Randomized, Placebo-Controlled, Double-Blind, Multicenter Study to Determine the Efficacy and Safety of Vedolizumab in Prevention of Endoscopic Recurrence of Crohn's Disease in Patients with Ileo-colonic Surgical Resection and Ileocolonic Anastamosis : REPREVIO (recurrence prevention with Entyvio)

Postoperative recurrence of Crohn*s disease (CD) is virtually inevitable, with
more than 80 per cent of patients having endoscopic recurrence 1 year after
surgery and approximately 10 per cent of patients suffering from clinical
recurrence per year following surgery. Since the vast majority (>75 %) of CD
patients require surgery during their disease course , it is of paramount
importance to develop therapeutic interventions that alter the *natural
history* of CD recurrence in order to avoid further bowel loss and eventually
intestinal failure.
Available preventive therapies have, so far, been disappointing. While
corticosteroids have been totally ineffective, aminosalicyates and thiopurines
have had only marginal effects on the severity and incidence of postoperative
CD recurrence. Recently, however, the effects of the anti-TNF antibody
infliximab were studied in pilot trial at a single academic center. The results
were extremely encouraging in favor of anti TNF treatment and this finding led
to a larger placebo-controlled trial (Prevent) to investigate the benefits of
infliximab in the postoperative setting.
Nonetheless, prolonged treatment with anti-TNF agents, in particular infliximab
has been associated with significant toxicity and loss of response.
Furthermore, many patients that have been exposed to IFX in the past may have
developed antibodies leading to diminished biologic effects. Even without
antibodies against IFX, the risk of delayed hypersensitivity reactions after a
significant drug holiday is important.
As a consequence, it is of great value to explore alternative therapeutic
options that can be used long-term without significant toxicity and without
loss of effect. Vedolizumab (VDZ), a highly selective anti-integrin antibody,
appears to be an extremely suitable candidate for this indication. Specifically
in the earliest phases of postoperative Crohn*s disease, where inflammatory
cells are recruited into the mucosa after exposure to intestinal content, this
drug may prove to be at its maximal efficacy. In addition, the first trials
with vedolizumab in IBD are showing limited long-term toxicity which would
allow prolonged treatment.
The current proposal aims at studying the effects of vedolizumab to prevent
postoperative recurrence of CD. Similar to the first IFX trial by Rugeiro et
al., a relatively small trial would suffice to demonstrate the beneficial
effects of vedolizumab. Typically, a trial of this type would use *endoscopic*
recurrence as its primary endpoint, because it has been demonstrated repeatedly
and consistently that the endoscopic appearance in the first 1-2 years
following resection is extremely predictive of the ensuing clinical course of
CD. An endoscopic score has been developed for the purpose of prevention trial
and was shown to correlate with the clinical outcome.

The primary objective of this prospective placebo-controlled study is to assess
the ability of vedolizumab to prevent postoperative endoscopic recurrence of
Crohn*s disease in the neoterminal ileum.

A Randomized, Placebo-Controlled, Double-Blind, Multicenter Study

Vedolizumab 300 mg or placebo at week 0, 8 , 16 and 24.

The endoscopic procedure van cause abdominal discomfort and due to biopsies
there is an extreme small risk of perforation ( 1 in 10.000) of the bowel.
Blood drawing can cause discomfort , bruising and pain.

PML: Progressive mulitfocal leucoencephalopathy (PML) is a rare infection of
the brain caused by the John- Cunningham-virus (JC-virus). A lot of people are
carriers of the JC-virus, but they do not get PML. Patients with severely
impaired immune systems are more likely to develop this disease. This disease
was diagnosed in a few patients who were treated with a medication called
natalizumab (Tysabri®). The overall risk of developing PML is estimated as less
than 1 in 1,000. Up to now, no known cases of PML have been reported by
patients who have been, or are currently treated with vedolizumab . However,
development of PML symptoms in patients who are receiving vedolizumab have to
be assessed. The local investigator will assess these symptoms. In this way,
symptoms of PML can be identified early and the study treatment can be put on
hold until the (unlikely) diagnosis is confirmed.