E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Clostridium
difficile Associated Diarrhea |
|
E.1.1.1 | Medical condition in easily understood language |
Clostridium
difficile Associated Diarrhea |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012734 |
E.1.2 | Term | Diarrhea, Clostridium difficile |
E.1.2 | System Organ Class | 100000004862 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objectives:
Efficacy
• To demonstrate the non-inferiority of CB-183,315 versus oral vancomycin in adult subjects with CDAD based on the difference in clinical response rates at end-of-therapy (EOT) in the mMITT
population using a non inferiority margin of 10%.
Safety
• To evaluate the safety of CB-183,315 in subjects with CDAD. |
|
E.2.2 | Secondary objectives of the trial |
Key secondary objectives
• To demonstrate that clinical response over time (defined as clinical response through the end of therapy and the sustained clinical response from end of therapy to Day 40) to CB-183,315 is
superior to oral vancomycin.
• To demonstrate that sustained clinical response to CB-183,315 at the end of the study is superior to oral vancomycin.
For other secondary objectives, please refer to the Protocol |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for enrollment, a subject must meet all of the following criteria prior to any study related procedures:
1. Informed Consent obtained and signed;
2. Age ≥18 and <90 years;
3. If female, subject must not be pregnant or nursing, and must be either:
a. Not of childbearing potential: defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy (no pragnency test required if 1 of theseconditions are met); or
b. If of childbearing potential (and confirmed to not be pragnent by a negative serum or urine pragnency test):
i. Must either abstaining from sexual intercourse or;
ii. Must practicing a barrier method of birth control (e.g., a diaphragm or contraceptive sponge) and 1of the following methods: oral or parenteral contraceptives (oral or parenteral contraceptive must have been used for at least 3 months prior to study drug administration), or
iii. Must have a vasectomized partner.
4. Has diarrhea with a minimum of three unformed bowel movements or >200 mL volume of stool for subjects with a collection device (eg. rectal tube or colostomy bag) over a period of 24 hours just prior to randomization/first dose of study drug; and
5. Has a positive result for C. difficile toxin by EIA, PCR, or a cell culture cytotoxin neutralization assay from a sample obtained within 48 hours prior to first dose of study drug. |
|
E.4 | Principal exclusion criteria |
A subject will not be enrolled if the subject meets any of the following criteria:
1. Toxic megacolon and/or known small bowel ileus;
2. Received treatment with intravenous immune globulin (IVIG) within 30 days prior to the first dose of study drug;
3. Received treatment with a fecal transplant within 7 days, and/or is anticipated to receive a fecal transplant during the study.
4. Antibacterial therapy specific for current CDAD:
• Received >4 doses or >24 hours of oral vancomycin for the current episode of CDAD prior to first dose of study drug.
• Received >4 doses or >24 hours of oral/IV metronidazole for the current episode of CDAD prior to first dose of study drug unless patient received at least 3 days of such therapy, and is
considered a treatment failure for CDAD.
• Received >24 hours of any other antibacterial for the current CDAD within 14 days prior to the first dose of study drug, unless considered a treatment failure for CDAD.
5. Received an investigational vaccine against C. difficile;
6. Received an investigational product containing monoclonal antibodies against toxin A or B within 180 days prior to first dose of study drug;
7. Patients with more than 2 episodes of CDAD, including the current episode, within 90 days of start of study therapy (i.e., patients can be enrolled with their 1st recurrence/2nd episode);
8. Major gastrointestinal (GI) surgery (i.e. significant bowel resection) within 3 months of enrollment;
9. History of prior inflammatory bowel disease: ulcerative colitis, Crohn’s disease, or microscopic colitis;
10. Continues to take loperamide, diphenoxylate/atropine, or cholestyramine during the duration of the study;
11. Continues to take opiate treatment unless on a stable dose as of onset of diarrhea and no increase in dose planned for the duration of the study;
12. Known positive stool cultures for other enteropathogens including but not limited to Salmonella, Shigella, and Campylobacter;
13. Known stool studies positive for pathogenic ova and/or parasites;
14. Known intolerance or hypersensitivity to daptomycin and/or vancomycin;
15. Life-threatening illness at the time of enrollment as measured by a score of 4 using a modified Horn’s index;
16.Poor concurrent medical risks with clinically significant co-morbid disease such that in the opinion of the Investigator the patient should not be enrolled;
17. Received an investigational drug or participated in any experimental procedure within 1 month prior to start of study therapy (Investigational use of approved products may be permitted with the approval of the Medical Monitor))
18. Subjects with HIV, whose latest CD4 count is <200 cells/mm3 or there is evidence of clinical immunosuppression;
19. Anticipated that systemic antibacterial therapy for a non-CDAD infection will be required for >7 days after start of study therapy;
20. Continues to take Saccharomyces or similar probiotic;
21. Concurrent intensive induction chemotherapy, radiotherapy, or biologic treatment for active malignancy
22. Unable/unwilling to comply with the protocol requirements;
23. Any condition that, in the opinion of the Investigator, might interfer with study objectives;
24. Life expectancy is less than 8 weeks. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
• Clinical Response at the end of therapy in the mMITT population |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoints
• Clinical response over time (defined as clinical response through the end of therapy and the sustained
clinical response from end of therapy to Day 40) in the mMITT population
• Sustained clinical response at the end of the study in the mMITT population
Other Efficacy Endpoints
• Sustained clinical response at Day 24 from start of treatment in the mMITT population
• Recurrence of CDAD from end of treatment to the end of study in the mMITT population
• Time to resolution of diarrhea in the mMITT population
• Time to reappearance of diarrhea from the end of treatment to the end of study among subjects with a clinical response in the mMITT population
• Clinical Response at end of therapy in the following subgroups:
o Subjects infected with C. difficile epidemic toxigenic BI/NAP1/027 strain
o Per Protocol 1 Subjects
• Sustained Clinical Response at end of study in the following subgroups:
o Subjects infected with C. difficile epidemic toxigenic BI/NAP1/027 strain
o Per Protocol 2 Subjects
• Health economic outcomes during the study between CB-183,315 and vancomycin, including the length of hospital stay and hospital admission rates |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The clinical response will be assessed through the
end of therapy and the sustained
clinical response from end of therapy to the end of the study.
Other Efficacy Endpoints will be evaluated at different timepoints as stated above. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the trial is defined as the last visit of the last subject undergoing the trial |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |