A Randomized, Double-Blind, Placebo-Controlled Phase 4 Study to Evaluate the Efficacy and Safety of Entyvio (Vedolizumab IV) in the Treatment of Chronic Pouchitis (EARNEST)

The surgical treatment of choice for patients with ulcerative colitis (UC) is
removal of the colon followed by construction of an ileal pouch anal
anastomosis (IPAA). Inflammation of the *pouch,* commonly called pouchitis, is
the most common long-term complication in these patients. Pouchitis is a poorly
understood condition, with a reported cumulative frequency of 23% to 46% over
10 to 11 years in patients who underwent an ileoanal pouch procedure.
Importantly, none of the experimental therapies have been shown to be effective
in clinical trials. Furthermore, due to their nonspecific mechanism of action,
use of some of these therapies may place patients at risk for infection
complications. Chronic or recurrent pouchitis is often managed with long-term
antibiotic administration, with metronidazole and ciprofloxacin being the
antibiotics most often prescribed. There are presently no approved drugs for
the treatment or prevention of pouchitis in the United States or Europe. Thus,
a large unmet medical need exists in the management of refractory pouchitis.
Therefore, well-designed prospective clinical trials specific for patients with
chronic or recurrent pouchitis are needed.

Vedolizumab IV is approved for the treatment of adult patients with moderately
to severely active UC and CD in several regions, including the United States
and European Union. The current study will generate meaningful data with
vedolizumab IV in the treatment of chronic or recurrent pouchitis.

Primary Objective:
To compare the efficacy of vedolizumab IV and placebo in terms of the
percentage of subjects with chronic or recurrent pouchitis achieving clinically
relevant remission.

Secondary Objectives:
To assess the efficacy of vedolizumab IV by:
- Percentage of subjects achieving mPDAI <5 and a reduction of overall score by
>=2 points from Baseline.
- Percentage of subjects achieving PDAI <7 and a reduction of overall score by
>=3 points from Baseline.
- Time to remission (defined as a PDAI score <7 and a decrease in PDAI score of
>=3 points from Baseline).
- Percentage of subjects achieving a partial response (defined as reduction of
mPDAI score by >=2 points from
Baseline).
- Change in PDAI endoscopic subscore.
- Change in PDAI histologic subscore.
- Change in total PDAI.
- Change in Inflammatory Bowel Disease Questionnaire (IBDQ), and Cleveland
Global Quality of Life (CGQL,
Fazio Score, 3 items).

Exploratory Objectives:
- To assess the change in Robarts Histopathology Index (RHI).
- To assess change in biomarkers (fecal calprotectin and C-reactive protein
[CRP]).
- Time to relapse of pouchitis symptoms and number of relapses.

Safety Objective:
To assess the safety of vedolizumab IV in chronic or recurrent pouchitis.

Phase 4, randomized, double-blind, placebo-controlled study to evaluate the
efficacy and safety of vedolizumab 300 mg intravenous (IV) infusion during a
34-week treatment period (with last dose at Week 30) using pouch endoscopy.
Approximately 110 subjects with a proctocolectomy and ileal pouch anal
anastomosis (IPAA) for ulcerative colitis (UC) who have developed chronic or
recurrent pouchitis will be enrolled.

Chronic or recurrent pouchitis is defined as a modified Pouchitis Disease
Activity Index (mPDAI) score >=5 assessed as the average from 3 days immediately
prior to the Baseline endoscopy and a minimum endoscopic subscore of 2 (outside
the staple or suture line) with either:
(a) >=3 recurrent episodes within 1 year prior to the Screening visit, each
treated with >=2 weeks of antibiotic or other prescription therapy, or
(b) requiring maintenance antibiotic therapy taken continuously for >=4 weeks
immediately prior to the Baseline Endoscopy Visit.

Subjects will be randomized in a 1:1 ratio to either the approved UC
vedolizumab dose regimen or placebo treatment at Day 1, Weeks 2, 6, 14, 22, and
30. All subjects will receive concomitant antibiotic treatment with
ciprofloxacin 500 mg twice daily from randomization through Week 4. Efficacy
will be assessed at Week 14 and Week 34.

Group 1: Vedolizumab Intravenously 300 mg at Day 1, Weeks 2, 6, 14, 22, and 30.
Group 2: Placebo Intravenously at Day 1, Weeks 2, 6, 14, 22, and 30.

All subjects will receive ciprofloxacin 500 mg twice daily through Week 4.
Additional ciprofloxacin will be allowed, as needed, for flares after Week 14.

As of 19 November 2016, no side effects have been seen in more than 20% of
subjects of 4200 subjects who received at least 1 dose of vedolizumab in the IV
clinical trials.

Other side effects, reported in 2-9% of patients, include:
• nausea.
• fever.
• stomach pain.
• upper respiratory tract infection.
• tiredness.
• vomiting.
• low levels of red blood cells (anemia).
• cough.
• back pain.
• Bronchitis.
• flu.
• urinary tract infection.
• dizziness.
• diarrhea.
• sinus infection.
• flu-like illness.
• rash.
• sore throat.
• itching.
• swollen ankles.
• pains in arms or legs.
• stomach flu.
• an infected cavity filled with pus near the anus or rectum (anal abscess).
• small tunnel which connects an infected gland inside the anus to an opening
on the skin around the anus (anal fistula).

Since many of these symptoms are commonly reported in patients with UC or CD,
it is unclear which may be related to vedolizumab, which may be related to the
underlying illness, and which may have occurred by chance.

In addition to the risks listed above, vedolizumab and study procedures may
have unknown risks. There is always the possibility that the patient will have
a side effect that is currently unknown or not expected.

As with any drug, allergic reactions may occur. If you have a very bad allergic
reaction, you could die. Some things that happen during an allergic reaction
are:
• a rash (reddening or blistering of the skin).
• Difficulty breathing.
• wheezing when you breathe.
• sudden drop in blood pressure.
• swelling around the mouth, throat, or eyes.
• fast pulse.
• sweating.


There is a possibility of a greater chance of getting an infection, difficulty
fighting off an infection, or reactivation of an old infection.

There is a possibility that treatment with vedolizumab could cause reactivation
of an old infection such as tuberculosis (TB).

Patients with inflammatory bowel disease have an increased risk for colon
cancer, and some of the drugs that are currently being used for treating CD and
UC can increase the risk of certain cancers. Less than 1% of patients who
received vedolizumab as part of the UC and CD studies were diagnosed with
cancer, including colon cancer. It is also not known whether the events of
cancer happened by chance or whether vedolizumab was a contributing factor.

No cases of Progressive Multifocal Leukoencephalopathy (PML), a serious and
sometimes fatal brain infection, have been reported in people receiving
vedolizumab. There is currently not enough information to know if vedolizumab
will increase the risk of PML and a risk of PML cannot be ruled out.

Deaths have occurred in patients participating in vedolizumab clinical trials.
The details of these cases were reviewed by an Independent Safety Monitoring
Board that oversaw the safety of these patient studies. No changes in
monitoring of the trials were recommended by the Board.