Σε πρώτη φάση παρακαλούμε να μας ενημερώσετε για την επιθυμία συμμετοχής στη μελέτη μέχρι τις 31 Ιουλίου, ώστε η έναρξη του αμιγώς προοπτικού σκέλους να γίνει την 1η Σεπτεμβρίου 2022.

Παρακαλείσθε όσοι επιθυμείτε να λάβετε μέρος στη καταγραφή και δεν έχετε ήδη δηλώσει την πρόθεσή σας,
να στείλετε μήνυμα στο info@eomifne.gr, με κοινοποίηση στους υπευθύνους: gbamias@gmail.com & kchalakatevaki@gmail.com.

 

Title: Efficacy and safety of the anti-p40 mAb Ustekinumab in patients with Ulcerative Colitis in a ‘real-world’ clinical setting

Research group
Study principal investigator: Pr. Giorgos Bamias, GI-UNIT, 3RD Academic Dpt. of Internal Medicine, National & Kapodistrian University of Athens, Sotiria Hospital

Study co-ordinator: Dr. Konstantina Chalakatevaki GI-UNIT, 3RD Academic Dpt. of Internal Medicine, National & Kapodistrian University of Athens, Sotiria Hospital. The current study will also be the topic for the PhD thesis of Dr. Chalakatevaki.

Study participants: a) all the investigators from IBD/GI centers from Greece who will respond positively to the invitation call from EOMIFNE b) Pr. Maria Gazouli, who will deliver the molecular and immunological assays in her laboratory

Coordinating center: GI-UNIT, 3RD Academic Dpt. of Internal Medicine, National & Kapodistrian University of Athens, Sotiria Hospital

Background
The therapeutic armamentarium for patients with UC has been expanded considerably in recent years, and it now includes 5 biologics and one small-molecule, with the perspective for additional agents to become available in the next few years. As options will increase, however, it will become of the upmost significance to recognize the patient profiles that mostly match with each particular agent, as well as clarify with the greatest detail the efficacy and safety characteristics of the various drugs. These currently unmet needs in ulcerative colitis, emphasize the importance of collecting data from large cohorts of patients who will receive those medications not in the highly regulated protocols of clinical trials, but in real-world, everyday clinical practice settings. Similarly, the discovery of clinical and molecular biomarkers with the ability to predict satisfactory response (or the lack of it) to available treatments would be critical in order to accomplish higher response rates.

Ustekinumab is a monoclonal antibody against the p40 chain, which is shared by IL-23 [p40/p19 dimer] and IL-12 [p40/p35 dimer]. Ustekinumab has been approved for the therapy of various immune-mediated inflammatory conditions which affect the joints, the skin and the intestinal bowel. Although already in use for CD since 2016, ustekinumab was recently granted approval for use in patients with moderate-to-severe UC in order to achieve clinical remission and maintain it as well as induce histo-endoscopic mucosal improvement and healing. An initial standard intravenous dose based on the weight of the patient (260, 390 or 520mg) is administered followed by a subcutaneous dose of 90mg every 8 weeks. It has been reported that some patients treated with ustekinumab experience improvement regarding the total number of daily stools as early as 7 days after intravenous induction dose and a significant amount of patients achieve symptomatic remission and normalized C-reaction protein levels by week 2. In Greece unrestricted permission for prescribing the drug was given in March 2022. Thus, it is expected that the number of patients who will receive this medication will increase rapidly in the following period. Furthermore, clinical information regarding the efficacy and safety of ustekinumab in patients with UC still rely on the regulatory trials and few real-word reports. Thus, there is a need to obtain more data, including information regarding the performance of this treatment in Greek patients with UC. Our study aims to answer some of these questions.

Research hypothesis
Our hypothesis is that the long-term follow-up of patients with Ulcerative colitis who will commence treatment with ustekinumab will enable us to understand the efficacy and safety characteristics of this biological therapy and discover clinical, laboratory and/or molecular biomarkers who will predict response to this treatment or the lack of it.

Research Aims
The overall goal of this study is to prospectively follow-up the majority of Greek patients with UC who will commence therapy with ustekinumab.

Primary Aim: to define the long-term efficacy (1 & 2-yrs) of ustekinumab in patients with UC in a large population of Greek patients.

Secondary aims:
- to define the short-term efficacy [end of induction period at 16-wks)
- to investigate the predictive value of short-term response for the long-term persistence of ustekinumab administration and therapeutic effect
- to evaluate the long-term treatment persistence of ustekinumab beyond the 2-year timepoint
- to define the percentage of patients who need treatment intensification
- to detect the biological (inflammatory biomarker) response to ustekinumab both at short- and long-term timepoints
- to discover clinical prognostic characteristics for long-term efficacy of ustekinumab
- to delineate the safety profile and recognize any new signals
- to detect the effect of ustekinumab in the quality of life of patients
- to detect the effect of ustekinumab on extraintestinal manifestations of ulcerative colitis.
- to detect serological and molecular signatures that may predict response or failure to treatment with ustekinumab
- to demonstrate the effect of ustekinumab on demanding long-term treatment targets such as endoscopical and/or histological healing/improvement.

Study design
A call will be sent from the Greek IBD Club to all of its members to invite them to participate in the study. All participating IBD centers will recruit patients with UC who will commence treatment with ustekinumab. Therapeutic decisions will be completely up to the treating gastroenterologists without any interference by the study Committee. Recruitment will conclude by the 31st of May 2023 [or Dec 31 2023, depending on patient recruitment numbers]. All participating centers will use a unified database [attached to the current proposal] where they will insert all relevant demographic, clinical and laboratory information. Relevant data entries will be done at baseline and then at weeks 8, 16, 54, 81 & 104, as shown in the diagram below. Patients will be informed regarding participation in the study and sign an informed consent. We will get approval from the Internal Ethics Committee of the Sotiria Hospital and the National and Kapodistrian University of Athens. [The consent form is attached].

 

The primary endpoint will be drug persistence during the study period [as reported be ustekinumab administration at 1- and 2-yrs].

Secondary endpoints will include:

• clinical response [pre-defined as 50% decrease from baseline in PRO2 according to STRIDE-II] in all time points
• steroid-free clinical remission [predefined as PMS≤2 without steroids with no score>1 and/or PRO2 (rectal bleeding = 0 and stool frequency = 0] in all time points.
• Endoscopic improvement [any decrease from baseline in endo-Mayo and/or UCEIS] at any time point.
• Endoscopic healing [Endo-Mayo score=0 or UCEIS 0/1 (for vascular pattern)] at any time point
• Histological healing [as defined by Nancy Histological Index of ≤ 1 and/or Robarts Histopathology Index of ≤3 (without lamina propria or epithelial neutrophils)].
• Safety signals will also be recorded and reported.
• Based on these criteria patients with UC will be divided into responders and non-responders to ustekinumab and the two groups will be compared in various aspects.
• Clinical improvement of extraintestinal manifestations.

METHODOLOGY-EXPERIMENTAL TECHNIQUES

Clinical assessment: the following parameters will be assessed at each timepoint to calculate the rates of primary and secondary outcomes: PRO-1/rectal bleeding [0 = no bleeding, 1 = streaks of blood with stools less than 50% of time, 2 = obvious blood with stool more than 50% of the time, 3 = passes blood without stool]; PRO-2/bowel movement [0 = normal number of stools for patient, 1 = 1–2 more stools than normal, 2 = 3–4 more stools than normal, 3 = 5 + more stool than normal]; Physician’s Global Assessment [PGA] [0= Normal (sub scores are mostly 0), 1= Mild disease (sub scores are mostly 1), 2=  moderate disease (subscores usually 1 or 2), 3= Severe disease (sub scores are mostly 2 to 3)]

EIMs: the presence of extraintestinal manifestations will be assessed at baseline and will be revaluated at each timepoint based on whether they remain active during therapy. Newly presented EIMs will also be recorded.

Laboratory assessment: at each timepoint we will collect laboratory values as indicated in the attached excel file. The investigators will be encouraged to include fecal calprotectin in their regular assessments.

Endoscopical Endoscopy will be performed at the discretion of the treating gastroenterologists.  It is expected, however, that, according to common clinical practice, the majority of patients will have endoscopy at baseline and at one or more timepoints during the treatment. We will use the endoscopical Mayo score [0=Normal or inactive, 1=Mild Erythema, decreased vascular pattern, mild friability, 2=Moderate marked erythema, absent vascular pattern, friability, erosions, 3=Severe spontaneous bleeding, ulceration] and the UCEIS [Vascular: 0=Normal Normal vascular pattern with arborization of capillaries clearly defined, or with blurring or patchy loss of capillary margins, 1=Patchy obliteration Patchy obliteration of vascular pattern, 2=Obliteration Complete obliteration of vascular pattern; Bleeding: 0=None, No visible blood 1=Mucosal Some spots or streaks of coagulated blood on surface of the mucosa ahead of the scope which can be washed away, 2=Luminal mild Some free liquid blood in the lumen 3=Luminal moderate or severe Frank blood in the lumen ahead of endoscope or visible oozing from mucosa after washing intraluminal blood or visible oozing from a hemorrhagic mucosa; Erosions and ulcers: 0=None, Normal mucosa without visible erosions or ulcers, 1=Erosions Tiny (≤5 mm) defects in the mucosa of a white or yellow color with a flat edge, 2=Superficial ulcers Larger (>5 mm) defects in the mucosa which are discrete fibrin-covered ulcers in comparison with erosion, but remain superficial, 3=Deep ulcers Deep excavated defects in the mucosa with a slightly raised edge]. The percentage of patients achieving histological normalization or improvement from baseline will be recorded. 

Histological assessment Endoscopical biopsies will be collected at every endoscopy and disease severity will be scored according to validated scoring systems [Robarts Histological index, RHI = 1 × chronic inflammatory cell infiltrate (0–3) + 2 × lamina propria neutrophils (0–3) + 3 × neutrophils in epithelium (0–3) + 5 × erosions or ulceration (0–3). Total sum of the RHI ranges from 0 to 33] Nancy Histological Index: Ulceration 0–1: Yes or no Acute inflammatory cell infiltrate 0–3: none; mild; moderate; severe Chronic inflammatory cell infiltrate 0–3: none; mild; moderate; severe. Nancy Histological Index [ranging from 0 to 4]. The percentage of patients achieving histological remission will be recorded. Scoring will be performed by an expert pathologist [Pr. Stratigoula Sakellariou], who will be blinded to the clinical outcomes.

Immunophenotyping We will also collect biological material [biopsies, serum, peripheral blood cells] from a subset of patients that are followed in the largest participating centers.  These materials will be used for analysis via molecular and immunological techniques in order to discover biomarkers with predictive value for response to ustekinumab. Immunophenotyping will be done via transcriptomic analysis of total RNA extracted from endoscopical biopsies or cellular pellets from peripheral blood.  In addition, serum of patients will be stored and used for analysis of protein content for various inflammatory markers, using multiplex assays.

TDM. Stored serum will also be used for measuring levels of ustekinumab at the various time-points.  TDM monitoring and association with treatment outcomes.

Statistical analysis. All data will be inserted into a common database and analysis will be done via the SPSS statistical tool. We will perform descriptive statistics to assess the efficacy of ustekinumab for the primary and various secondary endpoints of the study.  In addition, we will perform comparative analysis of responders vs. non-responders, in regards to clinical, serological, molecular and TDM parameters.  This will help us to identify baseline or early-timepoint markers with prognostic value for 1 or 2-year efficacy or treatment failure.

 Feasibility ≤ 1/2 page

Several multicenter studies have been completed and are currently running under the auspices of EOMIFNE.  We expect high participation from all over Greece, and we anticipate no problems in completing the tasks of the study.  The coordinator will regularly check upon the progress of the data collection.  We expect that within the timeframe of the study we will be able to gather a large number of patients with UC who will be treated with ustekinumab. 

Impact of the research

We consider our study of clinical significance because it is important to understand the clinical performance of biologics [in this case of ustekinumab] in real-world settings, since it is known that a large percentage of patients do not fulfil the inclusion criteria for the regulatory trials, which provide very controlled information on a subset of participants with very defined characteristics.  There are only few real-world trials at the moment and all of them have been analysed retrospectively.  In contrast, we propose a prospective collection of data, which adds value to our proposed work.  It should be noted at this point, that ustekinumab is not reimbursed in several countries, which gives us an advantage over them as in Greece the medication is available without restriction. Furthermore, should we be able to discover clinical prognostic factors that predict response to ustekinumab this would be an important advancement of knowledge.  Similarly, analysis of the collected biological material will help us to investigate whether transciptomic analysis from biopsies or peripheral blood cells and immunophenotyping of serum may be helpful in defining the subsets of patients with high or low probability for response to ustekinumab. It should be noted that currently there is no way to select the patients with the highest probability of response neither those who will probably fail the treatment.  Consequently, our study is of value as it will provide criteria for increasing the efficacy rates for the treatment of UC patients with ustekinumab. 

Detailed budget

The clinical part of the study requires no funding. The clinical part of the study requires no funding. No salaries will be provided to any of the participating scientists. For the experimental part, we estimate a budget of €20.000tht will be used for the whole period of 2 years. A detailed analysis of the cost is provided below.

Histological analysis: Biopsy specimens will be collected, and then transferred and stored at the Department of Pathology of the National and Kapodistrian University of Athens, under the supervision of Pr. Sakellariou. We estimate a total cost of €3.000 for the expenses of a technician fee and expendables for biopsy processing for analysis, including regents for immunostaining of specific biomarkers that will be discovered after transcriptomic analysis.

Transcriptomic analysis: After collecting an adequate number of biopsies and cellular pellets from peripheral blood, we will extract RNA and then perform full transcriptomic analysis analyzing in comparative fashion responders vs. non-responders to ustekinumab. We estimate a total cost of €9.000 for a period of two years.

Serological immunophenotyping: After collecting an adequate number of sera from responders and non-responders, we will use multiplex assays for common inflammatory biomarkers in a comparative fashion. We estimate a total cost of €6.000 for a period of two years.

TDM: We will set the assay for measuring serum levels of ustekinumab in the laboratory of Pr. Gazouli. We estimate a total cost of €2.000 for a period of two years.

Βιβλιογραφία (references)

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