Clostridium Difficile-Associated Diarrhea (CDAD)
Conditions
Keywords
Clostridium difficile, Clostridium difficile-Associated Diarrhea, Prophylaxis, Hematopoietic Stem Cell Transplantation
Brief summary
The objective of this study is to demonstrate the efficacy and safety of Fidaxomicin versus placebo for prophylaxis against Clostridium difficile-Associated Diarrhea (CDAD) in adult participants undergoing hematopoietic stem cell transplantation (HSCT). The primary hypothesis is that Fidaxomicin is superior to placebo in preventing CDAD in participants undergoing HSCT.
Interventions
DRUGfidaxomicin
Fidaxomicin 200 mg tablet once daily from the start (+/- 2 days) of condition (prior to transplantation) or at the time of Fluoroquinolone initiation. Study drug treatment will continue until 7 days after either neutrophil engraftment or the completion of any Fluoroquinolone antibiotic regimen (whichever occurs later). Study drug treatment will stop at onset of CDAD or no longer than 40 days of duration, even if other antibiotics are still administered or neutrophil engraftment extends beyond 40 days.
DRUGPlacebo
Placebo tablet once daily from the start (+/- 2 days) of condition (prior to transplantation) or at the time of Fluoroquinolone initiation. Treatment will continue until 7 days after either neutrophil engraftment or the completion of any Fluoroquinolone antibiotic regimen (whichever occurs later). Treatment will stop at onset of CDAD or no longer than 40 days of duration, even if other antibiotics are still administered or neutrophil engraftment extends beyond 40 days.
Sponsors
Optimer Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female 18 years of age or older. * Females of childbearing potential must be using an adequate and reliable method of contraception (e.g., abstinence, barrier with additional spermicide foam or jelly, intrauterine device, hormonal contraception). Males and females must agree to avoid conception during treatment and for four weeks following the end of study treatment. * Is undergoing HSCT with planned Fluoroquinolone prophylaxis. * Informed consent is provided.
Exclusion criteria
* Ongoing active CDAD infection (as evidenced by clinical signs of diarrhea along with the presence of either toxin A and/or B \[or their respective genes, tcdA and/or tcdB\] of C. difficile in the stool) or current treatment for CDAD. * Undergoing cord blood transplants. * Has fulminant colitis, toxic megacolon, or ileus. * A history of inflammatory bowel disease (ulcerative colitis or Crohn's disease). * Women who are pregnant or are actively breast feeding (all women of childbearing potential must have a negative pregnancy test result prior to dosing study drug). * Use of any drugs potentially useful in the treatment of CDAD (e.g. oral Vancomycin, Metronidazole, oral Bacitracin, Fusidic Acid, Rifaximin, and Nitazoxanide). * Any other condition that, in the opinion of the investigator, would jeopardize the safety or rights of the participant in the study, would make it unlikely for the participant to complete the study, or would confound the results of the study. * Participation in other clinical research studies utilizing an investigational agent within one month prior to screening and during the study treatment period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 30 Days Post-treatment Follow-up. | Up to 30 days post-treatment | CDAD is defined as follows: Diarrhea: (change in bowel habits with \>3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 60 Days Post-treatment. | Up to 60 days post-treatment | CDAD is defined as follows: Diarrhea: (change in bowel habits with \>3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented. |
| Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to Day 70 of Study. | Up to Day 70 of study | CDAD is defined as follows: Diarrhea: (change in bowel habits with \>3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fidaxomicin 200 mg Fidaxomicin tablet once daily for no longer than 40 days | 301 |
| Placebo Placebo tablet once daily for no longer than 40 days | 299 |
| Total | 600 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 24 | 22 |
| Overall Study | Confirmed CDAD | 14 | 31 |
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | Not Treated | 4 | 7 |
| Overall Study | Protocol Violation | 43 | 27 |
| Overall Study | Reason not provided | 4 | 4 |
| Overall Study | Withdrawal by Subject | 20 | 18 |
Baseline characteristics
| Characteristic | Fidaxomicin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.1 Years STANDARD_DEVIATION 12 | 55.1 Years STANDARD_DEVIATION 13.23 | 55.1 Years STANDARD_DEVIATION 12.62 |
| Sex: Female, Male Female | 125 Participants | 103 Participants | 228 Participants |
| Sex: Female, Male Male | 176 Participants | 196 Participants | 372 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 297 / 300 | 298 / 300 |
| serious Total, serious adverse events | 98 / 300 | 92 / 300 |
Outcome results
Primary
Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 30 Days Post-treatment Follow-up.
CDAD is defined as follows: Diarrhea: (change in bowel habits with \>3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented.
Time frame: Up to 30 days post-treatment
Population: mITT consisting of all randomized participants undergoing HSCT who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fidaxomicin | Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 30 Days Post-treatment Follow-up. | 28.6 Percentage of participants |
| Placebo | Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 30 Days Post-treatment Follow-up. | 30.8 Percentage of participants |
p-value: 0.277895% CI: [-5.1, 9.5]One-sided Wald p-value
Secondary
Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 60 Days Post-treatment.
CDAD is defined as follows: Diarrhea: (change in bowel habits with \>3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented.
Time frame: Up to 60 days post-treatment
Population: mITT consisting of all randomized participants undergoing HSCT who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fidaxomicin | Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 60 Days Post-treatment. | 35.2 Percentage of participants |
| Placebo | Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to 60 Days Post-treatment. | 35.8 Percentage of participants |
p-value: 0.44295% CI: [-7.1, 8.2]One-sided Wald p-value
Secondary
Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to Day 70 of Study.
CDAD is defined as follows: Diarrhea: (change in bowel habits with \>3 unformed bowel movements in a 24 hour period) and the presence of either toxin A and/or B (or their respective genes, tcdA and/or tcdB) of C. difficile in the stool determined by C. difficile toxin assay. Wald 95% Confidence Intervals (CI) are presented.
Time frame: Up to Day 70 of study
Population: mITT consisting of all randomized participants undergoing HSCT who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fidaxomicin | Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to Day 70 of Study. | 29.2 Percentage of participants |
| Placebo | Percentage of Participants With Occurrence of CDAD From Start of Study Treatment up to Day 70 of Study. | 31.1 Percentage of participants |
p-value: 0.309195% CI: [-5.5, 9.2]One-sided Wald p-value