker discovery will be coupled to calculation of the health-economic benefits of such an approach. We aim to determine from a healthcare and a societal perspective, the 2 years´ cost-utility, as well as a model-based lifelong incremental cost-utility of the innovative strategy compared to usual care. Uncertainty analyses will be performed and budget impact for the Belgian healthcare and social security (work disability) system will be calculated. Consistent with the increased call for transparency in health economic modelling, we aim to make our model available as a semi-open source model. 5. To increase awareness among referring physicians (general practitioners, other specialties that may evaluate patients with early SpA) and patient-advocacy groups about the value of early recognition and treatment in rheumatology. It is still a great challenge to diagnose patients in an early stage of their disease. The delay between symptoms and diagnosis in SpA is still several years. As discussed above, it has been shown that in later stages of the disease, the treatment effect (even with bDMARDs) may be less impressive and chronic therapy is needed without possibility of drug withdrawal (leading to a high socioeconomic burden). The broad set-up of SPARTACUS across health institutes in Flanders will greatly facilitate the awareness and direct implementation of early arthritis strategies among physicians. Finally, results from SPARTACUS will provide evidence that will facilitate discussions with patients about treatment choices and ensure realistic treatment expectations and optimal health behaviour in patients with early pSpA. ;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT01064856 -
Study of Adalimumab in Participants With Peripheral Spondyloarthritis (SpA)
|
Phase 3 |