Optimal Treatment for Recurrent Clostridium Difficile

Conditions

Clostridium, Difficile, Fidaxomicin, Vancomycin

Keywords

Clostridium, Difficile, Fidaxomicin, Vancomycin, Recurrent, Pulse, Taper

Brief summary

The purpose of this study is to determine whether fidaxomicin and vancomycin followed by taper and pulse vancomycin treatment are superior to standard vancomycin treatment for the treatment of recurrent Clostridium difficile infection.

Detailed description

Abstract Clostridium difficile is the most common cause of healthcare-associated infectious diarrhea among adults in industrialized countries. In addition to diarrhea, C. difficile infection (CDI) may also result in serious complications such as shock, toxic megacolon, colectomy, and death. The Centers for Disease Control and Prevention (CDC) has estimated C. difficile results in 250,000 hospital infections, 14,000 deaths, and $1 billion in excess costs annually. Recurrent CDI is the most challenging clinical dilemma facing clinicians who treat this disease. An estimated 30% of patients who respond to initial treatment with either vancomycin or metronidazole develop recurrent CDI, usually within 1-4 weeks of completing treatment. The primary objective of this study is to determine whether 1) standard fidaxomicin treatment and 2) standard vancomycin treatment followed by taper and pulse vancomycin treatment are superior to standard vancomycin treatment alone for sustained clinical response at day 59 for all treatments, for participants with either their first or second recurrence of CDI. Veterans presenting with a first or second CDI recurrence will be screened, consented and randomly assigned in a double-blind manner equally to one of three treatment groups: 1) a 10 day course of oral vancomycin (VAN-TX), 2) a 10 day course of fidaxomicin (FID-TX) or 3) a 31 day course of vancomycin which includes a taper and pulse following daily treatment (VAN-TP/P). Symptom resolution is defined as an improvement or resolution of diarrhea ( 3 unformed bowel movements over 24 hours) for 48 consecutive hours compared to the participant's baseline. Recurrence is defined as having diarrhea (\>3 loose or semi-formed stools over 24 hours for 48 consecutive hours). A sample size of 459 randomized study participants is required to obtain 91% global power to detect a 16% absolute difference (expected proportion of 31% in the VAN-TX group) in sustained clinical response (D- COM) proportion for at least one comparison (VAN-TP/P vs. VAN-TX, FID-TX vs. VAN-TX) at the family wised error rate (FWER) 0.05 level. The marginal probability (disjunctive power) of detecting 16% absolute difference for each comparison is 81%. The expected withdrawal rate prior to day 59 (prior outcome assessment) is estimated to be 10%. If both FID-TX and VAN-TP/P are found to be superior to VAN-TX, then the non-inferiority of VAN-TP/P to FID-TX will be assessed. With the assumption that sites recruit 4 participants (site average) per year for sites primarily recruiting from the main hospital and nearby CBOCS, and 6 participants (site average) per year for sites that could partner with independent VAMCs (Independent VAMCs LSI Application will be reviewed and approved by Central IRB) that are close in distance to allow a shared site coordinator (WOC appointed) at an increased funding level, the study is expected to complete enrollment of 459 participants within 6 years with 90 days of follow-up. This includes 2 years of pilot phase plus transitioning period from pilot phase to full study, and 4 years of full study. There were 6 sites in the pilot phase and will have 24 units (26 sites) in full phase (including 5 pilot sites and 21 additional sites). Sites that are significantly below the recruitment target for an extensive period may be considered for termination. The recruitment timeline and the number of sites will be re-evaluated based on the actual recruitment rate, the number of sites still recruiting, whether replacement or additional sites will be added, the study time period on administrative recruitment hold due to COVID-19 pandemic, and available funding resources.

Johnson S, Gerding DN, Li X, Reda DJ, Donskey CJ, Gupta K, Goetz MB, Climo MW, Gordin FM, Ringer R, Johnson N, Johnson M, Calais LA, Goldberg AM, Ge L, Haegerich T.

2022-04-075 citations

10.1016/j.cct.2022.106756

Interventions

DRUGFidaxomicin

200 mg PO twice daily for 10 days

DRUGVancomycin with Taper/Pulse

125 mg PO four times daily for 10 days, followed by 125 mg once daily x 7 days, then once every other day x 7 days, then once every 3rd day x 7 days

DRUGVancomycin

125 mg PO for times daily for 10 days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Informed consent obtained and signed * Age \> 18 * If female, participant must not be pregnant or nursing * Negative pregnancy test required for females \<61 years of age or without prior hysterectomy * Confirmed current diagnosis of CDI, determined by having * \>3 loose or semi-formed stools for participants over 24 hours AND * Positive stool assay for C. difficile * EIA positive for toxin A/B; or * Cytotoxin assay; or * Nucleic Acid Amplification Test (NAAT, PCR or LAMP) based detection of toxigenic C. difficile * Current episode represents the first recurrent episode of CDI within 3 months of the primary CDI episode in a patient who has not had CDI in the 3 months prior to the primary episode OR a second recurrent CDI episode occurring within 3 months of the first recurrent episode, as defined above * At least one of the previous CDI episodes must have been confirmed by a stool assay for C. difficile

Exclusion criteria

* Inability to provide informed consent * Inability to take oral capsules * Receipt of \>72 hours of antibiotics considered effective in the treatment of CDI, including: * metronidazole * vancomycin * fidaxomicin * nitazoxanide * rifaximin * Prior infusion of bezlotoxumab within the previous 6 months * Known presence of fulminant CDI, including hypotension, severe ileus or GI obstruction or incipient toxic megacolon * Receipt of more than a single course of oral vancomycin, fidaxomicin, or a vancomycin tapering regimen since the primary episode of CDI as defined above * Known allergy to vancomycin or fidaxomicin * Acute or chronic diarrhea due to inflammatory bowel disease or other cause (e.g., presence of an ileostomy or colostomy) that would confound evaluation of response to CDI treatment * Anticipation of need for long term systemic antibiotic treatment (beyond 7 days) * Patients with an active diagnosis of COVID-19 will be excluded from the study, but patients who have recovered (per current CDC guidance on discontinuation of transmission-based precautions) can be included in the study.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	Day 59 for all treatment regimens.	The Primary outcome will be sustained clinical response as measured at study day 59 for all treatment regimens. Sustained clinical response is a composite outcome that includes symptom resolution during treatment without any of the following (as assessed on day 59): 1. Diarrhea recurrence 2. Other non-fatal clinical events including severe abdominal pain, toxic megacolon (where diarrhea ceases but is not a beneficial outcome), and colectomy 3. Death

Secondary

Measure	Time frame	Description
Sustained Diarrhea Composite Outcome (D-COM) at 28 Days Post End of Therapy	28 Days Post End of Therapy	Sustained Diarrhea Composite Outcome (D-COM) at 28 days Post End of Therapy- Secondary Analyses of Primary Outcome. Sustained clinical response without recurrent CDI (CDI-COM) at 28 days post end of therapy for all three treatment regimens. Sustained clinical response was defined using the same criteria as previously stated except that the endpoint will be 28 days after the last dose of treatment drug for each treatment arm (day 38 for vancomycin and fidaxomicin, and day 59 for vancomycin taper/pulse).Sustained clinical response is a composite endpoint defined as symptom resolution during treatment without diarrhea recurrence, mortality or other important clinical outcomes at any time during the follow-up period. Those participants failing to meet the criteria of symptom resolution (diarrhea resolution) by the end of the active treatment (day 10 for all groups), or who experience a recurrence during the follow-up period, will be considered study treatment failures.
Clostridium Difficile Infection Composite Outcome (CDI-COM)	Day 59 post randomization	Clostridium difficile Infection Composite Outcome (CDI-COM) at day 59 post randomization. Sustained response in CDI-COM is defined using the same composite endpoint criteria as was used in the D-COM composite outcome but with confirmation of no CDI recurrence by a negative C. difficile stool assay test (i.e., proportion of subjects who achieve symptom resolution by day 10 without recurrent CDI, without non-fatal clinical events, and without death).
Symptom Resolution	Day 10 since randomization	The percentage of participants who had symptom resolution by Day 10 post randomization
CDI Recurrence	Day 90 since randomization	CDI recurrence following initial symptom resolution
Diarrhea Recurrence	Day 90 since randomization	Diarrhea recurrence with confirmation of recurrent CDI following initial symptom resolution
C.Diff Health Related Quality of Life (HRQOL)	Day 10 since randomization	Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline (day 0) to day 10. The HRQOL is measured with patient self-reported 32-item questionnaire. The summary measure, CDiff32-QOL, is the total score that sums over 32 individual items with each item rated on a 5-point Likert scale and then transformed to a 100-point scale with higher score indicating better C.diff Health Related QOL in general. The full scale of the HRQOL: 1-5 on a 5-point Likert scale and 0-100 on the 100-point scale; the minimum: 0 on the 100-point scale and maximum value: 100 on the 100-point scale. The summary measure (32 items) range on the 100-point scale: 0-3200.
Sustained Clinical Response (D-COM) BI/NAP1/027 Strain as "Yes"	Day 59 since randomization	Sustained clinical response (D-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (yes) at study enrollment; etc.). The sliced analysis was used to break down the subgroup factors into different sub-levels and then to explore the differences between treatment group (VAN-TP and FDX) and VAN control group at each level.
Sustained Clinical Response (D-COM) With the BI/NAP1/027 Strain no	Day 59 since randomization	Sustained clinical response (D-COM) at day 59 for subgroups (infection with the BI/NAP1/027 strain (no) at study enrollment; etc.). The sliced analysis was used to break down the subgroup factors into different sub-levels and then to explore the differences between therapy group (VAN-TP and FDX) and VAN control group at each level.
Sustained Diarrhea Composite Outcome (D-COM) at 90 Days After Randomization	90 Days After Randomization	Sustained Diarrhea Composite Outcome (D-COM) at 90 days after Randomization - Secondary Analyses of Primary Outcome

Countries

Puerto Rico, United States

Contacts

STUDY_CHAIRStuart B. Johnson, MD BA

Edward Hines Jr. VA Hospital, Hines, IL

STUDY_CHAIRDale N Gerding, MD

Edward Hines Jr. VA Hospital, Hines, IL

Participant flow

Participants by arm

Arm	Count
Fidaxomicin Standard 10-day fidaxomicin treatment for Clostridium difficile Fidaxomicin: 200 mg PO twice daily for 10 days	105
Vancomycin T/P Standard 10-day vancomycin treatment followed by taper and pulse vancomycin treatment for Clostridium difficile Vancomycin with Taper/Pulse: 125 mg PO four times daily for 10 days, followed by 125 mg once daily x 7 days, then once every other day x 7 days, then once every 3rd day x 7 days	102
Vancomycin Standard 10-day vancomycin treatment for Clostridium difficile Vancomycin: 125 mg PO for times daily for 10 days	101
Total	308

Baseline characteristics

Characteristic	Fidaxomicin	Vancomycin T/P	Vancomycin	Total
Age, Continuous	66.6 years STANDARD_DEVIATION 12.5	67.7 years STANDARD_DEVIATION 11.9	67.9 years STANDARD_DEVIATION 12	67.4 years STANDARD_DEVIATION 12.1
Race/Ethnicity, Customized African American	15 Participants	18 Participants	19 Participants	52 Participants
Race/Ethnicity, Customized Other	3 Participants	4 Participants	3 Participants	10 Participants
Race/Ethnicity, Customized White	86 Participants	80 Participants	79 Participants	245 Participants
Sex: Female, Male Female	12 Participants	6 Participants	11 Participants	29 Participants
Sex: Female, Male Male	93 Participants	96 Participants	90 Participants	279 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	8 / 102	2 / 100	3 / 100
other Total, other adverse events	7 / 102	15 / 100	12 / 100
serious Total, serious adverse events	34 / 102	30 / 100	27 / 100

Outcome results

Primary

Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens

The Primary outcome will be sustained clinical response as measured at study day 59 for all treatment regimens. Sustained clinical response is a composite outcome that includes symptom resolution during treatment without any of the following (as assessed on day 59): 1. Diarrhea recurrence 2. Other non-fatal clinical events including severe abdominal pain, toxic megacolon (where diarrhea ceases but is not a beneficial outcome), and colectomy 3. Death

Time frame: Day 59 for all treatment regimens.

Population: mITT Primary Analysis: Missing primary outcome D-COM at Day 59 in the mITT analysis was imputed by an imputation model.~mITT Sensitivity Analysis 1: Missing primary outcome D-COM at Day 59 was treated as failure.~mITT Sensitivity Analysis 2: Missing outcomes were excluded as a complete case analysis.~PP analysis: Participants who 1) failed to respond by day 10 or completed day 59 follow-up and (2) took 80% of their assigned drug according to the pill count (Per-Protocol population).

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Fidaxomicin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Primary Analysis	44 Participants
Fidaxomicin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Sensitivity Analysis 1	40 Participants
Fidaxomicin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Sensitivity Analysis 2	40 Participants
Fidaxomicin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	PP Analysis	39 Participants
Vancomycin T/P	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	PP Analysis	55 Participants
Vancomycin T/P	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Primary Analysis	58 Participants
Vancomycin T/P	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Sensitivity Analysis 2	56 Participants
Vancomycin T/P	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Sensitivity Analysis 1	56 Participants
Vancomycin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	PP Analysis	42 Participants
Vancomycin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Sensitivity Analysis 1	42 Participants
Vancomycin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Sensitivity Analysis 2	42 Participants
Vancomycin	Number of Participants With Sustained Clinical Response as Measured at Study Day 59 for All Treatment Regimens	mITT Primary Analysis	44 Participants

Secondary

C.Diff Health Related Quality of Life (HRQOL)

Change in patient reported C.diff Health Related Quality of Life (HRQOL) from baseline day 0 to day 59. The HRQOL is measured with patient self-reported 32-item questionnaire. The summary measure, CDiff32-QOL, is the total score that sums over 32 individual items with each item rated on a 5-point Likert scale and then transformed to a 100-point scale with higher score indicating better C.diff Health Related QOL in general. The full scale of the HRQOL: 1-5 on a 5-point Likert scale and 0-100 on the 100-point scale; the minimum: 0 on the 100-point scale and maximum value: 100 on the 100-point scale. The summary measure (32 items) range on the 100-point scale: 0-3200.

Time frame: day 0- day 59