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

Phase 2

Completed

Conditions: Diarrhea
Clostridium Difficile Infection

Interventions: Drug: CB-183,315
Drug: Vancomycin
Drug: Placebo

Registration Number: NCT01085591

Lead Sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 210

Inclusion Criteria

Not provided

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CB-183,315, 125 mg	Placebo	125 milligrams (mg) CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days.
CB-183,315, 250 mg	Placebo	250 mg CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days.
CB-183,315, 125 mg	CB-183,315	125 milligrams (mg) CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days.
CB-183,315, 250 mg	CB-183,315	250 mg CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days.
Vancomycin, 125 mg	Vancomycin	125 mg vancomycin administered orally four times a day for 10 days.

Primary Outcome Measures

Name	Time	Method
Number of Participants With a Clinical Response Outcome of Clostridium Difficile Infection Cure at the End of Study Treatment	Baseline (Day 0) through Study Day 19	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.
Number of Participants With a Clinical Response Outcome of Failure or Unable to Evaluate at the End of Study Treatment	Baseline (Day 0) through Study Day 19	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With a Recurrence of Clostridium Difficile Infection Through the 4-week Follow-up Period	Study Day 10 up to Study Day 40	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).
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	Baseline (Day 0) through Study Day 12	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
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	Study Day 10 up to Study Day 40	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.
Median Time to Resolution of Diarrhea	Baseline (Day 0) through Study Day 12	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).

Trial Locations

Locations (31): Atlanta Institute for Medical Research, Inc
🇺🇸
Decatur, Georgia, United States
University of Chicago
🇺🇸
Chicago, Illinois, United States
Gastrointestinal Specialists of Georgia PC
🇺🇸
Marietta, Georgia, United States
William Beaumont Hospital
🇺🇸
Royal Oak, Michigan, United States
Mercury Street Medical Group - Research Group
🇺🇸
Butte, Montana, United States
Queen's University
🇨🇦
Kingston, Ontario, Canada
SMBD- Jewish General Hospital G-139
🇨🇦
Montreal, Quebec, Canada
DiGiovanna Institute for Medical Education and Research
🇺🇸
North Massapequa, New York, United States
Wellstar Infectious Disease
🇺🇸
Marietta, Georgia, United States
Remington Davis Inc.
🇺🇸
Columbus, Ohio, United States
Centre Hospitalier Universitaire de Québec
🇨🇦
Quebec City, Quebec, Canada
Providence Hospital Clinical Research Center
🇺🇸
Washington, District of Columbia, United States
Metropolitan Gastroentrology Group
🇺🇸
Chevy Chase, Maryland, United States
St. Joseph Healthcare
🇨🇦
Hamilton, Ontario, Canada
Idaho Falls Infectious Disease, PLLC
🇺🇸
Idaho, Idaho, United States
Ochsner Clinic Foundation
🇺🇸
New Orleans, Louisiana, United States
University of Calgary, Foothills Medical Center
🇨🇦
Calgary, Alberta, Canada
Missouri Baptist Medical Center
🇺🇸
Saint Louis, Missouri, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Centre Hospitalier Universitaire de Sherbrooke
🇨🇦
Sherbrook, Quebec, Canada
Centre de Sante et des Services Sociaux de Chicoutimi
🇨🇦
Chicoutimi, Quebec, Canada
Henry Ford Health System
🇺🇸
Detroit, Michigan, United States
University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
Mount Sinai Hospital
🇨🇦
Toronto, Ontario, Canada
Washington Hospital Center
🇺🇸
Washington, District of Columbia, United States
Central Florida Internists
🇺🇸
Saint Cloud, Florida, United States
Tufts University School of Medicine
🇺🇸
Boston, Massachusetts, United States
MeritCare Clinical Research
🇺🇸
Fargo, North Dakota, United States
Maisonneuve Rosemont Hospital
🇨🇦
Montreal, Quebec, Canada
Centre hopitalier regional de Trois-Rivieres
🇨🇦
Trois-Rivieres, Quebec, Canada
University of Kansas Medical Center
🇺🇸
Kansas City, Kansas, United States