EUS Evaluation of Perianal and Peri-rectal Fistulizing Crohn's Disease With CERTOLIZUMAB Treatment

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to assess perianal and perirectal fistula healing (complete closure) based on endoscopic ultrasound (EUS) evaluation at 3 months and by PDAI (Pouchitis Disease Activity Index) and Fistula Drainage assessment by 6 months, showing no fistula (new or recurrence) in treatment of Crohn's' disease patient with Certolizumab (Cimzia).

Detailed Description
-----------------
Peri-anal ( located around the anus, the opening of the rectum to the outside of the body) fistulae are a major complication of Crohn's disease and occur in almost 30% of patients. Patients with perianal fistulae suffer from severe pain, perianal drainage, and have significant impairment of quality of life. Initial studies of Infliximab and Adalimumab in patients with CD have shown perianal fistula healing with these medications. Infliximab and Adalimumab are medications which reduce the effects of a substance in the body that can cause inflammation. They are also used to treat Crohn's disease after other drugs have been tried without successful treatment of symptoms. Although no studies have specifically evaluated Certolizumab (Cimzia) treatment in fistulizing Crohn's disease, there is evidence to its efficacy. Certolizumab reduces the effects of a substance in the body that can cause inflammation. Certolizumab is used to treat the symptoms of Crohn's disease after other drugs have been tried without successful treatment of symptoms. Studies with a small number of patients who use Cimzia did not show any significant effect on fistula closure. However, in a larger subgroup of patients with fistulae in PRECiSE 2 43.3% of those who received 3 induction injections of certolizumab followed by placebo, and 53.6% of those on certolizumab 400mg continuous treatment had fistula closure defined as no drainage on gentle compression of at least 50% of open fistulae at any 2 consecutive visits, at least 3 weeks apart. Perianal disease activity is usually monitored clinically. In clinical studies, two evaluation methods have been used in attempts to unify the definition of perianal disease activity. One method is the perianal Crohn's disease activity index (PDAI) which involves questions regarding discharge, pain/ restriction of activities, restriction of sexual activity, type of perianal disease, degree of induration (with scores >/=5 indicating active disease, with decrease in PDAI of 2 or more points indicates improvement, and consider 0 as healed. PDAI scale (Pouchitis Disease Activity Index). This scale analyzes and summarizes different criteria: clinical, endoscopic and histological. Among clinical symptoms, an important factor is the number of stools exceeding the post-operative average, bleeding, re-occuring stomachaches, as well as body temperature above 37.8°C or 100°F. Pouchitis is a term to describe inflammatory changes in the pouch created from the lower part of the ileum. The patients suffer from high body temperature, stomachaches and watery stools with small amounts of mucus, blood and soiling. An exam based technique, used in the Precise trials is the Fistula Drainage Assessment indicating improvement or remission with closure of individual fistulae defined as no fistula drainage despite gentle finger compression, improvement defined as a decrease from baseline in the number of open draining fistulae of greater than or equal to 50 percent for at least 2 consecutive visits (i.e. at least 4 weeks), and remission defined as closure of all fistulae that were draining at baseline for at least 2 consecutive visits (i.e., at least 4 weeks). However both have not been validated, and the response levels are usually evaluated several months into treatment. If another method could provide early assessment / predictors of healing, it could make the decision for the treatment of the gastroenterologist as well as the patient, easier to determine if they should continue the biologic or stop. Studies have evaluated the use of endoscopic ultrasound (EUS) to follow fistula assessment and healing, but none have specifically assessed this in response to certolizumab treatment. EUS is increasingly used and has been found to be equally accurate in the evaluation of perianal fistulae compared to MRI of the pelvis. An accurate assessment and classification of fistulae can facilitate further management including surgical planning, further medical treatment, or a combination of both. EUS can evaluate for fistulae as well as abscesses and the relation to the anatomic landmarks of the rectum including the sphincter muscles as well as adjacent organs such as vagina and the bladder. EUS has the advantage of being more convenient for the patient than an MRI. An MRI can take a long duration, can cause anxiety in those that are claustrophobic, and is expensive. EUS is usually performed with sedation and by the treating physician allowing a more personal evaluation of the fistula anatomy and correlation of endoscopic mucosal findings. Thus, we propose to evaluate the use of certolizumab in Crohn's disease patients with peri-anal and peri-rectal fistulae (an abnormal passage that leads from an abscess or hollow organ or part to the body surface or from one hollow organ or part to another) and to assess their response and healing (A perirectal abscess is a collection of pus in the deep tissues surrounding the anus. Perirectal and perianal abscesses are thought to develop from the glands surrounding the anus) based on EUS findings. This study can help provide recommendations on fistula classification of EUS and use this classification to provide EUS - based early predictors of response of treatment with certolizumab.

Official Title
-----------------
EUS Evaluation of Perianal and Peri-rectal Fistulizing Crohn's Disease With CERTOLIZUMAB Treatment

Conditions
-----------------
Crohns Disease

Intervention / Treatment
-----------------
* Drug: Certolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Conventional therapy here indicates non-biologic therapy. Study subjects would have failed conventional and standard regimens of treatment such as immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) or mesalamines or corticosteroids. Certolizumab is actually an approved regimen of treatment for Crohn's disease as patients with perianal fistulas fall under those with moderately to severely active disease. It is not an off-label indication, therefore would not require an IND. The study goal is to look at EUS as a tool to determine how fistula healing occurs with the use of certolizumab which is one of the biologic therapies used to treat fistulizing Crohn's disease. Crohn's disease patients with peri-anal or peri-rectal fistulizing disease. Moderate to severe Crohn's disease patients between the ages of 18 and 70 years with active peri-anal or peri-rectal fistula. Exclusion Criteria: Pre-existing fistula improving on current medical therapy. Contraindication to certolizumab use. Prior use of anti-TNF-alpha.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Certolizumab<br>Subjects will take the study drug certolizumab for 8 weeks. They will undergo a endoscopy before study drug and then again after study is complete. The study doctor will be looking for complete closure of the peri-anal fistula identified at visit 1 after the use of certolizumab based on and endoscopic ultrasound (EUS). | Drug: Certolizumab<br>* Certolizumab 200mg-400mg subcutaneous every 2 weeks for 8 weeks.<br>* Other names: Cimzia;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The response rate | The primary objective of this study is to assess perianal and perirectal fistula healing (complete closure) based on endoscopic ultrasound (EUS) evaluation at 3 months and by PDAI (Pouchitis Disease Activity Index) and Fistula Drainage assessment by 6 months, showing no fistula (new or recurrence) on treatment of Certolizumab (Cimzia) in Crohn's's disease patient s. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fistula healing based on EUS | The secondary objectives: 1. To define an Endoscopic Ultrasound (EUS)-based classification system which will compare and analyze perianal and perirectal fistulizing (abnormal opening between two hollow organs) in Crohn's disease. 2. To compare the EUS classification to PDAI and Fistula Drainage Assessment scores. 3. To determine EUS-based early predictors which can be summarized by the findings/results of the EUS procedure of fistula healing with Certolizumab (Cimzia) treatment. | 6 months |