A Comparison of Fidaxomicin and Vancomycin in Patients With CDI Receiving Antibiotics for Concurrent Infections

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT02692651
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 144
• Locations: 2
• Arms: 2
• Actual Duration (Months): 49.7
• Patients Per Site: 72
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Clostridium Difficile Infection (CDI)	Drug: Fidaxomicin; Drug: Vancomycin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Comparison of Fidaxomicin and Oral Vancomycin for the Treatment of Clostridium Difficile Infection (CDI) in Hospitalized Patients Receiving Concomitant Antibiotics for the Treatment of Concurrent Systemic Infections
• Actual Study Start Date: May 1, 2017
• Actual Primary Completion Date: May 23, 2021
• Actual Study Completion Date: Jun 23, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Fidaxomicin Fidaxomicin 200 mg PO BID for 10 days or until the end of the duration of concomitant antibiotic exposure, whichever is longer.	Drug: Fidaxomicin; 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.; Other Names: Dificid, Dificlir, OPT-80, PAR-101
Active Comparator: Vancomycin Vancomycin 125 mg PO QID for 10 days or until the end of the duration of concomitant antibiotic exposure, whichever is longer.	Drug: Vancomycin; 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.; Other Names: Vancocin

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 30-day Mortality [40 to 114 days]

   Death in subjects who completed the study treatment and died within 30 days after end of treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48109
2	St. Joseph Mercy Hospital	Ypsilanti	Michigan	United States	48197

Sponsors and Collaborators

• University of Michigan
• Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: A. Krishna Rao, MD, MS, University of Michigan

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 4, 2019

More Information

Publications

None provided.

• Responsible Party: Krishna Rao, Assistant Professor of Internal Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT02692651
• Other Study ID Numbers: Merck Fidaxo
• First Posted: Feb 26, 2016
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Krishna Rao, Assistant Professor of Internal Medicine, University of Michigan: vancomycin; fidaxomicin; CDI; diarrhea
• Additional relevant MeSH terms: Infections; Communicable Diseases; Clostridium Infections; Vancomycin; Fidaxomicin

Study Results

Participant Flow

Arm/Group Title	Vancomycin	Fidaxomicin
Arm/Group Description	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.	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.
Period Title: Study Treatment
STARTED	70	74
COMPLETED	54	64
NOT COMPLETED	16	10
Period Title: Study Treatment
STARTED	54	64
COMPLETED	50	60
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Fidaxomicin	Vancomycin	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	74	70	144
Age, Customized (Count of Participants)
<65	51 68.9%	40 57.1%	91 63.2%
65-74	15 20.3%	20 28.6%	35 24.3%
>74	8 10.8%	10 14.3%	18 12.5%
Sex: Female, Male (Count of Participants)
Female	40 54.1%	35 50%	75 52.1%
Male	34 45.9%	35 50%	69 47.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 2.7%	3 4.3%	5 3.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 13.5%	5 7.1%	15 10.4%
White	61 82.4%	61 87.1%	122 84.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.4%	1 1.4%	2 1.4%
Region of Enrollment (Count of Participants)
United States	74 100%	70 100%	144 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	26.7	28.2	27.4
Patients in ICU at enrollment (Count of Participants)
Count of Participants [Participants]	12 16.2%	11 15.7%	23 16%
History of C difficile infection (Count of Participants)
Count of Participants [Participants]	16 21.6%	8 11.4%	24 16.7%
History of cancer (Count of Participants)
Count of Participants [Participants]	34 45.9%	38 54.3%	72 50%
History of stem cell transplant (Count of Participants)
Count of Participants [Participants]	4 5.4%	10 14.3%	14 9.7%
History of inflammatory bowel disease (Count of Participants)
Count of Participants [Participants]	3 4.1%	2 2.9%	5 3.5%
History of Proton Pump Inhibitors use (Count of Participants)
Count of Participants [Participants]	29 39.2%	30 42.9%	59 41%
White blood cell count (1000 cells/μL) [Mean (Full Range) ]
Mean (Full Range) [1000 cells/μL]	9.46	7.93	8.7
Creatinine (mg/dl) [Mean (Full Range) ]
Mean (Full Range) [mg/dl]	1.11	1.36	1.23

Outcome Measures

1. Primary Outcome

Title	Clinical Cure: Resolution of Diarrhea
Description	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

Outcome Measure Data

Analysis Population Description

Intention to treat analysis

Arm/Group Title	Fidaxomicin	Vancomycin
Arm/Group Description	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.	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.
Measure Participants	74	70
Count of Participants [Participants]	54 73%	44 62.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fidaxomicin, Vancomycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.195
	Comments
	Method	Chi-squared, Corrected
	Comments

2. Secondary Outcome

Title	Recurrence of CDI
Description	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)

Outcome Measure Data

Analysis Population Description

Subjects who completed study treatment and were alive at the end of 30-day follow-up.

Arm/Group Title	Fidaxomicin	Vancomycin
Arm/Group Description	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.	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.
Measure Participants	60	50
Count of Participants [Participants]	2 2.7%	2 2.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fidaxomicin, Vancomycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.99
	Comments
	Method	Chi-squared, Corrected
	Comments

3. Secondary Outcome

Title	30-day Mortality
Description	Death in subjects who completed the study treatment and died within 30 days after end of treatment
Time Frame	40 to 114 days

Outcome Measure Data

Analysis Population Description

Subjects who completed the study treatment

Arm/Group Title	Fidaxomicin	Vancomycin
Arm/Group Description	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.	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.
Measure Participants	64	54
Count of Participants [Participants]	4 5.4%	4 5.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fidaxomicin, Vancomycin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.999
	Comments
	Method	Chi-squared, Corrected
	Comments

Adverse Events

Time Frame	Treatment period + 30 days, ranging from a total of 40 to 114 days.
Adverse Event Reporting Description	Adverse events collected with follow-up surveys and by clinical alerts.
Arm/Group Title	Fidaxomicin		Vancomycin
Arm/Group Description	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.		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.
All Cause Mortality
	Fidaxomicin		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/74 (9.5%)		11/70 (15.7%)
Serious Adverse Events
	Fidaxomicin		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/74 (14.9%)		13/70 (18.6%)
Gastrointestinal disorders
Hospitalization	5/74 (6.8%)	5	2/70 (2.9%)	2
General disorders
Hospitalization	0/74 (0%)	0	1/70 (1.4%)	1
Hepatobiliary disorders
Hospitalization	1/74 (1.4%)	1	1/70 (1.4%)	1
Infections and infestations
Hospitalization	0/74 (0%)	0	4/70 (5.7%)	4
Nervous system disorders
Hospitalization	1/74 (1.4%)	1	2/70 (2.9%)	3
Renal and urinary disorders
Hospitalization	1/74 (1.4%)	1	1/70 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
Hospitalization	2/74 (2.7%)	3	4/70 (5.7%)	4
Skin and subcutaneous tissue disorders
Hospitalization	2/74 (2.7%)	2	1/70 (1.4%)	1
Other (Not Including Serious) Adverse Events
	Fidaxomicin		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/74 (0%)		0/70 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.