Back to resultsStudy of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-005)
Primary Purpose
Clostridium Difficile Infection
Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Surotomycin
Vancomycin
Placebo
Sponsored by
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
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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Surotomycin
Vancomycin
Arm Description
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
125 mg Vancomycin over-encapsulated capsule administered orally, four times daily for a daily total dose of 500 mg, for 10 days
Outcomes
Primary Outcome Measures
Adjusted Percentage of Participants With a Clinical Outcome of Cure at the End of Treatment (EOT)
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.
Percentage of Participants With at Least One 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. 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).
Percentage of Participants With at Least One Serious Adverse Event (SAE)
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.
Percentage of Participants Who Discontinued 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. 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
Number of Participants With Clinical Response Over Time
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).
Adjusted Percentage of Participants With Sustained Clinical Response at the End of Study
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.
Adjusted Percentage of Participants With Sustained Clinical Response at 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.
Adjusted Percentage of Participants With Recurrence of CDAD at End of Study
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.
Time to Resolution of Diarrhea
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.
Time to Reappearance of Diarrhea From End of Treatment to the End of Study
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.
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
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.
Adjusted Percentage of Participants Per Protocol 1 Population With a Clinical Response at the End of Treatment
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.
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
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.
Adjusted Percentage of Participants From the Per Protocol 2 Population With a Sustained Clinical Response at the End of Study
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01597505
Brief Title
Study of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-005)
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
July 2019
Overall Recruitment Status
Completed
Study Start Date
May 16, 2012 (Actual)
Primary Completion Date
March 20, 2015 (Actual)
Study Completion Date
March 20, 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
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.
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
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
606 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Surotomycin
Arm Type
Experimental
Arm Description
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
Arm Title
Vancomycin
Arm Type
Active Comparator
Arm Description
125 mg Vancomycin over-encapsulated capsule administered orally, four times daily for a daily total dose of 500 mg, for 10 days
Intervention Type
Drug
Intervention Name(s)
Surotomycin
Other Intervention Name(s)
CB-183,315
Intervention Description
250 mg Surotomycin over-encapsulated tablet administered orally, twice daily for a daily total dose of 500 mg, for 10 days
Intervention Type
Drug
Intervention Name(s)
Vancomycin
Intervention Description
125 mg Vancomycin over-encapsulated capsule administered orally, four times daily for a daily total dose of 500 mg, for 10 days
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo for Surotomycin over-encapsulated tablet administered orally, twice daily for 10 days
Primary Outcome Measure Information:
Title
Adjusted Percentage of Participants With a Clinical Outcome of Cure at the End of Treatment (EOT)
Description
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.
Time Frame
Up to 13 days
Title
Percentage of Participants With at Least One 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. 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).
Time Frame
Up to Day 50
Title
Percentage of Participants With at Least One Serious Adverse Event (SAE)
Description
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.
Time Frame
Up to Day 50
Title
Percentage of Participants Who Discontinued 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. 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).
Time Frame
Up to Day 13
Secondary Outcome Measure Information:
Title
Number of Participants With Clinical Response Over Time
Description
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).
Time Frame
Up to Day 41
Title
Adjusted Percentage of Participants With Sustained Clinical Response at the End of Study
Description
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.
Time Frame
Up to Day 50
Title
Adjusted Percentage of Participants With Sustained Clinical Response at Day 24
Description
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.
Time Frame
Day 24
Title
Adjusted Percentage of Participants With Recurrence of CDAD at End of Study
Description
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.
Time Frame
Up to Day 50
Title
Time to Resolution of Diarrhea
Description
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.
Time Frame
Up to Day 13
Title
Time to Reappearance of Diarrhea From End of Treatment to the End of Study
Description
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.
Time Frame
Up to Day 50
Title
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
Description
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.
Time Frame
Up to Day 13
Title
Adjusted Percentage of Participants Per Protocol 1 Population With a Clinical Response at the End of Treatment
Description
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.
Time Frame
Up to Day 13
Title
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
Description
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.
Time Frame
Up to Day 50
Title
Adjusted Percentage of Participants From the Per Protocol 2 Population With a Sustained Clinical Response at the End of Study
Description
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.
Time Frame
Up to Day 50
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility 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.
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
28480267
Citation
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 Jan 19;4(1):ofw275. doi: 10.1093/ofid/ofw275. eCollection 2017 Winter.
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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Study of CB-183,315 in Participants With Clostridium Difficile Associated Diarrhea (MK-4261-005)
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