Clostridium Infections, Diarrhea
Conditions
Keywords
CDAD, Clostridium difficile, diarrhea, Clostridium difficile-Associated Diarrhea
Brief summary
This is a comparative study to investigate the safety and efficacy of PAR-101/OPT-80 (fidaxomicin) versus vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD).
Detailed description
The primary objective of this pivotal study is to investigate the safety and efficacy of PAR-101/OPT-80 versus vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD). The cure rates at end of therapy and recurrence rates will be evaluated and compared.
Interventions
DRUGPAR-101/OPT-80
capsules
DRUGVancomycin
Capsules
Sponsors
Optimer Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males/females with CDAD * Females must use adequate contraception * Signed informed consent
Exclusion criteria
* Life-threatening CDAD * Toxic megacolon * Pregnant * Concurrent use of diarrheal agents * Participation in other trials
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cure Rate at End of Therapy | Study day 10 (+/- 2 days) | Percentage of subjects with 3 or fewer unformed stools for 2 consecutive days and maintained through the end of therapy, and the subject no longer needed specific anti-Clostridium antibacterial treatment after completion of the course of study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence | Study days 11-40 | Percentage of subjects with the re-establishment of diarrhea to an extent(based on frequency of passed unformed stools) that was greater than that noted on the last day of study medication, and the demonstration of either toxin A or B or both of C. difficile, and retreatment with CDI anti-infective therapy was needed. |
| Global Cure | End of Study | Achieving a cure response at end of treatment and not having a recurrence at any time up to the post-study visit. |
Countries
Belgium, Canada, France, Germany, Italy, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled from April 2007 to November 2009 by centers in the United States, Canada, France, Spain, Belgium, Germany, United Kingdom, Italy, and Sweden.
Participants by arm
| Arm | Count |
|---|---|
| Vancomycin 125 mg administered 4 times daily (q6hr) | 256 |
| PAR-101/OPT-80 200 mg administered twice daily (q12hr) | 253 |
| Total | 509 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up | mITT failure | 34 | 31 |
| Treatment | criteria for mITT population | 4 | 11 |
Baseline characteristics
| Characteristic | PAR-101/OPT-80 | Total | Vancomycin |
|---|---|---|---|
| Age, Continuous | 64.1 years STANDARD_DEVIATION 18 | 63.4 years STANDARD_DEVIATION 18.1 | 62.7 years STANDARD_DEVIATION 18.3 |
| Region of Enrollment Belgium | 22 participants | 42 participants | 20 participants |
| Region of Enrollment Canada | 79 participants | 161 participants | 82 participants |
| Region of Enrollment France | 11 participants | 19 participants | 8 participants |
| Region of Enrollment Germany | 18 participants | 37 participants | 19 participants |
| Region of Enrollment Italy | 14 participants | 27 participants | 13 participants |
| Region of Enrollment Spain | 5 participants | 9 participants | 4 participants |
| Region of Enrollment Sweden | 4 participants | 11 participants | 7 participants |
| Region of Enrollment United Kingdom | 26 participants | 53 participants | 27 participants |
| Region of Enrollment United States | 74 participants | 150 participants | 76 participants |
| Sex: Female, Male Female | 149 Participants | 310 Participants | 161 Participants |
| Sex: Female, Male Male | 104 Participants | 199 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 177 / 260 | 186 / 264 |
| serious Total, serious adverse events | 58 / 260 | 70 / 264 |
Outcome results
Primary
Cure Rate at End of Therapy
Percentage of subjects with 3 or fewer unformed stools for 2 consecutive days and maintained through the end of therapy, and the subject no longer needed specific anti-Clostridium antibacterial treatment after completion of the course of study medication.
Time frame: Study day 10 (+/- 2 days)
Population: Analysis data is modified intent to treat (mITT) population. The mITT population consists of subjects that had CDAD confirmed by \>3 unformed bowel movements in the 24 hours prior to randomization and a positive toxin assay and received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vancomycin | Cure Rate at End of Therapy | 86.7 Percentage of Participants |
| PAR-101/OPT-80 | Cure Rate at End of Therapy | 87.7 Percentage of Participants |
Comparison: H0: C(OPT-80) - C(VAN) \<= -10% Power calculation is based on cure rate of 85% in both treatment groups, non-inferiority margin of 10%, 2.5% (1-sided) type I error rate with approximately 90% power gives a total of 530 subjects.95% CI: [-4.8, 6.8]
Secondary
Global Cure
Achieving a cure response at end of treatment and not having a recurrence at any time up to the post-study visit.
Time frame: End of Study
Population: The analysis population is mITT, subjects that achieved a cure response at end of treatment and not having a recurrence at any time up to the Post-study visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vancomycin | Global Cure | 63.3 Percentage of Participants |
| PAR-101/OPT-80 | Global Cure | 76.7 Percentage of Participants |
p-value: 0.00195% CI: [5.4, 21.1]Chi-squared
Secondary
Recurrence
Percentage of subjects with the re-establishment of diarrhea to an extent(based on frequency of passed unformed stools) that was greater than that noted on the last day of study medication, and the demonstration of either toxin A or B or both of C. difficile, and retreatment with CDI anti-infective therapy was needed.
Time frame: Study days 11-40
Population: The analysis population is mITT, for subjects who met the primary endpoint of cure, was analyzed for the recurrence rates of diarrhea up to the Poststudy Visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vancomycin | Recurrence | 27.0 Percentage of Participants |
| PAR-101/OPT-80 | Recurrence | 12.6 Percentage of Participants |
p-value: <0.00195% CI: [-21.6, -7]Chi-squared