Pragmatic randomised controlled study to assess the effectiveness of two patient management
strategies in mild-to-moderate Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory condition of the rectum and
the colon, for which the etiology still remains unknown. The severity of
colitis is usually graded as mild, moderate or severe according to clinical and
endoscopic parameters, mainly including the number of daily stools compared to
the normal habits, presence of blood in faeces, and presence of mucosal lesions
at endoscopy. Up to 75% of UC patients have a mild-to-moderate course of
disease, whereas up to 25% of patients may need further therapy escalation and,
in case of failure to all medications, may undergo proctocolectomy.
The standard of care is represented by monitoring clinical activity such as
stool frequency (SF) above the normal, and rectal bleeding (RB). Biomarkers of
intestinal inflammation, such as C-reactive protein (CRP) and faecal
calprotectin (FC) have been recommended for monitoring in UC patients. However,
these biomarkers do not drive clinical decisions, since the presence of
elevated CRP or FC is not sufficient to change therapeutic strategies but just
an indication to perform a colonoscopy, which is invasive and poorly
appreciated by the patients.

The European Crohn*s Colitis Organisation (ECCO) guidelines on the management
of UC recommend a step-up approach for mild-to-moderate UC. However, there is
no clear evidence on timely escalation and de-escalation of therapies, and
what are the best targets to be used as a basis for clinical decisions in these
patients.

In 2014, the Selecting Therapeutic Targets in Inflammatory Bowel Disease
(STRIDE) Consensus agreed on the main targets for therapy. In UC patients, they
recommended resolution of clinical signs of disease activity and endoscopic
remission as the best targets to achieve in UC patients.
Remission of intestinal inflammation biomarkers, such as C-reactive protein
(CRP) and faecal calprotectin (FC) is still considered as an adjunctive target
due to lack of scientific evidence to recommend treatment optimisation by
taking into account biomarkers alone. Two randomised-controlled trials added
evidence supporting FC as a valid biomarker for UC management. In both trials,
increasing dose of mesalazine resulted in reduced FC levels, and low FC levels
were associated with decreased risk of relapse.

Recently, the CALM trial (which assessed the effect of tight control management
strategy in patients with Crohn*s disease (CD)) has demonstrated that therapy
modifications based on elevated biomarkers of inflammation is superior in
achieving better disease control than a symptom-based approach. No similar data
are currently available in UC. Therefore, we aim to provide evidence that a
treat-to-target approach based on tight monitoring on non-invasive parameters,
such as clinical symptoms and FC can provide significantly higher benefit for
the patients in terms of UC disease control and quality of life improvement
versus a symptom-based approach.

The purpose of this pragmatic randomised controlled study is to compare two
patient management strategies in mild-to-moderate UC disease. The goal of the
study is to propose a new patient management strategy to both physicians and
patients, as an alternative to achieve better disease outcome. The design of
this study has been set in order to demonstrate and compare the potential
correlation between the 2 proposed management strategies (interventional and
reference) with the disease outcome in real-world settings. As such, this
pragmatic randomised controlled study has been defined to be the best suitable
study design to address our study primary objective of assessing and comparing
the effectiveness of two patient management strategies. This study design will
impose a randomisation process (1:1) in order to balance groups between known
and unknown prognostic factors at study entry.

Study period follow-up:
The aim to explore the effectiveness of a clinical strategy based on endoscopic
remission and mucosal healing in UC, in line with the key clinical trials
available in the literature, and the current recommendation by the European
Medicine Agency for clinical trials in UC, we will evaluate all the relevant
outcomes at 12 months from the baseline.

Control Group:
In order to minimise the variability within different clinical practices, the
control group used in this randomised study has been designed to standardise
and reflect as much as possible the current and recommended clinical practice,
and therefore has been defined as *Reference*. Today, UC patient management is
based on monitoring of clinical symptoms only (PRO-2) and recommended to be
performed on a quarterly basis during active phase of the disease or on a
semi-annually basis during remission.

Medicinal Products:
In this study, the management strategy per se is the subject of the
investigation, and not any specific individual drugs, or FC home test. As such,
physicians will choose the treatment as per their usual practice, provided
these are in line with the ECCO guidelines for medical management of mild-to
moderate UC21 and prescribed as per SmPC recommendations. No drugs will be
supplied to the sites as to not influence any prescribing patterns.

This is a prospective, pragmatic, multi-centre, randomised controlled clinical
study to be conducted in patients with active mild-to-moderate ulcerative
colitis. Each patient will be randomised and followed-up for a total study
duration of 12 months (independently of the arm assigned).

All consecutive adult patients with a mild-to-moderate UC disease in newly
active status, defined with RB >= 1 and Mayo endoscopic subscore >= 1, will be
screened to participate in the study.
Patients who will meet all inclusion criteria and none of the exclusion
criteria will be enrolled to the study and randomised (1:1) to one of the 2
following arms:
• Interventional arm: Treatment optimisation (escalation/de-escalation)
performed by the investigator will be triggered based on patient
self-monitoring of Faecal Calprotectin (FC) values and/or clinical symptoms
(PRO-2). FC Test will be done by the patient at home every month during active
disease, every 3 months in remission, or when patient feels the need/presents
clinical symptoms.

• Reference arm: Treatment optimisation (escalation/de-escalation) performed by
the investigator will be triggered based on clinical symptoms only (PRO-2
scoring). Clinical symptoms (PRO-2) will be assessed during clinic visits
scheduled every 3-months during active disease, every 6 months during
remission, or when patient feels the need; as per recommended standard practice.
Therapy adjustment (escalation or de-escalation steps) will be the same for all
enrolled patients and performed by the treating physician. Therapy will be
optimised in line with the ECCO guidelines for medical management of UC and
prescribed as per SmPC recommendations.

All enrolled patients will be followed-up from Baseline/Randomisation up to
12-months study period.

Efficacy will be measured over 12-months study period, using endoscopic, rectal
bleeding and stool frequency results. Also will score change of three
questionnaires be compared. At last the change of therapy, number of
hospitalisations, procedures, visits to outpatient clinic/calls. In the
interventional group will FC value change be evaluated.

The monitoring of Mild-to-Moderate Ulcerative Colitis at home with the
CalproSmart*-home-test will be compared against monitoring Mild-to-Moderate
Ulcerative Colitis at the hospital.

Although several FC home tests are CE Marked (European Conformity) and
distributed in most of the European countries, it is not yet widely used and
prescribed by the physicians in routine practice. Despite of FC home tests may
represent a burden to patients, especially if it needs to be conducted at
monthly intervals during active phase of the disease, this non-invasive
diagnostic tool may represent an alternative to endoscopies, which are invasive
and poorly appreciated by the patients, and require some availabilities out of
work/school from the patient to attend out-patient clinical visits.
The CalproSmart* home test will be used as part of this study protocol and will
make study patients able to monitor their disease level at their own homes,
ensuring an adequate and effective medical treatment regimen performed by the
physician. As per local approved Instructions For Use (IFU), the home test is
categorized as an in vitro diagnostic tool but users of the self-test must
consult a physician before changing medication based on the test results. The
treatment decision will be made by the physician and patients will not be
allowed to self-escalate without approval from physician and will be prescribed
by physicians in accordance with current ECCO guidelines, which are referenced
throughout the whole study protocol. Therefore, no additional risks associated
to treatments and/or study mandated monitoring procedures via the home test are
expected for the patients taking part in the study.

Invasive burden may occur at end of study, an endoscopy. Completion of the
questionnaires may cause emotional burden.

It is recognized by patient associations that diagnostic and/or management of
UC relapses are often delayed due to symptoms hidden by the patients and
reluctance to perform endoscopy. Timely reaction is therefore critical by both
patients and physicians, strengthening the need for further guidance on
clinical practice. Prior studies showed that active involvement of patients in
management of UC flares may bring a new UC patient management pathway, which
could have the potential to provide patient with clinical and economic benefits.

OPTIMISE will further continue into that direction and will propose and
evaluate a clear UC patient management strategy, including frequency and
triggers for both patient self-monitoring and therapy optimisation, which will
be in alignment with current guidelines for mild-to-moderate active UC21. As
such, this study will enable us to evaluate its effectiveness versus current
standard practice (reference arm) in relation to disease outcome and reinforce
that treatment optimisation (escalation or de-escalation) based on FC level is
a valuable option for mild-to-moderate UC patients in routine practice.
Ultimately, OPTIMISE will strengthen the scientific evidence that FC biomarker
can be incorporated as a new treatment target for mild-to-moderate UC.