Evaluating the Combined Effect of Vedolizumab and Semi-Vegetarian Diet on Ulcerative Colitis.

Specific Aims:

Hypothesis to be investigated: the integrated treatment effect of controlling inflammatory
process through vedolizumab in active UC patients can be synergistically enhanced with a
structured semi-vegetarian dietary intervention

Background and Significance:

Research of fecal microflora in UC has shown its influential role on the disease
pathogenesis. In UC patients, the adaptive immune system is dysregulated and hyper-reactive
to the commensal intestinal microflora in susceptible individuals and the diversity of
intestinal flora decreases, called dysbiosis, by 30% to 50%. For the treatment of moderate to
severe UC, tumor necrosis factor (TNF) antagonists, although efficacious but predispose
patients to serious infection. Vedolizumab, a humanized monoclonal antibody that specifically
recognizes the α4β7 heterodimer, selectively blocking the migration of leukocytes into
inflamed intestinal tissue, has been shown to achieve clinical response and clinical
remission in patients with moderate to severely active UC (clinical response 47% vs. 25%
(placebo) at week 6 and clinical remission 42% vs. 16% (placebo) at week 52) in patients with
moderate to severely active UC. In epidemiological study, western diet characterized with
high in animal fat and low in fruits and vegetables has been found associated with an
increased risk of IBD. In murine models, diets high saturated animal fats has been shown to
be associated with dysbiosis, increased intestinal permeability, decreased mucus layer, and
increased release of pro-inflammatory cytokines. Additive in processed food, such as
emulsifiers, has been recently found with impact on the mouse gut microbiota promoting
colitis and metabolic syndrome. Enteral nutritional therapy has been demonstrated effective
in pediatric IBD patients; however, the application to adult IBD patients has not been widely
accepted partly because of compliance and adherence to the diet. Recently, non-enteral
dietary interventions, such as semi-vegetarian diet, specific carbohydrate diet, and IBD
exclusion diet, have gained attention based on small non-randomized trials. In a small
prospective clinical trial in CD patients, semi-vegetarian diet was well tolerated and 93%
(16 out of 17) of patients remained in clinical remission, compared with 33% (2 out of 6
patients) in an omnivorous diet group, at 2 years. A well-designed randomized clinical trial
using a structured dietary intervention, which integrates the merits of previously proposed
diets, is warranted, especially in conjunction with the current standard of care (e.g.
vedolizumab) and the novel normalization of dysbiosis through structured semi-vegetarian
dietary intervention.

Research Design and Methods:

Study Design or Overview:

This study is a pilot study of evaluating the synergistic effect of vedolizumab in
conjunction with structured semi-vegetarian dietary intervention on the treatment of active
UC patients who will be under the treatment of Vedolizumab. Subjects will be screened at
outpatient clinic visit appointments and interested, qualified subjects will be consented and
offered participation in this trial. Once consent has been obtained, baseline values will be
established and subjects will begin treatment. A final visit for evaluation and collection of
lab samples will be conducted at the end of the study at week 14.

Investigative Agent: vedolizumab in conjunction with semi-vegetarian dietary intervention:

Single interventional group: vedolizumab (300mg) IV infusions at week 0, 2, 6, 14 (as current
standard of care) and concurrently on structured semi-vegetarian diet Duration of Therapy: 14
weeks; Duration of time on study: 14 weeks Structured semi-vegetarian dietary intervention
(see supplementary material): Eligible study subjects will be counseled with a registered
dietician and complete a Food Frequency Questionnaire to record and monitor the dietary
pattern that the patient has at different time points, including prior to UC flare, current
diet, diet during and after study.

The patient will be on a structured semi-vegetarian diet described below: (Specific recipes
and food preparation will be provided during the counselling session with a dietician).

- Gradually increase calories, up to 25-30 kcals/kg/day

- Gradually add fiber (ex. white rice 2-5 days, then mixed rice 70% white to 30% brown
rice) in an instructed regimen

- Daily vegetables, fruits, legumes, potatoes, probiotic food (miso, pickled vegetables),
plain yogurt

- Encourage no smoking, regular physical exercise, moderate to no use of alcohol,
regularity of meals, no snacking

- Foods to strictly limit/avoid: bread, cheese, margarine, fast foods, carbonated
beverages, highly processed foods

- Diet excludes completely: Animal fat and Trans saturated fats, red meat and processed
meat, sugar, emulsifiers (CMC, PS-80)

Sample Size:

Since this is a pilot study, no formal study power and sample size calculation is needed. The
investigators plan to recruit 10 study subjects for the single interventional group.

Data Collection:

Clinical Assessments:

The primary outcome: Clinical response at week 6 (which is defined as ≥3 improvement in Mayo
score (see page 4 for reference table), and a decrease of at least 30% from the baseline
score).

The secondary outcome: Clinical response at week 14(which is defined as ≥3 improvement in
Mayo score (see page 4 for reference table), and a decrease of at least 30% from the baseline
score).

The investigators will also collect stool samples before (week -1) and after (week 14) the
dietary interventions for microbiome study.

Data Analysis:

Univariate descriptive statistics and frequency distributions will be calculated, as
appropriate for all variables including the primary and secondary outcomes. Baseline values
for demographic, clinical, and outcome variables (primary and secondary) will be tabulated
for the single interventional group. Primary outcome (clinical response rate at week 6) of
this pilot study result will be non-analytically compared to the previously reported 47.1%
from the previous clinical trial of vedolizumab alone in moderately to severe UC patients

Feasibility and Time Frame:

This is a pilot study and 10 study subjects will be enrolled by the end of 2017. Based on the
current volume of eligible patients at the institution, it will be expected to complete the
recruitment in 3 to 4 months. The completion of this study is estimated to be within 4
months.

Inclusion Criteria:

- 18 years or older

- diagnosed with active UC (with a Mayo score ≥4, with an endoscopic Mayo Clinic score
≥1, and disease that extended 15 cm or more from the anal verge)

- failed with prior mesalamine therapy

- Patients who were previously exposed to mesalamine or steroids will have a 30-day
washout period before being enrolled

- Patients who were previously exposed to tumor necrosis factor (TNF) antagonists will
have a 60-day washout period before being enrolled

- For patients who were previously exposed to glucocorticoids, immunosuppressive
medications (i.e., azathioprine, 6-mercaptopurine, or methotrexate), or TNF
antagonists, a documentation of unsuccessful previous treatment (i.e., lack of
response or unacceptable adverse events) is required

- A diagnosis of UC confirmed by biopsy obtained at the index colonoscopy or flexible
sigmoidoscopy.

Exclusion Criteria:

- Patients who have been on semi-vegetarian diet before the trial will be excluded

- pregnancy or lactation

- an unstable or uncontrolled medical disorder

- an anticipated requirement for major surgery

- history of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch,
Koch pouch, or ileostomy for UC, or planned bowel surgery

- unable to give informed consent

- current diagnosis of fulminant colitis or toxic megacolon, abdominal abscess,
symptomatic colonic stricture, stoma

- disease limited to the rectum (ulcerative proctitis)

- current total parenteral nutrition

- positive Clostridium difficile stool assay

- history of an infection requiring intravenous antimicrobial therapy within 1 month or
oral antimicrobial therapy within 2 weeks

- history of listeria, histoplasmosis, chronic or active hepatitis B or C infection,
human immunodeficiency virus, immunodeficiency syndrome, untreated tuberculosis

- history of central nervous system demyelinating disease

- history of malignancy other than a successfully treated nonmetastatic cutaneous
squamous cell or basal cell carcinoma or localized carcinoma in situ of the cervix, or
evidence of dysplasia or malignancy on the screening colonoscopy/flexible
sigmoidoscopy with biopsy

- Any of the following laboratory abnormalities during the screening period:

1. Hemoglobin level <8 g/dL

2. WBC count <3 × 109/L

3. Lymphocyte count <0.5 × 109/L

4. Platelet count <100k/L or >1200k/L

5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper
limit of normal (ULN)

6. Alkaline phosphatase >3 × ULN, g) Serum creatinine >2 × ULN

- Antibiotic use within past 14 days; Probiotics use within past 7 days