AppenDectomy Vs ANti TNF-a in Inducing Clinical and EnDoscopic Remission in Left-sided Ulcerative Colitis

Study Overview
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Brief Summary
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Ulcerative Colitis (UC) is a chronic Inflammatory Bowel Disease (IBD) characterized by a multifactorial etiology, a variable involvement of large bowel, and a relapsing-remitting course. In order to keep the disease in a quiescent status and to prevent relapses, a significative percentage of UC patients will remain on long-term drug therapy. However, long-term immunosuppressant therapy is not free of risks and complications: in fact, these therapies have an impact on both healthcare system resources and patients' quality of life; more, there are even concerns regarding the side effects of long-term immunosuppressant therapy. Over the past 20 years, a considerable amount of evidence was produced to support the immunomodulatory role of the appendix in the development and course of UC: there is a strong inverse relationship between previous appendectomy and development of the UC. One of the proposed theories to justify this link is that the appendix could act as a reservoir for commensal bacteria that can be secreted into the colon, affecting its microbiome and immunological response; another theory describes the appendix as the priming site for the cytokine production and the immunological cascade that may trigger inflammation in colon and rectum. The idea of this study moves from these assumptions: the investigators aim to evaluate the impact of appendectomy in patients with UC who are candidates to the treatment with biologics (Anti TNF-a), because of conventional therapies failure. To further reduce any ethical problems and significantly lower any surgical morbidity, investigators will restrict the study population to only patients with active left-sided colitis, so that the surgery for appendectomy will take place on a non-inflamed cecum. By undertaking this study, the investigators hope to a) learn more about the role of appendix and the impact of appendectomy in the clinical history of Ulcerative Colitis; b) demonstrate that laparoscopic appendectomy, a relatively simple surgical procedure that can also be performed in day-surgery with a very low expected complication rate, is a treatment that is superior to biological therapy, avoiding patients starting a chronic, long-lasting therapy, with the consequent risk of immunosuppression, and with possible higher costs for the health system in the long term.

Official Title
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ADVANCED-UC TRIAL: AppenDectomy Vs ANti TNF-a in Inducing Clinical and EnDoscopic Remission in Left-sided Ulcerative Colitis - A Randomized Clinical Trial

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Procedure: Appendectomy
* Drug: Infliximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 or above Patients with a confirmed diagnosis of left-sided UC (extended up to the mid transverse colon) Patients with active disease refractory to conventional treatment and candidates for anti- TNF-a treatment Patients who have given consent to the surgical procedure Exclusion Criteria: Patients under the age of 18 Lack of diagnostic certainty of Ulcerative Colitis / Crohn's disease diagnostic doubt Patients who previously received appendectomy Patients who have had previous laparotomic abdominal surgery, which could make the appendectomy more complex Patients with Severe Acute Colitis/Toxic Megacolon Patients who have not given their consent to the intervention Patients who receive a different surgical procedure from appendectomy because of intraoperative complications Pregnant patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>Infliximab | Drug: Infliximab<br>* Administration of Infliximab (Anti-TNF-a biologic drug)<br>|
| Experimental: Group 2<br>Appendectomy | Procedure: Appendectomy<br>* Laparoscopic appendectomy is a relatively simple surgical procedure that can be performedby most surgeons, either on an outpatient basis or with a single-night hospital stay. The laparoscopic approach is now the recommended option due to faster recovery times and fewer wound complications.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steroid Free Clinical Remission | Steroid Free Clinical Remission at 3 and 12 months (defined as Partial Mayo score </=2, with no individual sub-score >1) | 3 months | 
| Steroid Free Clinical Remission | Steroid Free Clinical Remission at 3 and 12 months (defined as Partial Mayo score </=2, with no individual sub-score >1) | 12 months | 
| Endoscopic remission | Endoscopic remission at 3 and 12 months (defined as MAYO CU score </ = 1) | 3 months | 
| Endoscopic remission | Endoscopic remission at 3 and 12 months (defined as MAYO CU score </ = 1) | 12 months | 
| Assessment of Quality of Life | Assessment of Quality of Life at 3 and 12 months, through the SIBDQ (Short Inflammatory Bowel Disease Questionnaire, ranging from 10, meaning poor quality of life, to 70, meaning optimal quality of life) | 3 months | 
| Assessment of Quality of Life | Assessment of Quality of Life at 3 and 12 months, through the SIBDQ (Short Inflammatory Bowel Disease Questionnaire, ranging from 10, meaning poor quality of life, to 70, meaning optimal quality of life) | 12 months | 
| Assessment of Quality of Life | Assessment of Quality of Life at 3 and 12 months, through the SF-36 questionnaire (Short-form 36) | 3 months | 
| Assessment of Quality of Life | Assessment of Quality of Life at 3 and 12 months, through the SF-36 questionnaire (Short-form 36) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response | Clinical Response at 3 and 12 months (defined as a reduction of the MAYO SCORE of at least 3points). MAYO SCORE ranges from 0 (inactive disease) to 3 (severe disease activity). | 3 months | 
| Clinical Response | Clinical Response at 3 and 12 months (defined as a reduction of the MAYO SCORE of at least 3points). MAYO SCORE ranges from 0 (inactive disease) to 3 (severe disease activity). | 12 months | 
| Failure rate | Evaluation of the failure rate at 3, 12 and 24 months (evaluated as the rate of use of the biological or colectomy in the treatment group, as the rate of use of a second biological or colectomy in the control group) | 3 months | 
| Failure rate | Evaluation of the failure rate at 3, 12 and 24 months (evaluated as the rate of use of the biological or colectomy in the treatment group, as the rate of use of a second biological or colectomy in the control group) | 12 months | 
| Failure rate | Evaluation of the failure rate at 3, 12 and 24 months (evaluated as the rate of use of the biological or colectomy in the treatment group, as the rate of use of a second biological or colectomy in the control group) | 24 months | 
| Complication assessment | Complication assessment: Treatment-related serious adverse events will be compared between the two groups. The Dindo-Clavien Classification will be used within 30 days of the procedure in patientsundergoing appendectomy. For patients undergoing biologics, the cumulative rate of treatment- related serious adverse events up to 12 months will be considered. Hospitalization rates will also be assessed as a consequence of adverse events to treatment. | 30 days | 
| Complication assessment | Complication assessment: Treatment-related serious adverse events will be compared between the two groups. The Dindo-Clavien Classification will be used within 30 days of the procedure in patientsundergoing appendectomy. For patients undergoing biologics, the cumulative rate of treatment- related serious adverse events up to 12 months will be considered. Hospitalization rates will also be assessed as a consequence of adverse events to treatment. | 12 months | 
| Histological remission | Evaluation of histological remission at 3 and 12 months with the Geboes score (ranging from 0, histological remission, to 22, severe inflammatory injury). In patients undergoing appendectomy, the appendix will also be histologically evaluated with the same Geboes score in addition to the presence of PARP (peri-appendicular patches). | 3 months | 
| Histological remission | Evaluation of histological remission at 3 and 12 months with the Geboes score (ranging from 0, histological remission, to 22, severe inflammatory injury). In patients undergoing appendectomy, the appendix will also be histologically evaluated with the same Geboes score in addition to the presence of PARP (peri-appendicular patches). | 12 months | 
| Immunohistochemical evaluation | Immunohistochemical evaluation of the IgA / IgG ratio and correlation between the findings onthe appendix and the findings on colonic biopsy at 3 and 12 months. | 3 months | 
| Immunohistochemical evaluation | Immunohistochemical evaluation of the IgA / IgG ratio and correlation between the findings onthe appendix and the findings on colonic biopsy at 3 and 12 months. | 12 months | 
| Colectomy rate | Evaluation of Colectomy rate at 12, 24 and 60 months | 12 months | 
| Colectomy rate | Evaluation of Colectomy rate at 12, 24 and 60 months | 24 months | 
| Colectomy rate | Evaluation of Colectomy rate at 12, 24 and 60 months | 60 months |