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Study of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-005)

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ClinicalTrials.gov Identifier: NCT01597505
Recruitment Status : Completed
First Posted : May 14, 2012
Results First Posted : February 28, 2018
Last Update Posted : September 11, 2018
Sponsor:
Information provided by (Responsible Party):
Cubist Pharmaceuticals LLC

Brief Summary:
606 participants with Clostridium Difficile Associated Diarrhea (CDAD) participated in this study and received either oral vancomycin or CB-183,315 (surotomycin) in a blinded fashion. Treatment lasted for 10 days and participants were followed up for at least 40 days and a maximum of 100 days. The purpose of this study was to evaluate how well surotomycin treats CDAD as compared to vancomycin.

Condition or disease Intervention/treatment Phase
Clostridium Difficile Infection Drug: Surotomycin Drug: Vancomycin Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 606 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blinded, Active-Controlled Study of CB-183,315 in Patients With Clostridium Difficile Associated Diarrhea
Actual Study Start Date : May 16, 2012
Actual Primary Completion Date : March 20, 2015
Actual Study Completion Date : March 20, 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diarrhea

Arm Intervention/treatment
Experimental: Surotomycin
250 mg Surotomycin over- encapsulated tablet administered orally, twice daily for a daily total dose of 500 mg; and Placebo over encapsulated tablet administered orally, twice daily for 10 days
Drug: Surotomycin
250 mg Surotomycin over-encapsulated tablet administered orally, twice daily for a daily total dose of 500 mg, for 10 days
Other Name: CB-183,315

Drug: Placebo
Placebo for Surotomycin over-encapsulated tablet administered orally, twice daily for 10 days

Active Comparator: Vancomycin
125 mg Vancomycin over-encapsulated capsule administered orally, four times daily for a daily total dose of 500 mg, for 10 days
Drug: Vancomycin
125 mg Vancomycin over-encapsulated capsule administered orally, four times daily for a daily total dose of 500 mg, for 10 days




Primary Outcome Measures :
  1. Adjusted Percentage of Participants With a Clinical Outcome of Cure at the End of Treatment (EOT) [ Time Frame: Up to 13 days ]
    A clinical outcome of cure at EOT was determined by resolution of diarrhea, defined as ≤ 2 loose stools per 24-hour period for at least 2 consecutive days and the lack of need for additional antibiotics to treat the current CDAD episode after completion of the study treatment period. Participants requiring a collection device were considered to have resolution of diarrhea when the volume of stool (over a 24-hour period) was decreased by 75% as compared to baseline or the participant was no longer passing liquid stool. The estimated adjusted percentage was a weighted average across all strata, constructed using Mehrotra-Railkar continuity-corrected minimum risk (MRc) stratum weights.

  2. Percentage of Participants With at Least One Adverse Event (AE) [ Time Frame: Up to Day 50 ]
    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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. AEs may be new events or may be pre-existing conditions that have become aggravated or have worsened in severity or frequency; or may be clinically significant changes from baseline in physical examination, laboratory tests, or other diagnostic investigation (e.g. laboratory results, x-ray findings).

  3. Percentage of Participants With at Least One Serious Adverse Event (SAE) [ Time Frame: Up to Day 50 ]
    A SAE is any adverse experience occurring at any dose that results in any of the following outcomes: death; a life-threatening experience, referring to a situation in which the participant was at risk of death at the time of the event, requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is considered to be an important medical event.

  4. Percentage of Participants Who Discontinued Treatment Due to an AE [ Time Frame: Up to Day 13 ]
    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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. AEs may be new events or may be pre-existing conditions that have become aggravated or have worsened in severity or frequency; or may be clinically significant changes from baseline in physical examination, laboratory tests, or other diagnostic investigation (e.g. laboratory results, x-ray findings).


Secondary Outcome Measures :
  1. Number of Participants With Clinical Response Over Time [ Time Frame: Up to Day 41 ]
    Clinical response over time as measured by those without treatment failure, recurrence, death, or lost to follow-up, measured as the number of participants without failure events (survivors) through the end of therapy (reported for Day 14) and from end of therapy to Day 40 (reported for Day 41).

  2. Adjusted Percentage of Participants With Sustained Clinical Response at the End of Study [ Time Frame: Up to Day 50 ]
    Sustained clinical response at the end of study was achieved by participants who had a clinical outcome of cure at the end of treatment (Days 40-50) and did not experience a recurrence of CDAD, did not die, were not lost to follow-up, and did not have end of study visit prior to Day 40. The estimated adjusted percentage was a weighted average across all strata, constructed using MRc stratum weights.

  3. Adjusted Percentage of Participants With Sustained Clinical Response at Day 24 [ Time Frame: Day 24 ]
    Sustained clinical response at Day 24 was defined as participants who had a clinical outcome of cure at Day 24, who did not experience a recurrence of CDAD, did not die, were not lost to follow-up. Only the first failure event was counted per participant. The estimated adjusted percentage was a weighted average across all strata, constructed using MRc stratum weights.

  4. Adjusted Percentage of Participants With Recurrence of CDAD at End of Study [ Time Frame: Up to Day 50 ]
    Participants with recurrences were defined as those who were cured at the end of therapy and had a recurrence or were lost to follow-up, died or had a Day 40 -50 contact prior to Day 40. The estimated adjusted percentage was a weighted average across all strata, constructed using MRc stratum weights.

  5. Time to Resolution of Diarrhea [ Time Frame: Up to Day 13 ]
    Time to resolution of diarrhea with =< 2 unformed bowel movements (UBM) per 24-hour period was calculated as the date/time of last UBM minus the date/time of the first dose of study drug.

  6. Time to Reappearance of Diarrhea From End of Treatment to the End of Study [ Time Frame: Up to Day 50 ]
    Time to reappearance of diarrhea with >= 3 UBM per 24-hour period was calculated as the last date/time of study drug dose to the date/time of first reappearance of 3 or more UBMs among participants who were cured at end of treatment.

  7. Adjusted Percentage of Participants With a Clinical Response at the End of Treatment for Infections Deemed to be Caused by the C. Difficile BI/NAP1/027 Strain at Baseline [ Time Frame: Up to Day 13 ]
    Clinical response corresponded to a clinical outcome of cure at the end of treatment, and was achieved by participants with infections deemed to be caused by the C. difficile BI/NAP1/027 strain at baseline, who did not fail treatment, did not die, or were not lost to follow-up at the end of treatment. The estimated adjusted percentage was a weighted average across all strata, constructed using MRc stratum weights.

  8. Adjusted Percentage of Participants Per Protocol 1 Population With a Clinical Response at the End of Treatment [ Time Frame: Up to Day 13 ]
    Clinical response corresponded to a clinical outcome of cure at the end of treatment, and was achieved by participants who did not fail treatment, did not die, or were not lost to follow-up at the end of treatment. The estimated adjusted percentage was a weighted average across all strata, constructed using MRc stratum weights.

  9. Adjusted Percentage of Participants With a Sustained Clinical Response at the End of Study for Infections Deemed to be Caused by the C. Difficile BI/NAP1/027 Strain at Baseline [ Time Frame: Up to Day 50 ]
    Sustained clinical response at the end of study was achieved by participants with infections deemed to be caused by the C. difficile BI/NAP1/027 strain at baseline, who had a clinical outcome of cure at the end of treatment (Day 13) and did not experience a recurrence of CDAD, did not die, were not lost to follow-up, and did not have end of study visit prior to Day 40. The estimated adjusted percentage was a weighted average across all strata, constructed using MRc stratum weights.

  10. Adjusted Percentage of Participants From the Per Protocol 2 Population With a Sustained Clinical Response at the End of Study [ Time Frame: Up to Day 50 ]
    Sustained clinical response at the end of study was achieved by participants who had a clinical outcome of cure at the end of treatment (Days 40-50) and did not experience a recurrence of CDAD, did not die, were not lost to follow-up, and did not have end of study visit prior to Day 40. Only the first failure event per participant was counted. The estimated adjusted percentage was a weighted average across all strata, constructed using MRc stratum weights.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

To be included in this study, participants must:

  • Sign a consent form;
  • Be >= 18 and < 90 years of age;
  • Have diarrhea, at least 3 times during one day, or 200 mL or liquid stool if using a rectal device;
  • Test positive for Clostridium difficile;
  • If female, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study.

Participants will not be allowed into the study if they:

  • Have toxic megacolon and/or known small bowel ileus;
  • Have received treatment with intravenous immune globulin (IVIG) within the past 30 days;
  • Have 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;
  • Have received a certain amount of antibacterial therapy specific for current CDAD, unless it is not working;
  • Have received an investigational vaccine against C. difficile;
  • Have received an investigational product containing monoclonal antibodies against toxin A or B within 180 days;
  • Had more than 2 episodes of CDAD within 90 days;
  • Had major gastrointestinal (GI) surgery (i.e. significant bowel resection) within 3 months (this does not include appendectomy or cholecystectomy);
  • Have history of prior inflammatory bowel disease: ulcerative colitis, Crohn's disease, or microscopic colitis;
  • Are unable to discontinue loperamide, diphenoxylate/atropine, or cholestyramine during the duration of the study;
  • Are 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;
  • Had stool studies positive for pathogenic ova and/or parasites;
  • Have an intolerance or hypersensitivity to daptomycin and/or vancomycin;
  • Have life-threatening illness at the time of enrollment;
  • Have poor concurrent medical risks that in the opinion of the Investigator the participant should not enroll;
  • Have received an investigational drug or participated in any experimental procedure within 1 month;
  • Have human immunodeficiency virus (HIV), a cluster of differentiation 4 (CD4) < 200 cells/mm3 within 6 months of start of study therapy;
  • Anticipate that certain antibacterial therapy for a non-CDAD infection will be required for > 7 days;
  • Are unable to discontinue Saccharomyces or similar probiotic;
  • Are on a concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy;
  • Are unable to comply with the protocol requirements;
  • Have any condition that, in the opinion of the Investigator, might interfere;
  • Are not expected to live for less than 8 weeks.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01597505


Sponsors and Collaborators
Cubist Pharmaceuticals LLC
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Publications of Results:
Boix V, Fedorak RN, Mullane KM, Pesant Y, Stoutenburgh U, Jin M, Adedoyin A, Chesnel L, Guris D, Larson KB, Murata Y. Primary outcomes from a phase 3, randomized, double-blind, active-controlled trial of surotomycin in subjects with Clostridium difficile infection. Open Forum Infect Dis. 2017;4(1):ofw275. doi: 10.1093/ofid/ofw275

Responsible Party: Cubist Pharmaceuticals LLC
ClinicalTrials.gov Identifier: NCT01597505     History of Changes
Other Study ID Numbers: 4261-005
LCD-CDAD-10-07 ( Other Identifier: Cubist Study Number )
MK-4261-005 ( Other Identifier: Merck Protocol Number )
2012-000252-34 ( EudraCT Number )
First Posted: May 14, 2012    Key Record Dates
Results First Posted: February 28, 2018
Last Update Posted: September 11, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

Keywords provided by Cubist Pharmaceuticals LLC:
CDAD
Clostridium difficile Associated Diarrhea
CDI
Clostridium difficile Infection
Diarrhea

Additional relevant MeSH terms:
Diarrhea
Signs and Symptoms, Digestive
Signs and Symptoms
Vancomycin
Anti-Bacterial Agents
Anti-Infective Agents