Study of CB-183,315 in Patients With Clostridium Difficile Infection

Inclusion Criteria:

To be eligible for enrollment, a subject must meet all of the following criteria prior to any study related procedures:

1. Informed Consent obtained and signed;
2. Age ≥ 18 years;

3. If female, subject is non-lactating, and is either:

   • Not of childbearing potential, defined as postmenopausal for at least one year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy;
   • Of childbearing potential and is practicing the barrier method of birth control along with one of the following methods: oral or parenteral contraceptives for three months prior to study drug administration, a vasectomized partner, or abstinence from sexual intercourse.
4. Established non-severe or severe CDI (after DMC review) with a positive stool test for toxin A and/or B within 72 hours prior to first dose of study drug; Note: Patients with severe C. difficile infection must not be enrolled in the beginning of the study. Severe patients can only be enrolled after written notification by the DMC Chair has been received by the Sponsor.

Exclusion Criteria:

A subject will not be enrolled if s/he meets any of the following criteria:

1. Female and pregnant or lactating;
2. Toxic megacolon and/or known small bowel ileus;
3. Received treatment with intravenous immune globulin (IVIG) within 30 days prior to the first dose of study drug;

4. Antibacterial therapy specific for current CDI:

   • Received more than 24 hours of oral/IV metronidazole for the current episode of CDI prior to first dose of study drug unless patient received at least 3 days of oral/IV metronidazole, and is considered a failure.
   • Received more than 24 hours of oral vancomycin for the current episode of CDI prior to first dose of study drug.
   • Received more than 24 hours of any other antibacterial therapy specific for current CDI within 14 days prior first dose of study drug, unless considered a failure.
5. Patients with more than 2 episodes of CDI within 90 days (i.e., patients can be enrolled with their 1st recurrence/2nd episode);
6. Major GI surgery (i.e. significant bowel resection) within 3 months of enrollment (this does not include appendectomy or cholecystectomy);
7. History of prior inflammatory bowel disease: ulcerative colitis, Crohn's disease, or microscopic colitis;
8. Unable to stop loperamide, diphenoxylate, and cholestyramine during the duration of the study;
9. Unable to stop opiate treatment, unless on a stable dose as of onset of diarrhea and no change in dose planned for the duration of the study;
10. Known positive stool cultures for other enteropathogens, including but not limited to Salmonella, Shigella and Campylobacter;
11. Known stool studies positive for ova and/or parasites;
12. Known intolerance or hypersensitivity to daptomycin and/or vancomycin;
13. Poor concurrent medical risks with clinically significant co-morbid disease such that in the opinion of the Investigator the patient should not be enrolled;
14. Received an investigational drug or participated in any experimental procedure within 1 month prior to study entry;
15. Previously enrolled in this study;
16. Received an investigational vaccine against C. difficile;
17. Subjects with known Hepatitis B or Hepatitis C who have ALT or AST >2.5 X ULN and/or Bilirubin > 1.5 X ULN;
18. HIV positive, unless controlled (i.e., on triple therapy) and with a CD4 >200 cells/mm3;
19. Anticipated that systemic antibacterial therapy for a non-CDI infections will be required for >7 days after start of study therapy;
20. Concurrent therapy with daptomycin;
21. Unable to discontinue Saccharomyces or similar probiotic;
22. Known active IV drug or alcohol abuse;
23. Concurrent intensive chemotherapy, radiotherapy or biologic treatment for active malignancy (may only be enrolled after consultation with Medical Monitor);
24. Unable to comply with the protocol requirements;
25. Any condition that, in the opinion of the Investigator, might interfere with study objectives;
26. Life expectancy is less than 6 weeks.

Additional Exclusions for Subjects with Severe CDI

In addition to the criteria listed above, a subject who meets the definition of severe CDI will not be enrolled if the subject meets any of the following criteria:

1. Age >80;
2. Hypotension, defined by sustained systolic blood pressure <90 mmHg, or need for vasopressors to maintain blood pressure;
3. Abdominal rebound tenderness on examination;

4. Acute kidney insufficiency defined by:

   • oliguria (< 20 cc urine output per hour over a 4 hour period not responsive to attempts to increase renal perfusion) OR
   • non-perfusion (e.g. pre-renal) related azotemia with initial creatinine (Study Baseline) > 2.5 mg/dL and BUN >40 mg/dL with no prior history of chronic kidney disease;
5. Unable to tolerate oral medications due to persistent vomiting;
6. WBC > 30,000/mm3.