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A Study of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-006)

Primary Purpose

Clostridium Difficile Infection

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
CB-183,315
Vancomycin
Placebo
Sponsored by
Cubist Pharmaceuticals LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Clostridium Difficile Infection focused on measuring CDAD, Clostridium difficile Associated Diarrhea, CDI, Clostridium difficile Infection, Diarrhea

Eligibility Criteria

18 Years - 89 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Is able to read and sign a consent form;
  • Is from ≥18 to <90 years of age;
  • Has diarrhea, at least 3 times during one day, or 200 mL or liquid stool if using a rectal device;
  • Tests positive for Clostridium difficile;
  • If female, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study.

Exclusion Criteria:

  • Has toxic megacolon and/or known small bowel ileus;
  • Has received treatment with intravenous immune globulin (IVIG) within the past 30 days;
  • Has received treatment with a fecal transplant within 7 days, and/or if the doctor anticipates to give the participant a fecal transplant during the study;
  • Has received a certain amount of antibacterial therapy specific for current CDAD, unless it is not working;
  • Has received an investigational vaccine against Clostridium difficile;
  • Has received an investigational product containing monoclonal antibodies against toxin A or B within 180 days;
  • Has more than 2 episodes of CDAD within 90 days;
  • Has had major gastrointestinal (GI) surgery (i.e. significant bowel resection) within 3 months (this does not include appendectomy or cholecystectomy);
  • Has a history of prior inflammatory bowel disease: ulcerative colitis, Crohn's disease, or microscopic colitis;
  • Is unable to discontinue loperamide, diphenoxylate/atropine, or cholestyramine during the duration of the study;
  • Is unable to discontinue opiate treatment unless on a stable dose;
  • Has known positive stool cultures for other enteropathogens including but not limited to Salmonella, Shigella, and Campylobacter;
  • Has had stool studies positive for pathogenic ova and/or parasites;
  • Has an intolerance or hypersensitivity to daptomycin and/or vancomycin;
  • Has a life-threatening illness at the time of enrollment;
  • Has poor concurrent medical risks that in the opinion of the Investigator the participant should not enroll;
  • Has received an investigational drug or participated in any experimental procedure within 1 month;
  • Has human immunodeficiency virus (HIV), a cluster of differentiation (CD) 4 count <200 cells/mm^3 within 6 months of start of study therapy;
  • Anticipates that certain antibacterial therapy for a non-CDAD infection will be required for >7 days;
  • Is unable to discontinue Saccharomyces or similar probiotic;
  • Is on a concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy;
  • Is unable to comply with the protocol requirements;
  • Has any condition that, in the opinion of the Investigator, might interfere;
  • Is not expected to live for less than 8 weeks.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    CB-183,315

    Vancomycin

    Arm Description

    Participants took CB-183,315 250 mg twice daily (b.i.d.) and placebo capsules b.i.d. by mouth for 10 days.

    Participants took vancomycin 125 mg four times daily (q.i.d.) by mouth for 10 days.

    Outcomes

    Primary Outcome Measures

    Adjusted Percentage of Participants Meeting Clinical Response Criteria for Cure at End of Treatment (EOT)
    The percentage of participants considered "cured" (i.e., ≤2 loose stools per 24 hour period for at least 2 consecutive days and no need for additional antibiotics during the 3 days following EOT) was determined in the mMITT population. A CDAD diagnosis was defined as: 1) diarrhea with a minimum of 3 unformed bowel movements (UBM) or >200 mL volume of stool for participants with a collection device (e.g., rectal tube or colostomy bag) over 24 hours; and 2) a positive result for Clostridium difficile toxin by enzyme immunoassay (EIA), polymerase chain reaction (PCR), or a cell culture cytotoxin neutralization assay. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.
    Percentage of Participants Experiencing an Adverse Event (AE)
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.
    Percentage of Participants Discontinuing From Study Treatment Due to an AE
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.

    Secondary Outcome Measures

    Number of Clinical Failure Events up to Day 40
    The total number of clinical failure events, which included treatment failure, CDAD recurrence, death, or being lost to follow-up, occurring during each time period was determined in each arm.
    Adjusted Percentage of Participants With Sustained Clinical Response at End of Study
    The percentage of participants with sustained clinical response was determined for each arm. Sustained clinical response was declared when participants had a clinical outcome of cure at EOT, did not experience any CDAD recurrence, did not die, were not lost to follow-up, and did not have the end of study visit prior to Day 40. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.

    Full Information

    First Posted
    May 10, 2012
    Last Updated
    August 19, 2022
    Sponsor
    Cubist Pharmaceuticals LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01598311
    Brief Title
    A Study of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-006)
    Official Title
    A Randomized, Double-Blinded, Active-Controlled Study of CB-183,315 in Patients With Clostridium Difficile Associated Diarrhea
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2022
    Overall Recruitment Status
    Completed
    Study Start Date
    May 16, 2012 (Actual)
    Primary Completion Date
    July 26, 2015 (Actual)
    Study Completion Date
    August 25, 2015 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Cubist Pharmaceuticals LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    A total of 608 participants with Clostridium Difficile Associated Diarrhea (CDAD) will participate in this study; participants will receive either oral vancomycin or CB-183,315 in a blinded fashion. Treatment will last for 10 days and participants will be followed up for at least 40 days and a maximum of 100 days. The purpose of this study is to evaluate how well CB-183,315 treats CDAD as compared to vancomycin.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Clostridium Difficile Infection
    Keywords
    CDAD, Clostridium difficile Associated Diarrhea, CDI, Clostridium difficile Infection, Diarrhea

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    608 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    CB-183,315
    Arm Type
    Experimental
    Arm Description
    Participants took CB-183,315 250 mg twice daily (b.i.d.) and placebo capsules b.i.d. by mouth for 10 days.
    Arm Title
    Vancomycin
    Arm Type
    Active Comparator
    Arm Description
    Participants took vancomycin 125 mg four times daily (q.i.d.) by mouth for 10 days.
    Intervention Type
    Drug
    Intervention Name(s)
    CB-183,315
    Other Intervention Name(s)
    Surotomycin
    Intervention Description
    CB-183,315 250 mg white coated tablet over-encapsulated in a size 00 opaque hard gelatin capsule.
    Intervention Type
    Drug
    Intervention Name(s)
    Vancomycin
    Intervention Description
    Vancomycin hydrochloride 125 mg capsule over-encapsulated in size 00 opaque hard gelatin capsule.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Placebo size 00 opaque hard gelatin capsules.
    Primary Outcome Measure Information:
    Title
    Adjusted Percentage of Participants Meeting Clinical Response Criteria for Cure at End of Treatment (EOT)
    Description
    The percentage of participants considered "cured" (i.e., ≤2 loose stools per 24 hour period for at least 2 consecutive days and no need for additional antibiotics during the 3 days following EOT) was determined in the mMITT population. A CDAD diagnosis was defined as: 1) diarrhea with a minimum of 3 unformed bowel movements (UBM) or >200 mL volume of stool for participants with a collection device (e.g., rectal tube or colostomy bag) over 24 hours; and 2) a positive result for Clostridium difficile toxin by enzyme immunoassay (EIA), polymerase chain reaction (PCR), or a cell culture cytotoxin neutralization assay. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.
    Time Frame
    Up to 3 days after EOT (up to Day 13)
    Title
    Percentage of Participants Experiencing an Adverse Event (AE)
    Description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.
    Time Frame
    Up to 30 days after EOT (up to Day 40)
    Title
    Percentage of Participants Discontinuing From Study Treatment Due to an AE
    Description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment.
    Time Frame
    Up to EOT (up to Day 10)
    Secondary Outcome Measure Information:
    Title
    Number of Clinical Failure Events up to Day 40
    Description
    The total number of clinical failure events, which included treatment failure, CDAD recurrence, death, or being lost to follow-up, occurring during each time period was determined in each arm.
    Time Frame
    Up to 30 days after EOT (up to Day 40)
    Title
    Adjusted Percentage of Participants With Sustained Clinical Response at End of Study
    Description
    The percentage of participants with sustained clinical response was determined for each arm. Sustained clinical response was declared when participants had a clinical outcome of cure at EOT, did not experience any CDAD recurrence, did not die, were not lost to follow-up, and did not have the end of study visit prior to Day 40. Percentages were first stratified according to age (<75 or ≥75 years) and number of previous CDAD episodes (0 or ≥1) and constructed using Mehrotra-Railkar continuity-corrected minimum-risk stratum weights, and the weighted averages were then derived across strata in order to calculate the adjusted percentage.
    Time Frame
    Up to 40 days after EOT (up to Day 50)

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    89 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Is able to read and sign a consent form; Is from ≥18 to <90 years of age; Has diarrhea, at least 3 times during one day, or 200 mL or liquid stool if using a rectal device; Tests positive for Clostridium difficile; If female, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study. Exclusion Criteria: Has toxic megacolon and/or known small bowel ileus; Has received treatment with intravenous immune globulin (IVIG) within the past 30 days; Has received treatment with a fecal transplant within 7 days, and/or if the doctor anticipates to give the participant a fecal transplant during the study; Has received a certain amount of antibacterial therapy specific for current CDAD, unless it is not working; Has received an investigational vaccine against Clostridium difficile; Has received an investigational product containing monoclonal antibodies against toxin A or B within 180 days; Has more than 2 episodes of CDAD within 90 days; Has had major gastrointestinal (GI) surgery (i.e. significant bowel resection) within 3 months (this does not include appendectomy or cholecystectomy); Has a history of prior inflammatory bowel disease: ulcerative colitis, Crohn's disease, or microscopic colitis; Is unable to discontinue loperamide, diphenoxylate/atropine, or cholestyramine during the duration of the study; Is unable to discontinue opiate treatment unless on a stable dose; Has known positive stool cultures for other enteropathogens including but not limited to Salmonella, Shigella, and Campylobacter; Has had stool studies positive for pathogenic ova and/or parasites; Has an intolerance or hypersensitivity to daptomycin and/or vancomycin; Has a life-threatening illness at the time of enrollment; Has poor concurrent medical risks that in the opinion of the Investigator the participant should not enroll; Has received an investigational drug or participated in any experimental procedure within 1 month; Has human immunodeficiency virus (HIV), a cluster of differentiation (CD) 4 count <200 cells/mm^3 within 6 months of start of study therapy; Anticipates that certain antibacterial therapy for a non-CDAD infection will be required for >7 days; Is unable to discontinue Saccharomyces or similar probiotic; Is on a concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy; Is unable to comply with the protocol requirements; Has any condition that, in the opinion of the Investigator, might interfere; Is not expected to live for less than 8 weeks.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Medical Director
    Organizational Affiliation
    Merck Sharp & Dohme LLC
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
    IPD Sharing URL
    http://engagezone.msd.com/ds_documentation.php
    Citations:
    PubMed Identifier
    28961905
    Citation
    Daley P, Louie T, Lutz JE, Khanna S, Stoutenburgh U, Jin M, Adedoyin A, Chesnel L, Guris D, Larson KB, Murata Y. Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial. J Antimicrob Chemother. 2017 Dec 1;72(12):3462-3470. doi: 10.1093/jac/dkx299.
    Results Reference
    result
    PubMed Identifier
    32747931
    Citation
    Cheknis A, Devaris D, Chesnel L, Dale SE, Nary J, Sambol SP, Citron DM, Goering RV, Johnson S. Characterization of Clostridioides difficile isolates recovered from two Phase 3 surotomycin treatment trials by restriction endonuclease analysis, PCR ribotyping and antimicrobial susceptibilities. J Antimicrob Chemother. 2020 Nov 1;75(11):3120-3125. doi: 10.1093/jac/dkaa297.
    Results Reference
    derived

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    A Study of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-006)

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