Study of CB-183,315 in Participants With Clostridium Difficile Infection
Condition: Clostridium Difficile Infection; Diarrhea
MeSH terms: Infections; Communicable Diseases; Clostridium Infections; Diarrhea
Intervention: CB-183,315; Placebo; Vancomycin
Intervention MeSH terms: Vancomycin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 210.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: CDI; Clostridium difficile Infection; Diarrhea

Summary:

      This is a randomized, double-blind, single-placebo, active-controlled, dose ranging parallel
      group design with 3 arms. Two dose regimens of CB-183,315 dosed twice daily will be compared
      with the active comparator oral vancomycin (125 milligrams (mg ) four times daily).
      Participants with diarrhea at risk for Clostridium difficile infection (CDI) [for example,
      received prior or concomitant antibiotic(s)] will be identified and tested for C. difficile
      toxin in stool using an enzyme immunoassay (EIA), or polymerase chain reaction (PCR) per the
      usual standard of care. Eligible participants will be consented, undergo baseline
      evaluations, and will be randomized in a blinded fashion to one of 3 treatment arms.

      Participants will be randomized to receive either 125 mg CB-183,315 twice daily alternating
      with placebo tablets twice daily, 250 mg CB-183,315 twice daily alternating with placebo
      tablets twice daily or 125 mg oral vancomycin four times dailyover a period of 10 days in a
      1:1:1 fashion.
    

Eligibility criteria:

        To be eligible for enrollment, a participant must meet all of the following criteria prior
        to any study related procedures:

          -  Informed Consent obtained and signed

          -  Age ≥ 18 years

          -  If female, participant is non-lactating, and is either:

               -  Not of childbearing potential, defined as postmenopausal for at least 1 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 3
                  months prior to study drug administration, a vasectomized partner, or abstinence
                  from sexual intercourse

          -  Established non-severe or severe CDI (after Data Monitoring Committee [DMC] review)
             with a positive stool test for toxin A and/or B within 72 hours prior to first dose of
             study drug.

        Exclusion Criteria:

        A participant will not be enrolled if s/he meets any of the following criteria:

          -  Female and pregnant or lactating

          -  Toxic megacolon and/or known small bowel ileus

          -  Received treatment with intravenous (IV) immune globulin within 30 days prior to the
             first dose of study drug

          -  Antibacterial therapy specific for current CDI or that may be effective for CDI even
             if given for a different indication:

               -  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 oral/intravenous metronidazole OR any other
                  therapy specific for the current episode of CDI immediately prior to first dose
                  of study drug unless the participant received at least 3 days of such therapy,
                  and is considered a treatment failure for CDI.

               -  Received more than 24 hours of oral/intravenous metronidazole for any other
                  indication in the 3 days prior to first dose of study drug.

          -  Participants with more than 2 episodes of CDI within 90 days (that is, participants
             can be enrolled with their 1st recurrence/2nd episode)

          -  Major gastrointestinal (GI) surgery (that is, significant bowel resection including
             total colectomy with ileostomy) within 3 months of enrollment (this does not include
             appendectomy or cholecystectomy)

          -  History of prior inflammatory bowel disease: ulcerative colitis, Crohn's disease, or
             microscopic colitis

          -  Unable to stop loperamide, diphenoxylate, and cholestyramine during the duration of
             the study

          -  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

          -  Known positive stool cultures for other enteropathogens, including but not limited to
             Salmonella, Shigella and Campylobacter

          -  Known stool studies positive for ova and/or parasites

          -  Known intolerance or hypersensitivity to daptomycin and/or vancomycin

          -  Poor concurrent medical risks with clinically significant co-morbid disease such that
             in the opinion of the Investigator the participant should not be enrolled

          -  Received an investigational drug or participated in any experimental procedure within
             1 month prior to study entry

          -  Previously enrolled in this study

          -  Received an investigational vaccine against C. difficile

          -  Participants with known Hepatitis B or Hepatitis C who have alanine aminotransferase
             or aspartate aminotransferase > 2.5 times the upper limit of normal (ULN) and/or
             bilirubin > 1.5 times the ULN

          -  Human immunodeficiency virus positive, unless controlled (that is, on triple therapy)
             and with a CD4 > 200 cells per millimeter cubed (cellsmm˄3)

          -  Anticipated that systemic antibacterial therapy for a non-CDI infections will be
             required for >7 days after start of study therapy

          -  Concurrent therapy with daptomycin

          -  Unable to discontinue Saccharomyces or similar probiotic

          -  Known active IV drug or alcohol abuse

          -  Concurrent intensive chemotherapy, radiotherapy or biologic treatment for active
             malignancy (may only be enrolled after consultation with Medical Monitor)

          -  Unable to comply with the protocol requirements

          -  Any condition that, in the opinion of the Investigator, might interfere with study
             objectives

          -  Life expectancy is less than 6 weeks

        Additional Exclusions for Participants with Severe CDI

        In addition to the criteria listed above, a participant who meets the definition of severe
        CDI will not be enrolled if the participant meets any of the following criteria:

          -  Age > 80

          -  Hypotension, defined by sustained systolic blood pressure < 90 millimeters of mercury
             (mmHg), or need for vasopressors to maintain blood pressure

          -  Abdominal rebound tenderness on examination

          -  Acute kidney insufficiency defined by:

               -  oliguria (< 20 cubic centimeter [cc] urine output per hour over a 4 hour period
                  not responsive to attempts to increase renal perfusion) or

               -  non-perfusion (for example, pre-renal) related azotemia with initial creatinine
                  (Baseline) > 2.5 milligrams per deciliter (mg/dL) and blood urea nitrogen (BUN) >
                  40 mg/dL with no prior history of chronic kidney disease

          -  Unable to tolerate oral medications due to persistent vomiting 2. White blood cell
             (WBC) count > 30,000/mm˄3