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

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

Status and phase: Completed; Phase 2

Conditions: Diarrhea; Clostridium Difficile Infection

Treatments: Drug: Vancomycin; Drug: Placebo; Drug: CB-183,315

Study type: Interventional

Funder types: Industry

Identifiers

NCT01085591

4261-007

LCD-DR-09-03 (Other Identifier)

Details and patient eligibility

About

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.

Enrollment: 210 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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210 participants in 3 patient groups

CB-183,315, 125 mg

Experimental group

Description:

125 milligrams (mg) CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days.

Treatment:

Drug: Placebo

Drug: CB-183,315

CB-183,315, 250 mg

Experimental group

Description:

250 mg CB 183,315 administered orally twice daily, alternating with twice daily oral administration of placebo tablets, for 10 days.

Treatment:

Drug: Placebo

Drug: CB-183,315

Vancomycin, 125 mg

Active Comparator group

Description:

125 mg vancomycin administered orally four times a day for 10 days.

Treatment:

Drug: Vancomycin