Induction of Clinical Response Using Rifaximin in Crohn's Disease

Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disease
conventionally categorized into Crohn's disease (CD) and Ulcerative Colitis (UC). CD affects
nearly 630,000 people in North America with up to 50,000 new people being diagnosed every
year. It is a chronic debilitating disease characterized by abdominal pain, malnutrition,
bloody diarrhea, fistula formation, intestinal perforations and strictures, and even
extra-intestinal manifestations such as joint pains and skin rashes. Nearly 80% of people
with CD will need surgical treatment at some point in their disease process. The majority of
CD subjects are diagnosed in young adulthood thereby subjecting them to many decades of
discomfort and medical intervention.

Antibiotics have been used to treat CD with variable response rates. The basis for antibiotic
therapy is that breakdown of the integrity of the mucosal barrier in the gastrointestinal
(GI) tract leads to a heightened inflammatory response to commensurate luminal bacteria. By
changing the composition or bacterial load in the intestinal lumen, it may be possible to
alter the immune response. Ciprofloxacin (Cipro) and metronidazole (Flagyl) are the best
studied antibiotics that have shown efficacy, but the effect is temporal and long term use
can lead to serious side effects. Rifaximin is a recent FDA approved antibiotic with broad
spectrum of activity, excellent safety profile, and minimal absorption from the GI tract.
Open label and small studies in IBD subjects show response rates up to 80% in CD subjects.
These studies were limited however in that they were not randomized placebo controlled
trials.

The investigators propose to conduct a randomized placebo controlled crossover trial of
rifaximin in CD subjects to assess initial clinical response compared to placebo.

Inclusion Criteria:

- Male or female subjects, 18 to 80 years of age, inclusive, that can themselves provide
written, informed consent and authorization of use of protected health information
prior to any study-related procedures and who are, in the opinion of the
investigator(s), likely to comply with all the requirements of the study

- Subjects must have a prior diagnosis of CD established by endoscopy and clinical
parameters as determined by the investigator(s) for at least 3 months prior to
randomization

- Subjects must be able to participate in all required follow-up visits and fill out all
related documentation (e.g. symptom diary)

- Subjects currently with moderately active disease defined as a CDAI 250-450

- Concomitant medications:

- If subjects are taking sulfasalazine or 5-ASA products prior to entry, the dose
must be stable for at least 4 weeks prior to the randomization

- If subjects are on azathioprine, 6-mercaptopurine, or methotrexate, they will
have had to be on a stable dosage for at least 8 weeks

- Subjects are allowed to be on corticosteroids at a dose equivalent to 20 mg or
less of prednisone, IF the dose has been stable for a minimum of 2 weeks.
Steroids must be held stable throughout the induction portion of the study. The
maximum dose of budesonide must not exceed 9mg per day and must also have been
stable for a minimum of 2 weeks.

- No oral or intravenous antibiotics within 4 weeks prior to randomization

- No current or past use of biological treatment within 6 weeks of randomization
into study (e.g. infliximab)

- If subjects have previously been on any of the above products but are no longer
taking them, they should not have received any of the relevant therapeutic
products within 4 weeks prior to randomization

- No other experimental or non-FDA approved medications are allowed. If the subject
has previously been on an experimental therapy, they must have not received the
therapy within the prior 8 weeks prior to randomization

- Subjects on concomitant medications for CD will not be allowed to change dosages
during the study

- If subjects are at increased risk of colorectal cancer (defined as having an 8-year
history of pan-colitis or 12 year history of left sided colitis), they will need to
have undergone a colonoscopy with pan-colonic surveillance biopsies within 2 years of
the screening visit. The biopsies must be negative for dysplasia

- Female or male subjects who are surgically sterilized or who are prepared to and agree
to practice a double-barrier form of birth control from the screening visit through 30
days (females) and 30 days (males), respectively, from the last dose of study
medication. Females who are more than 12 months post-menopausal are also eligible to
participate in the study

Exclusion Criteria:

- Evidence of active infection which may include any of the following

- Febrile ( > 38.5ºC)

- Positive blood culture within 2 weeks prior to randomization

- Evidence of toxic megacolon or abscess

- Positive stool culture for enteric pathogens, pathogenic ova or parasite, or a
positive assay for C. difficile toxin at screening

- Subjects with CDAI > 450

- Any current use or use within the last 8 weeks of an investigational drug

- Current or past use (within past 12 wks) of biological treatment

- Current or use within the last 4 weeks of any oral or intravenous antibiotic

- Anticipated increased dosage of any medication to treat CD

- Anticipated need for surgery within 12 weeks

- Known obstructive diseases of the gastrointestinal system

- Medical conditions requiring in-patient hospitalization

- Proctocolectomy, total colectomy, ileostomy, or stoma

- Severe cardiopulmonary disease:

- Congestive heart failure (NYHA Class III or IV)

- Severe cardiovascular or peripheral vascular disease

- Myocardial infarction, percutaneous coronary intervention, or bypass surgery
within the past 6 months

- Significant liver disease:

- Levels of SGOT [AST], SGPT [ALT], or alkaline phosphatase > 2.5x the upper limit
of the normal range for the laboratory performing test

- History of cirrhosis

- Renal insufficiency, defined as serum creatinine > 150% of the upper limit of the
normal range for the laboratory performing the test

- Abnormal hematology parameters defined as severe anemia with hemoglobin < 8.5 g/dL
and/or white blood cell count of < 3,500/ul

- Malignancy within the past 2 years other than surgically cured skin carcinoma or
cervical dysplasia (CIN I-II)

- History of dysplasia or carcinoma of the colon

- Pregnant, lactating, or planning to become pregnant during the course of the
investigational study

- Known history of allergic reaction to rifaximin or allergy to any of the rifamycin
antimicrobial agents (which include rifampin, rifabutin, and rifapentine)