Clostridium Difficile Infection (CDI)
Conditions
Keywords
vancomycin, fidaxomicin, CDI, diarrhea
Brief summary
Administration of concomitant antibiotics (CA) is a known risk factor for treatment failure in the treatment of CDI, as well as for recurrence of CDI. Recent data suggested that among patients receiving CA, fidaxomicin is superior to vancomycin. While these data are encouraging, many clinicians remain unclear on how to apply these data to patient care. Additionally, patients were excluded from the trials presented to the FDA if it was expected that they would require ≥ 7 days of CA. Therefore, the clinical question still remains of how to apply these data to the real world patient who requires a long course of CA and develops CDI while on therapy. We therefore propose an open label, comparative and prospective study of fidaxomicin 200 mg twice daily vs oral vancomycin 125 mg four times daily for the treatment of CDI among patients who are receiving a long course of CA. We hypothesize that fidaxomicin will be superior to vancomycin with respect to clinical cure for patients with CDI.
Interventions
DRUGFidaxomicin
Eligible patients randomized to receive open-label Fidaxomicin will receive 200 mg twice daily for 10 days or until the end of the duration of concomitant antibiotics exposure, whichever is longer.
DRUGVancomycin
Eligible patients randomized to Vancomycin will receive 125 mg orally four times daily for 10 days or until the end of the duration of concomitant antibiotics exposure, whichever is longer.
Sponsors
Merck Sharp & Dohme LLC
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients 18 years of age or older with \>3 unformed stools/24 hours with positive stool test for C. difficile. * Patients receiving ≥ 1 high or medium risk antibiotic for treatment of an infection other than CDI, for an anticipated duration of ≥ 5 days from the time of enrollment. * High risk: carbapenems, 2nd-4th generation cephalosporins, fluoroquinolones, clindamycin, and beta-lactam/beta-lactamase inhibitor combinations * Medium risk: 1st generation cephalosporin, macrolides\*, and aztreonam * \*The macrolide would be considered to be low risk if patients are receiving intermittent macrolides for prophylaxis only and not for treatment of an acute infection
Exclusion criteria
* Patients with severe-complicated disease that would compromise oral therapy (hypotenstion or shock, ileus or bowel obstruction, megacolon). * Patients with an allergy to oral vancomycin or fidaxomicin. * Patients anticipated to receive metronidazole after enrollment. * Patients who already received oral vancomycin or metronidazole (either oral or intravenous) for \> 24 hours within the preceding 72 hours at the time of enrollment. * Patients anticipated to receive adjunctive C. difficile therapy (rifaxamin, nitazoxanide, tigecycline) after enrollment. * Patients who are on laxatives before they are enrolled into the study, such as lactulose, if: * Patients have had a recent dose adjustment; * Baseline number of bowel movement while on laxatives is unknown. * Number of bowel movements and/or consistency has not changed from baseline. * Patients who have had colostomy or ileostomy * Patients who will have colostomy or ileostomy after enrollment and before study ends * Patients who are or will be on long-term (\>12 weeks) medium or high-risk antibiotics prophylaxis after enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure: Resolution of Diarrhea | length of treatment plus 2 days, from a minimum of 12 to a maximum of 86 days | Resolution of diarrhea defined as ≤ 3 unformed stools for 2 consecutive days maintained until the end of therapy and for 2 days afterwards. The treatment course was at least 10 days, but it could be extended to a maximum of 12 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence of CDI | 30 days after treatment's end (maximum of 114 days) | Recurrence is defined as all three of the following within 4 weeks after successfully completing study treatment: reappearance of symptoms of CDI (\>3 unformed stools in a 24 hour period; a positive stool PCR test for C. difficile; and the need for retreatment with an agent active against C. difficile). |
| 30-day Mortality | 40 to 114 days | Death in subjects who completed the study treatment and died within 30 days after end of treatment |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fidaxomicin Fidaxomicin pill 200 mg PO 2 times per day for 10 days or until the end of the duration of concomitant antibiotic exposure, whichever is longer. | 74 |
| Vancomycin Vancomycin solution 125 mg PO 4 times per day for 10 days or until the end of the duration of concomitant antibiotic exposure, whichever is longer. | 70 |
| Total | 144 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Post Study Treatment Follow-up | Death | 4 | 4 |
| Study Treatment | comfort care | 1 | 1 |
| Study Treatment | Death | 7 | 3 |
| Study Treatment | Protocol violation per treating team preference | 8 | 6 |
Baseline characteristics
| Characteristic | Fidaxomicin | Vancomycin | Total |
|---|---|---|---|
| Age, Customized <65 | 51 Participants | 40 Participants | 91 Participants |
| Age, Customized 65-74 | 15 Participants | 20 Participants | 35 Participants |
| Age, Customized >74 | 8 Participants | 10 Participants | 18 Participants |
| Body Mass Index (BMI) | 26.7 kg/m^2 | 28.2 kg/m^2 | 27.4 kg/m^2 |
| Creatinine | 1.11 mg/dl | 1.36 mg/dl | 1.23 mg/dl |
| History of cancer | 34 Participants | 38 Participants | 72 Participants |
| History of C difficile infection | 16 Participants | 8 Participants | 24 Participants |
| History of inflammatory bowel disease | 3 Participants | 2 Participants | 5 Participants |
| History of Proton Pump Inhibitors use | 29 Participants | 30 Participants | 59 Participants |
| History of stem cell transplant | 4 Participants | 10 Participants | 14 Participants |
| Patients in ICU at enrollment | 12 Participants | 11 Participants | 23 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 5 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 61 Participants | 61 Participants | 122 Participants |
| Region of Enrollment United States | 74 Participants | 70 Participants | 144 Participants |
| Sex: Female, Male Female | 40 Participants | 35 Participants | 75 Participants |
| Sex: Female, Male Male | 34 Participants | 35 Participants | 69 Participants |
| White blood cell count | 9.46 1000 cells/μL | 7.93 1000 cells/μL | 8.7 1000 cells/μL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 74 | 11 / 70 |
| other Total, other adverse events | 0 / 74 | 0 / 70 |
| serious Total, serious adverse events | 11 / 74 | 13 / 70 |
Outcome results
Primary
Clinical Cure: Resolution of Diarrhea
Resolution of diarrhea defined as ≤ 3 unformed stools for 2 consecutive days maintained until the end of therapy and for 2 days afterwards. The treatment course was at least 10 days, but it could be extended to a maximum of 12 weeks.
Time frame: length of treatment plus 2 days, from a minimum of 12 to a maximum of 86 days
Population: Intention to treat analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fidaxomicin | Clinical Cure: Resolution of Diarrhea | 54 Participants |
| Vancomycin | Clinical Cure: Resolution of Diarrhea | 44 Participants |
p-value: 0.195Chi-squared, Corrected
Secondary
30-day Mortality
Death in subjects who completed the study treatment and died within 30 days after end of treatment
Time frame: 40 to 114 days
Population: Subjects who completed the study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fidaxomicin | 30-day Mortality | 4 Participants |
| Vancomycin | 30-day Mortality | 4 Participants |
p-value: 0.999Chi-squared, Corrected
Secondary
Recurrence of CDI
Recurrence is defined as all three of the following within 4 weeks after successfully completing study treatment: reappearance of symptoms of CDI (\>3 unformed stools in a 24 hour period; a positive stool PCR test for C. difficile; and the need for retreatment with an agent active against C. difficile).
Time frame: 30 days after treatment's end (maximum of 114 days)
Population: Subjects who completed study treatment and were alive at the end of 30-day follow-up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Fidaxomicin | Recurrence of CDI | 2 Participants |
| Vancomycin | Recurrence of CDI | 2 Participants |
p-value: 0.99Chi-squared, Corrected