Award Title: MEErKAT  MEsenteric Excision and Kono-s Anastomosis Trial
Funder: Medical Research Council

Abstract: Crohn’s is a disease that makes the bowel red, swollen and painful.  It is a chronic disease.  This means that it is ongoing and lasts a life time, although people may have times when they are well and times when symptoms are more active. Some people get few flare-ups. Other people may have really bad and long lasting symptoms. At present there is no cure for Crohn’s, but drugs can treat the symptoms.  In some people the drugs do not work or stop working and these people may need surgery.  Whilst surgery can also stop symptoms for a long time, the disease can return. Further drugs and even further surgery may be needed. _x000D_
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Many surgeons feel that the way the bowel and the tissue containing the blood and other vessels supplying the bowel (the mesentery) is removed and the way the healthy bowel ends are re-joined  can affect the chances of getting further disease.   Two changes to the way surgeons operate have been proposed.  One involves taking out more of the mesentery and the other involves doing another type of bowel join.  This is known as the Kono-S join.  There are many fans of these recent surgical changes and we know that they are safe.  But we need to test that they are better than the usual method in stopping further disease. _x000D_
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So that we can test this we want to ask people who need surgery for their Crohn’s disease if they would let us carry out one or both of these methods.  We will then see if they have made the chances of further disease less one year later.  The type of surgery a person has will be decided by chance.  People would be checked as is usual by speaking to a doctor and having a telescopic camera test or colonoscopy through the back passage  to look at the bowel join.  _x000D_
We also need to see why these new methods may work.  Some clues may be found by looking at those who get further disease after surgery and seeing what part of the join the disease has come back to.  This can be done with the telescopic camera so long as the bowel is marked with a small tattoo at the time of the surgery.  We use these tattoos all the time when doing telescopic camera tests so we know they are safe.  The tattoo will only be seen if you look into the bowel. To try and understand what causes the different outcomes between methods, we will also do blood tests and take samples from different bowel areas before and after surgery to see how the immune system - which drives disease in Crohn's - is altered after the different operations._x000D_
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We have asked a patient panel to see if they think this is a good way to see if the new methods work. They have helped us to put this test together and are happy that it is safe and the right thing to do.   They will also help us to make sure  we  let other doctors and surgeons know the results of the study.

Lay Abstract: DESIGN_x000D_
Multicentre, superiority, 2×2 factorial, randomized, open-label trial with a minimum one-year follow-up. _x000D_
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SETTING_x000D_
12 UK NHS hospitals._x000D_
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POPULATION_x000D_
People undergoing ileocaecal resection for primary/recurrent Crohn’s disease where an anastomosis is carried out. Post operative medical treatment will be in line with the recommendations from the BSG guidelines._x000D_
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INTERVENTIONS_x000D_
Participants will be randomised (1:1:1:1) to one of four groups: (1) Kono-S + radical mesenteric resection; (2) Kono-S + close mesenteric resection; (3) Standard anastomosis + radical mesenteric resection; (4) Standard anastomosis + close mesenteric resection. A mechanistic component will determine in those that develop endoscopic recurrence, the locality and mechanism of that recurrence. _x000D_
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OUTCOMES._x000D_
Primary outcome_x000D_
Time to endoscopic recurrence (after a minimum of 12 months and maximum of 3 years follow-up) using Rutgeert’s score (>/=i2)._x000D_
Secondary outcomes_x000D_
1.	Incidence of severe endoscopic recurrence (Rutgeert’s score >/=i3); _x000D_
2.	Symptomatic recurrence at 12 months and at the end of the trial; _x000D_
3.	Time to recurrence for all groups; _x000D_
4.	Surgical recurrence at a minimum of 12 months and a maximum of three years; _x000D_
5.	Radiological and surgical anastomotic leak as defined by the latest consensus; _x000D_
6.	Other complications for each intervention; _x000D_
7.	Mesenteric disease activity index. _x000D_
Mechanistic outcomes_x000D_
1.	Locality of recurrence_x000D_
2.	Degree and anastomotic locality of peripheral blood mucosal and/or mesenteric fibrocytes and immune factors especially T cell clonality._x000D_
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SAMPLE SIZE_x000D_
We require 308 patients (77 per group; 154 per group for the factorial design) for 90% power; 5% (two-sided) significance, reduction in 1-year endoscopic recurrence from 50% to 30% (hazard ratio 0.515), 104 recurrences, surgeon effects (12 sites, 2 surgeons, ICC 0.01) and 5% attrition._x000D_
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PROJECT TIMETABLE _x000D_
M1-8 set-up; M9-20 internal RCT pilot, M21 stop/go assessment, M21-38 RCT main trial recruitment, M39-50 follow-up only; M51-56: closedown and analysis. _x000D_
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ELIGIBILITY CRITERIA_x000D_
People aged 18-75 years with Crohn’s Disease who have been clinically assessed as appropriate for ileocaecal resection and anastomosis. Exclusion criteria include those with markedly extensive inflammation affecting the vascular root of the mesentery seen on imaging or at operation; undergoing  stoma formation; contraindication to subsequent colonoscopy; inability to consent, pregnancy._x000D_
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MECHANISTIC SUBSTUDY_x000D_
The locality of recurrence will be investigated using endoscopic assessment of mucosa relative to mucosal tattoos placed at the time of operation. The degree and anastomotic locality of different fibrocytes and immune cells, focussing on mucosal T cell clonality and exhaustion, especially T cells with CD8 gene expression, will be compared before and after each intervention utilising flow cytometry, multiplex PCR and sequencing and qPCR. _x000D_
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COMPLEMENTARY SKILLS_x000D_
Clinical, methodological, statistical, immunological skills + patient experience.

Research Activity Codes: 6.4 SURGERY
Health Categories: ORAL AND GASTROINTESTINAL