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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-Blinded, Active-Controlled, Dose Ranging Study of CB-183,315 in Patients With Clostridium Difficile Infection.

Conditions
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Clostridium Difficile Infection, Diarrhea

Intervention / Treatment
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* Drug: CB-183,315
* Drug: Placebo
* Drug: Vancomycin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CB-183,315, 125 mg<br>125 milligrams (mg) CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days. | Drug: CB-183,315<br> <br> Drug: Placebo<br> <br> |
| Experimental: CB-183,315, 250 mg<br>250 mg CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days. | Drug: CB-183,315<br> <br> Drug: Placebo<br> <br> |
| Active Comparator: Vancomycin, 125 mg<br>125 mg vancomycin administered orally four times a day for 10 days. | Drug: Vancomycin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Clinical Response Outcome of Clostridium Difficile Infection Cure at the End of Study Treatment | The number of participants with an Investigator-assessed clinical response of cure is presented. The information to assess clinical response was collected at any time up to and including Day 19. | Baseline (Day 0) through Study Day 19 | 
| Number of Participants With a Clinical Response Outcome of Failure or Unable to Evaluate at the End of Study Treatment | The number of participants with investigator assessed clinical response of failure or unable to evaluate is presented. Clinical response was determined by the participant's condition on the second day following the last dose of study medication, unless considered a treatment failure. Treatment failures were assessed whenever they occurred and were carried forward to the end-of-treatment (EOT). The information to assess clinical response was collected at any time up to and including Day 19. | Baseline (Day 0) through Study Day 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Recurrence of Clostridium Difficile Infection Through the 4-week Follow-up Period | The number of participants with a recurrence of CDI is presented along with the number of participants without a recurrence and who were unable to be evaluated. Participants with a favorable outcome at the EOT (cure) were evaluated for recurrence of CDI. Only subjects deemed a cure at EOT were assessed for recurrence. This is the denominator used for all percentages. If diarrheal symptoms returned, participants were asked to indicate the number of unformed bowel movements (UBM) they had and have an additional C. difficile toxin test. The information to assess recurrence in participants who were deemed a cure at EOT was collected at any time during the 4-week Follow-up Period (FUP). | Study Day 10 up to Study Day 40 | 
| Number of Participants With a Clinical Response Outcome at the End of Study Treatment With and Without Infection Caused by C. Difficile BI/NAP1/027 Strain at Baseline | The number of participants with investigator assessed clinical response of cure, failure or unable to evaluate is presented and shown separately for participants with and without infection caused by C. difficile BI/NAP1/027 strain as determined at baseline. Clinical response was determined by the participant's condition on the second day following the last dose of study medication, unless considered a treatment failure. Treatment failures were assessed whenever they occurred and were carried forward to the EOT. The information to assess clinical response for infection caused by C. difficile BI/NAP1/027 strain at Baseline was collected at any time up to and including Day 12. Strain at Baseline=SAB | Baseline (Day 0) through Study Day 12 | 
| Number of Participants With a Recurrence of Clostridium Difficile Infection at the End of Study Treatment With and Without Infection Caused by C. Difficile BI/NAP1/027 Strain at Baseline | The number of participants with and without infection caused by C. difficile BI/NAP1/027 strain as determined at baseline with a recurrence of CDI is presented along with the number of participants without a recurrence and who were unable to be evaluated. Participants with a favorable outcome at the EOT (cure) were evaluated for recurrence of CDI. If diarrheal symptoms returned, participants were asked to indicate the number of UBM they had and have an additional C. difficile toxin test. The information to assess recurrence in participants who were deemed a cure at EOT was collected at any time during the 4-week FUP. Strain at Baseline=SAB. | Study Day 10 up to Study Day 40 | 
| Median Time to Resolution of Diarrhea | The median time to resolution of diarrhea is presented for evaluable participants in each treatment group. The time in days from the start of treatment (time of first dose of study drug) to resolution (time of the last UBM on the day before the first of 2 consecutive days of < 4 UBMs and sustained through the second day following the last dose of study drug). | Baseline (Day 0) through Study Day 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDI, Clostridium difficile Infection, Diarrhea