Clinical trial NCT01085591: Study of CB-183,315 in Participants With Clostridium Difficile Infection
Official title: A Randomized, Double-Blinded, Active-Controlled, Dose Ranging Study of CB-183,315 in Patients With Clostridium Difficile Infection.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Clostridium Difficile Infection
Diarrhea
Keywords: CDI
Clostridium difficile Infection
Diarrhea
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2010-03-12
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of Participants With a Clinical Response Outcome of Clostridium Difficile Infection Cure at the End of Study Treatment
timeFrame: Baseline (Day 0) through Study Day 19
measure: Number of Participants With a Clinical Response Outcome of Failure or Unable to Evaluate at the End of Study Treatment
timeFrame: Baseline (Day 0) through Study Day 19
Secondary outcomes:
measure: Number of Participants With a Recurrence of Clostridium Difficile Infection Through the 4-week Follow-up Period
timeFrame: Study Day 10 up to Study Day 40
measure: 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
timeFrame: Baseline (Day 0) through Study Day 12
measure: 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
timeFrame: Study Day 10 up to Study Day 40
measure: Median Time to Resolution of Diarrhea
timeFrame: Baseline (Day 0) through Study Day 12
Other outcomes:
Locations:
city: Washington
country: United States
facility: Providence Hospital Clinical Research Center
state: District of Columbia
city: Washington
country: United States
facility: Washington Hospital Center
state: District of Columbia
city: Saint Cloud
country: United States
facility: Central Florida Internists
state: Florida
city: Decatur
country: United States
facility: Atlanta Institute for Medical Research, Inc
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia PC
state: Georgia
city: Marietta
country: United States
facility: Wellstar Infectious Disease
state: Georgia
city: Idaho
country: United States
facility: Idaho Falls Infectious Disease, PLLC
state: Idaho
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Chevy Chase
country: United States
facility: Metropolitan Gastroentrology Group
state: Maryland
city: Boston
country: United States
facility: Tufts University School of Medicine
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Keego Harbor
country: United States
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Butte
country: United States
facility: Mercury Street Medical Group - Research Group
state: Montana
city: North Massapequa
country: United States
facility: DiGiovanna Institute for Medical Education and Research
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Fargo
country: United States
facility: MeritCare Clinical Research
state: North Dakota
city: Columbus
country: United States
facility: Remington Davis Inc.
state: Ohio
city: Calgary
country: Canada
facility: University of Calgary, Foothills Medical Center
state: Alberta
city: Hamilton
country: Canada
facility: St. Joseph Healthcare
state: Ontario
city: Kingston
country: Canada
facility: Queen's University
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Chicoutimi
country: Canada
facility: Centre de Sante et des Services Sociaux de Chicoutimi
state: Quebec
city: Montreal
country: Canada
facility: Maisonneuve Rosemont Hospital
state: Quebec
city: Montreal
country: Canada
facility: SMBD- Jewish General Hospital G-139
state: Quebec
city: Quebec City
country: Canada
facility: Centre Hospitalier Universitaire de Québec
state: Quebec
city: Sherbrook
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Trois-Rivieres
country: Canada
facility: Centre hopitalier regional de Trois-Rivieres
state: Quebec
Study officials:
References:
citation: Lee CH, Patino H, Stevens C, Rege S, Chesnel L, Louie T, Mullane KM. Surotomycin versus vancomycin for Clostridium difficile infection: Phase 2, randomized, controlled, double-blind, non-inferiority, multicentre trial. J Antimicrob Chemother. 2016 Oct;71(10):2964-71. doi: 10.1093/jac/dkw246. Epub 2016 Jul 17.