Clostridium Difficile Infection
Conditions
Keywords
CDAD, Clostridium difficile Associated Diarrhea, CDI, Clostridium difficile Infection, Diarrhea
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.
Interventions
DRUGCB-183,315
CB-183,315 250 mg white coated tablet over-encapsulated in a size 00 opaque hard gelatin capsule.
DRUGVancomycin
Vancomycin hydrochloride 125 mg capsule over-encapsulated in size 00 opaque hard gelatin capsule.
DRUGPlacebo
Placebo size 00 opaque hard gelatin capsules.
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Percentage of Participants Meeting Clinical Response Criteria for Cure at End of Treatment (EOT) | Up to 3 days after EOT (up to Day 13) | 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) | Up to 30 days after EOT (up to Day 40) | 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 | Up to EOT (up to Day 10) | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Clinical Failure Events up to Day 40 | Up to 30 days after EOT (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 | Up to 40 days after EOT (up to Day 50) | 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. |
Participant flow
Recruitment details
This study enrolled adult participants with Clostridium Difficile associated diarrhea (CDAD) at 104 study centers in North America, Asia-Pacific, and South America.
Participants by arm
| Arm | Count |
|---|---|
| CB-183,315 Participants took CB-183,315 250 mg b.i.d. and placebo b.i.d. by mouth for 10 days. | 285 |
| Vancomycin Participants took vancomycin 125 mg q.i.d. by mouth for 10 days. | 292 |
| Total | 577 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 13 |
| Overall Study | Assigned to CB but received vancomycin | 1 | 0 |
| Overall Study | Lost to Follow-up | 7 | 12 |
| Overall Study | No reason provided. | 0 | 5 |
| Overall Study | Physician Decision | 4 | 5 |
| Overall Study | Randomized but never treated | 8 | 5 |
| Overall Study | Treated but no confirmed CDAD | 9 | 8 |
| Overall Study | Withdrawal by Subject | 9 | 13 |
Baseline characteristics
| Characteristic | CB-183,315 | Vancomycin | Total |
|---|---|---|---|
| Age, Continuous | 57.6 Years STANDARD_DEVIATION 18.3 | 56.5 Years STANDARD_DEVIATION 18.3 | 57.1 Years STANDARD_DEVIATION 18.3 |
| Sex: Female, Male Female | 173 Participants | 194 Participants | 367 Participants |
| Sex: Female, Male Male | 112 Participants | 98 Participants | 210 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 294 | 11 / 301 |
| other Total, other adverse events | 53 / 294 | 72 / 301 |
| serious Total, serious adverse events | 33 / 294 | 39 / 301 |
Outcome results
Primary
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.
Time frame: Up to 3 days after EOT (up to Day 13)
Population: The analysis population consists of all randomized and treated participants with a confirmed CDAD diagnosis (mMITT population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CB-183,315 | Adjusted Percentage of Participants Meeting Clinical Response Criteria for Cure at End of Treatment (EOT) | 83.4 Adjusted percentage of participants |
| Vancomycin | Adjusted Percentage of Participants Meeting Clinical Response Criteria for Cure at End of Treatment (EOT) | 82.1 Adjusted percentage of participants |
95% CI: [-4.9, 7.6]
Primary
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.
Time frame: Up to EOT (up to Day 10)
Population: The analysis population consists of all randomized and treated participants (Safety Population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CB-183,315 | Percentage of Participants Discontinuing From Study Treatment Due to an AE | 3.7 Percentage of Participants |
| Vancomycin | Percentage of Participants Discontinuing From Study Treatment Due to an AE | 3.0 Percentage of Participants |
Primary
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.
Time frame: Up to 30 days after EOT (up to Day 40)
Population: The analysis population consists of all randomized and treated participants (Safety Population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CB-183,315 | Percentage of Participants Experiencing an Adverse Event (AE) | 52.4 Percentage of Participants |
| Vancomycin | Percentage of Participants Experiencing an Adverse Event (AE) | 60.1 Percentage of Participants |
Secondary
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.
Time frame: Up to 40 days after EOT (up to Day 50)
Population: The analysis population consists of all randomized and treated participants with a confirmed CDAD diagnosis (mMITT population).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CB-183,315 | Adjusted Percentage of Participants With Sustained Clinical Response at End of Study | 63.3 Adjusted percentage of participants |
| Vancomycin | Adjusted Percentage of Participants With Sustained Clinical Response at End of Study | 59.0 Adjusted percentage of participants |
95% CI: [-3.6, 12.2]
Secondary
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.
Time frame: Up to 30 days after EOT (up to Day 40)
Population: The analysis population consists of all randomized and treated participants with a confirmed CDAD diagnosis (mMITT population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CB-183,315 | Number of Clinical Failure Events up to Day 40 | Day 0 to Day 13 | 48 Number of Failure Events |
| CB-183,315 | Number of Clinical Failure Events up to Day 40 | Day 14 to Day 24 | 42 Number of Failure Events |
| CB-183,315 | Number of Clinical Failure Events up to Day 40 | Day 25 to Day 35 | 11 Number of Failure Events |
| CB-183,315 | Number of Clinical Failure Events up to Day 40 | Day 36 to Day 40 | 2 Number of Failure Events |
| Vancomycin | Number of Clinical Failure Events up to Day 40 | Day 36 to Day 40 | 2 Number of Failure Events |
| Vancomycin | Number of Clinical Failure Events up to Day 40 | Day 0 to Day 13 | 54 Number of Failure Events |
| Vancomycin | Number of Clinical Failure Events up to Day 40 | Day 25 to Day 35 | 11 Number of Failure Events |
| Vancomycin | Number of Clinical Failure Events up to Day 40 | Day 14 to Day 24 | 49 Number of Failure Events |