Community Research and Development Information Service - CORDIS


BIOCYCLE Report Summary

Project ID: 633168
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - BIOCYCLE (BIOlogical therapy CYCLEs towards tailored, needs-driven, safer and cost-effective management of Crohn’s disease)

Reporting period: 2015-04-01 to 2016-09-30

Summary of the context and overall objectives of the project

- What is the problem/issue being addressed?
Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disease affecting the gastro-intestinal tract and arising predominantly from an interaction between genetic and environmental factors. CD is characterized by recurrent attacks alternating with time spent in remission. The chronicity of CD has a significant impact on patients' Quality of Life (QoL). Multiple co-morbidities, linked to the disease itself (extra-intestinal manifestations, complications related to inflammation) and several adverse events raised by treatments are frequently associated to CD. Specific CD patients, such as adolescents, show also an increased risk for behavioral and emotional dysfunction.

Curative therapies do not yet exist and the current best treatments are symptoms relieving therapies. Biological (monoclonal antibodies against TNFα (such as e.g. Infliximab or Adalimumab) and immunosuppressive therapies represent a significant progress in the treatment of CD and have profoundly influenced the clinical practice.

The current gold standard of care is the combination of biologicals (including anti-TNFα) and anti-metabolites (such as methotrexate, mercaptopurine and azathioprine). This is Combo Therapy which efficacy has been successfully demonstrated in several large clinical trials. Until now, Combo Therapy is thought best used at early-stage of moderate-to-severe CD without interruption or indefinite periods of time and, if needed, with dose escalation. However, taking anti-metabolites and anti-TNFα is associated with potential life-threatening side-effects and anti-TNFα monoclonal antibodies may represent today almost 50% of the medical costs of Inflammatory Bowel Diseases (IBD). There is an unmet need to improve safety and costs while maintaining efficacy of the treatment during the remission periods of patients with CD.

Despite this need, treatment de-escalation to monotherapy with either anti-metabolite or with anti-TNFα has so far received limited attention in clinical trials, in contrast to the efforts already spent in inducing and maintaining remission.

- Why it is important for the society?
In the European Union, 3 Million people are affected by Inflammatory Bowel Disease (IBD) including CD. The incidence of CD has been increasing worldwide. People between 20 and 60 years (societies' main work force) represent 90% of the CD patients. CD cannot be cured at present and its chronicity affects patients' ability to complete personal, family or socio-professional plans. The impact on patients and society is high, as patients are often diagnosed at a young age and ill health may be lifelong. This translates into a huge impact both at the individual and societal level. An important impact on quality of life has been described. Each year, 15 to 20% of patients with CD require hospitalization for complications of the disease and estimates for surgical interventions during the life-long course of disease range from 57 to 80%. The total economic burden of CD is estimated to be 16.7 billion Euros/year in Europe and 15.5 billion dollars in the United-States. Optimal long-term treatment is paramount to maximize disease control allowing the patients to live as normally as possible and also to reduce direct and indirect costs. Beyond that, one can assume that information that we could collect on this topic in CD could be at least partly extrapolated to other Immune Mediated Inflammatory diseases like rheumatoid arthritis, ankylosing spondylitis or psoriasis, which are treated with the same kind of drugs and imply similar treatment strategies.

- What are the overall objectives?
The objective of the BIOCYCLE Project is to test and critically assess the benefits and risks of an innovative regimen for optimizing long-term CD maintenance treatment compared to current best treatment option. Starting from the current gold standard of care combining anti-TNFα + anti-metabolites, the new regimen consists in including Treatment Cycles upon needs after deep and prolonged remission has been reached. The cycle are characterized by periods where both drugs are administrated alternating with periods where either anti-TNFα or anti-metabolites is withdrawn. The objective is to improve both safety and sustaining costs while maintaining the same level of efficacy during the maintenance therapy.

To test, validate and assess whether the Treatment Cycles concept is appropriate and in which circumstances they should be implemented, the project targets a series of Specific Objectives. The consortium will generate and collect a large number of clinical data [the first specific objective is to run the SPARE clinical study: three arms-controlled clinical trial including 300 patients and comparing anti-TNFα withdrawal to anti-metabolites withdrawal to combo maintenance for CD in stable remission under Combo Therapy], costs-of-illness and costs-effectiveness data, information related to expectations of patients, caregivers/providers and healthcare systems regarding withdrawal of either anti-TNFα or anti-metabolites in Treatment Cycles, compared to Combo Therapy without interruption. A critical appraisal of the new regimen will be performed as well as its impact on overall CD management. This will progressively lead to recommendations and decision-making tools designed to appropriately optimize the maintenance therapy of patients with CD in function of their own needs and characteristics.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During this first 18 months period of the BIOCYCLE action, progress has essentially been made in the gathering of patients', healthcare providers' and Health Authorities' perspectives on long-term maintenance treatment in moderate-to-severe CD. We have also launched the SPARE clinical trial comparing different strategies of long-term maintenance treatment in CD and have included the first 40 patients. Finally, we also have developed some dissemination actions through specific meetings and publications.

1) Patients', healthcare providers' and Health Authorities' perspectives on the long-term maintenance treatment of moderate-severe CD.

A large survey has been performed in Europe and in the United States of America (US) asking gastroenterologists specialized in CD but with various degrees of practice what would be their favorite treatment option for long-term maintenance of moderate-severe CD. Overall, 309 gastroenterologists took part in the online survey. First of all, only 30% of US doctors and 10% of European doctors reported that more than half of their patients with moderate-severe CD were currently treated with Combo Therapy. However, less than half of the doctors in Europe and less than a quarter in the US would currently consider stopping combo therapy, particularly the anti-metabolite which is the preferred choice for both European and US doctors. Patients for which doctors would be more reluctant to stop combo therapy are patients with peri-anal disease, current smokers and patients with previous more severe disease history. The main reason for not stopping the combination therapy was the risk to develop disease complications (quoted by 73% of European doctors and 52% of US doctors). On the opposite, the main reason to stop combination therapy was side effects in general for European doctors and side effects and risk of cancer for US doctors.
This survey on doctors' view will now been completed by a large survey on patients' view, also in Europe and in US. The content and methodology of the survey has been validated and the survey will be performed by the end of 2016.
Because of their relatively low prevalence, Health Authorities usually do not consider IBD as a priority for the development of pathways of care, although it is sometimes mentioned as part of a broader ensemble of chronic diseases. Therefore, we choose to approach this aspect (Healthcare perspective on optimal long-term treatment of moderate-severe CD) through an indirect way, first working on the development of an integrated tool that would include all stakeholders and that would help decision making in this field. After interviewing doctors specialized in the field, a first model was generated, being a web-based platform allonwing the input of all stakeholders on the question of the continuation or withdrawal of a combination therapy for moderate-severe CD. The perception of this platform will now be assessed by physicians, patients and Health Authorities, before being in a later phase of the project, tested by these stakeholders and proposed to Health Authorities as integrated decision-making tool for routine use.

2) The SPARE Clinical Trial

SPARE is a three arms controlled clinical trial comparing continuous Combo Therapy to anti-TNFα withdrawal to anti-metabolites withdrawal, in patients with moderate-severe CD having reached long-term sustained remission under Combo Therapy. Over the last 18 months, we have obtained all ethical and Health Authorities approvals for the launch of the trial in France, Belgium, Germany, Sweden and the United Kingdom. Around 50 sites have successfully been initiated so far and recruitment has progressively started in Belgium since the autumn 2015 and in France, Sweden and Germany. The number of active sites is constantly growing and is currently around 20. More than 40 patients have been recruited so far. We aim at least 2 patients recruited by active site by the end of the year, hoping to reach 100 recruited patients and also hopping to have 70 initiated centres. Then, the big effort of recruitment will be over the year 2017, with a mean of 3 new patients to recruit over 1 year by the planned 70 participating centres.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

With the SPARE Clinical Trial (which is the main core of the global project) still at the beginning of its recruitment, most of the progress achieved beyond the state of the art comes from the healthcare providers' survey. This survey has highlighted a relatively low, and potentially insufficient, level of use of the Combo Therapy currently in Europe and the US, having in mind its powerful effect and its advantages in terms of efficacy to treat moderate-severe CD and heal intestinal mucosa. This could represent an underuse, motivated by safety issues potentially advocated by both doctors and patients. On the opposite, for the patients currently treated by Combo Therapy most of the doctors are not keen to contemplate treatment de-escalation, mainly because of the risk of disease complications.

These results are interesting because they highlight a large heterogeneity in practices in this complex field and suggest a probable suboptimal use of the Combo Therapy, being potentially underused as an induction and mid-term maintenance therapy and potentially overused as a long-term maintenance therapy in some patients. This emphasizes the need to collect clinical controlled data in this field (aim of the SPARE trial) as well as pharmaco-economic data, patients' perspectives and tools for patients stratification, all being specific objectives of the BIOCYCLE action.

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