Efficacy and Safety of Cadazolid Versus Vancomycin in Subjects With Clostridium Difficile - Associated Diarrhea

• ClinicalTrials.gov Identifier: NCT01987895
• Recruitment Status: Completed
• First Posted: November 20, 2013
• Results First Posted: May 4, 2018
• Last Update Posted: May 4, 2018
• Sponsor: Actelion
• Information provided by (Responsible Party): Actelion

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Clostridium Difficile Infection
• Interventions: Drug: Cadazolid; Drug: Vancomycin; Drug: Cadazolid-matching placebo; Drug: Vancomycin-matching placebo
• Enrollment: 632

Participant Flow

Recruitment Details	904 patients at 70 sites in 12 countries were screened, among whom 632 were enrolled in the IMPACT 1 trial at 64 sites located in North & South America, Europe and Australia.
Pre-assignment Details

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description	Subjects with Clostridium difficile-associated diarrhea (CDAD) received oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times a day (qid) for 10 days. Subjects were followed up for 30 days after the last dose of cadazolid. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)	Subjects with CDAD received oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days. Subjects were followed up for 30 day after the last dose of vancomycin. Subjects who had a first recurrence of CDAD during the follow-up period were offered to enter a re-treatment extension period with cadazolid (10 day of cadazolid + 30-day follow up)
Period Title: Overall Study
Started	306	326
Completed [1]	276	296
Not Completed	30	30
Reason Not Completed
Withdrawal by Subject	12	7
Physician Decision	8	10
Death	7	7
Lost to Follow-up	3	5
randomized before giving IC	0	1
[1] Include subjects who completed the main study + subjects who completed the re-treatment extension.

Baseline Characteristics

Arm/Group Title		Cadazolid	Vancomycin	Total
Arm/Group Description		Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days	Total of all reporting groups
Overall Number of Baseline Participants		302	318	620
Baseline Analysis Population Description		The baseline characteristics were defined using the modified intent-to-treat analysis set (mITT) including all randomized subjects who have received at least one dose of the study drug and had a confirmed diagnosis of CDAD
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	302 participants	318 participants	620 participants
18-64 years		180 59.6%	203 63.8%	383 61.8%
65-74 years		73 24.2%	70 22.0%	143 23.1%
75 years and older		49 16.2%	45 14.2%	94 15.2%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	302 participants	318 participants	620 participants
	Female	183 60.6%	195 61.3%	378 61.0%
	Male	119 39.4%	123 38.7%	242 39.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	302 participants	318 participants	620 participants
Black or African American		3 1.0%	9 2.8%	12 1.9%
Asian		2 0.7%	3 0.9%	5 0.8%
Native Hawaiian or Other Pacific Islander		1 0.3%	0 0.0%	1 0.2%
White		288 95.4%	299 94.0%	587 94.7%
Other		2 0.7%	4 1.3%	6 1.0%
Missing		6 2.0%	3 0.9%	9 1.5%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	302 participants	318 participants	620 participants
United States		101 33.4%	108 34.0%	209 33.7%
Canada		83 27.5%	88 27.7%	171 27.6%
Europe		111 36.8%	117 36.8%	228 36.8%
Other		7 2.3%	5 1.6%	12 1.9%
CDAD episode type strata [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	302 participants	318 participants	620 participants
First occurrence		238 78.8%	253 79.6%	491 79.2%
First recurrence		64 21.2%	65 20.4%	129 20.8%
		[1] Measure Description: CDAD episode type strata was defined as baseline stratification factor 'First occurrence' or 'First recurrence' of CDAD as recorded in the Interactive voice recognition system (IVRS) at the time of subject randomization. Number of subjects with first recurrence or first occurrence at randomization was assessed for each treatment group.
Initial strain of Clostridium difficile [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	302 participants	318 participants	620 participants
Hypervirulent strains		58 19.2%	82 25.8%	140 22.6%
Non-hypervirulent strains		226 74.8%	215 67.6%	441 71.1%
Unable to determine		18 6.0%	21 6.6%	39 6.3%
		[1] Measure Description: The strain of C. difficile at baseline was identified in the last stool sample collected up to treatment start date and with available C. difficile culture. Identification was done by polymerase chain reaction (PCR). The strains were categorized as hypervirulent strains (PCR ribotype 027, 078 or 244) or non-hypervirulent (other PCR ribotypes). The number of subjects with hypervirulent, non-hypervirulent strains at baseline was assessed for each treatment group. If PCR ribotype at baseline was not available, the subjects were classified as "unable to determine".
CDAD severity at baseline [1]; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	302 participants	318 participants	620 participants
Mild-Moderate		227 75.2%	243 76.4%	470 75.8%
Severe		59 19.5%	51 16.0%	110 17.7%
Unable to determine		16 5.3%	24 7.5%	40 6.5%
		[1] Measure Description: CDAD at baseline was considered as severe if the following criteria were met: maximum body temperature > 38.5 C, white blood cell counts > 15.0 x 10*9/L and rise in baseline serum creatinine > 50% compared to the level before CDAD diagnosis. Otherwise, it was considered as mild-moderate. The number of subjects with severe and mild-moderate CDAD at baseline was assessed for each treatment group. If any of the measurements required for derivation of severity was missing, the subjects were classified as "unable to determine".

Outcome Measures

1. Primary Outcome

Title	Clinical Cure Rate (CCR) in the Modified Intent-to-treat Population
Description	Clinical Cure (CC) is defined as: • Resolution of Diarrhea (≤ 3 unformed bowel movement per day for at least 2 consecutive days) on study treatment and maintained for 2 days after end-of-treatment (EOT), AND • No additional antimicrobial treatment active against Clostridium difficile-associated diarrhea (CDAD) or fecal microbiota transplant between first dose of study drug and 2 days after EOT. CCR is the percentage of subjects with Clinical Cure. Analyses are performed on two analysis sets. Results on the modified intent-to-treat set (mITT) are reported below.
Time Frame	Up to Day 12 on average (end-of-treatment + 2 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	302	318
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	83.8; (79.2 to 87.5)	85.2; (80.9 to 88.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of CCR for cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above -10%.
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -7.2 to 4.3
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson's score method

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	Sensitivity analysis with imputation for a single day with missing UBM data between one day before end-of-treatment (EOT) and 2 days after EOT
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of CCR for cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above -10%.
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -8.1 to 3.2
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson's score method

2. Primary Outcome

Title	Clinical Cure Rate (CCR) in the Per-protocol Population
Description	Clinical Cure (CC) is defined as: • Resolution of Diarrhea (≤ 3 unformed bowel movement per day for at least 2 consecutive days) on study treatment and maintained for 2 days after end-of-treatment (EOT), AND • No additional antimicrobial treatment active against Clostridium difficile-associated diarrhea (CDAD) or fecal microbiota transplant between first dose of study drug and 2 days after EOT. CCR is the percentage of subjects with Clinical Cure. Analyses are performed on two analysis sets. Results on the per-protocol set (PPS) are reported below.
Time Frame	Up to Day 12 on average (end-of-treatment + 2 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD and without protocol deviations that might affect the evaluation of the effect of the study drug on the primary variable.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	282	288
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	87.6; (83.2 to 90.9)	91.7; (87.9 to 94.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	[Not Specified]
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority of CCR for cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above -10%.
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	-4.1
	Confidence Interval	(2-Sided) 95%; -9.2 to 1.0
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson' score method

3. Secondary Outcome

Title	Sustained Cure Rate (SCR) in the Modified Intent-to-treat Population
Description	Sustained Cure is defined for each subject having Clinical Cure and no recurrence. SCR is the percentage of subjects with Sustained Cure. The main analysis is performed on the modified intent-to-treat set (mITT).
Time Frame	Between Day 38 and Day 42 on average (end-of-treatment + 28-32 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	302	318
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	65.6; (60.0 to 70.7)	62.3; (56.8 to 67.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Superiority of cadazolid versus vancomycin is demonstrated if the lower limit of the 95% confidence interval (CI) is above zero
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; -4.3 to 10.8
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson's score method

4. Secondary Outcome

Title	Kaplan-Meier Estimates for Resolution of Diarrhea
Description	Resolution of Diarrhea (ROD) is defined as no more than 3 unformed bowel movements per day for at least two consecutive days for subjects on study treatment. The Kaplan-Meier estimates (KM estimates) for having an event (ROD) are reported for each time point.
Time Frame	Up to Day 10

Outcome Measure Data

Analysis Population Description

The analyses were performed on the modified intention-to-treat population: all subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	302	318
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: KM estimate (%)
Day 1	46.7; (41.2 to 52.5)	45.9; (40.6 to 51.6)
Day 2	62.6; (57.2 to 68.0)	60.7; (55.4 to 66.1)
Day 3	69.9; (64.6 to 74.9)	71.1; (66.0 to 76.0)
Day 4	72.8; (67.7 to 77.7)	77.7; (73.0 to 82.1)
Day 5	77.8; (73.0 to 82.3)	80.2; (75.6 to 84.4)
Day 6	81.1; (76.5 to 85.3)	81.8; (77.3 to 85.8)
Day 7	82.5; (78.0 to 86.5)	84.6; (80.4 to 88.3)
Day 8	83.4; (79.0 to 87.4)	85.2; (81.1 to 88.9)
Day 9	83.8; (79.4 to 87.7)	85.2; (81.1 to 88.9)
Day 10	83.8; (79.4 to 87.7)	85.2; (81.1 to 88.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6016
	Comments	two-sided p-value (alpha 5%) based on log-rank test stratified by first occurrence / first recurrence and geographical region.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.14
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Change From Baseline to Day 3 in Clostridium Difficile Infection (CDI) Daily Symptoms Patient-Reported Outcome (CDI-DaySyms PRO) Domain Scores
Description	CDI-DaySyms PRO is a questionnaire assessing 10 symptoms relevant to subjects with CDAD and grouped into 3 domains: Diarrhea symptoms, Abdominal symptoms and Systemic/Other. The subjects rate the severity of each item as None, Mild, Moderate, Severe or Very severe, converted to numeric scores from 0 to 4, respectively. The daily domain score is calculated as the mean of the non-missing responses for that domain on that day. A negative value for change from baseline corresponds to an improvement in domain score. The three domains are evaluated in a hierarchical manner, starting with Diarrhea Symptoms, then Abdominal Symptoms, and finally Systemic/Other Symptoms. The least squares means (LSM) are computed on the scores.
Time Frame	Day 1 (baseline) and Day 3

Outcome Measure Data

Analysis Population Description

All subjects from the modified intent-to-treat population, excluding those who participated in the validation sub-study. No imputation of missing scores is performed prior to deriving response status. Subjects with missing values at baseline or at Day 3 are considered to be non-responders.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	246	260
Least Squares Mean (95% Confidence Interval); Unit of Measure: Score on a scale
Diarrhea symptoms	-1.233; (-1.37 to -1.09)	-1.235; (-1.37 to -1.10)
Abdominal symptoms	-0.623; (-0.74 to -0.51)	-0.710; (-0.82 to -0.60)
Other symptoms	-0.639; (-0.74 to -0.54)	-0.689; (-0.79 to -0.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	Comparison of the diarrhea domain scores
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9814
	Comments	Two-sided 5% alpha level was used
	Method	ANOVA
	Comments	ANOVA for repeated measurements was fitted using all values from Day 1 (baseline) to Day 12.
Method of Estimation	Estimation Parameter	Least Square Mean difference
	Estimated Value	0.002
	Confidence Interval	(2-Sided) 95%; -0.20 to 0.20
	Estimation Comments	The Least Square Means of the treatments differences for the changes from baseline at Day 3 were obtained using estimate statements

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	Comparison of the abdominal symptoms domain scores
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2879
	Comments	Two-sided 5% alpha level was used
	Method	ANOVA
	Comments	ANOVA for repeated measurements was fitted using all values from Day 1 (baseline) to Day 12
Method of Estimation	Estimation Parameter	Least Square Mean difference
	Estimated Value	0.087
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.25
	Estimation Comments	The Least Square Means of the treatments differences for the changes from baseline at Day 3 were obtained using estimate statements

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	Comparison of the systemic / other symptoms domain scores
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4880
	Comments	Two-sided 5% alpha level was used
	Method	ANOVA
	Comments	ANOVA for repeated measurements was fitted using all values from Day 1 (baseline) to Day 12
Method of Estimation	Estimation Parameter	Least Square Mean difference
	Estimated Value	0.050
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.19
	Estimation Comments	The Least Square Means of the treatments differences for the changes from baseline at Day 3 were obtained using estimate statements

6. Other Pre-specified Outcome

Title	Investigator's Assessment of Clinical Response (ICR) Rate at Visit 4 in the Modified Intent-to-treat Population
Description	ICR rate (%) is the percentage of subjects with clinical response assessed as cured according to the investigator's own judgement. Subjects with missing assessment are considered as not cured for the analysis. ICR rate is used as a supportive measure of the primary efficacy endpoint (CCR). Analyses are performed on two analysis sets. Results on the modified intent-to-treat set (mITT) are reported below.
Time Frame	Up to Day 12 on average (up to end-of-treatment + 2 to 4 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	302	318
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	89.7; (85.8 to 92.7)	91.5; (87.9 to 94.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	Exploratory analysis
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -6.5 to 2.9
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson's score method

7. Other Pre-specified Outcome

Title	Investigator's Assessment of Clinical Response (ICR) Rate at Visit 4 in the Per-protocol Population
Description	ICR rate (%) is the percentage of subjects with clinical response assessed as cured according to the investigator's own judgement. ICR rate (%) is the percentage of subjects with ICR assessed as cured. Subjects with missing assessment are considered as not cured for the analysis. ICR rate is used as a supportive measure of the primary efficacy endpoint (CCR). Analyses are performed on two analysis sets. Results on the per-protocol set (PPS) are reported below.
Time Frame	Up to Day 12 on average (up to end-of-treatment + 2 to 4 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD and without protocol deviations that might affect the evaluation of the effect of the study drug on the primary variable.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	282	288
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	92.2; (88.5 to 94.8)	94.1; (90.8 to 96.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	Exploratory analysis
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -6.2 to 2.3
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson's score method

8. Other Pre-specified Outcome

Title	Investigator's Assessment of Sustained Response Rate (ISR Rate) at Visit 5
Description	ISR rate (%) is the percentage of subjects assessed as Sustained Cure at Visit 5, according to the investigator's own judgement. Sustained Cure is defined for each subject having Clinical Cure and no recurrence. Subjects with missing assessment are considered as having 'Not Sustained Cure' for the analysis. ISR rate is used as a supportive measure of the secondary efficacy endpoint (SCR). Analyses are performed on the modified intent-to-treat set (mITT).
Time Frame	Between Day 38 and Day 42 on average (end-of-treatment + 28 to 32 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	302	318
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	73.8; (68.6 to 78.5)	70.1; (64.9 to 74.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	Exploratory analysis
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	3.7
	Confidence Interval	(2-Sided) 95%; -3.4 to 10.7
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson's score method

9. Other Pre-specified Outcome

Title	Sustained Cure Rate (SCR) in the Per-protocol Population
Description	Sustained Cure is defined for each subject having Clinical Cure and no recurrence. SCR is the percentage of subjects with Sustained Cure. The analyses performed on the modified intent-to- treat set (mITT) are repeated on the per-protocol set (PPS) for sensitivity.
Time Frame	Between Day 38 and Day 42 on average (end-of-treatment + 28-32 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study drug and had a confirmed diagnosis of CDAD and without protocol deviations that might affect the evaluation of the effect of the study drug on the primary variable.

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	282	288
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	68.8; (63.2 to 73.9)	67.7; (62.1 to 72.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cadazolid, Vancomycin
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	Sensitivity analysis
Method of Estimation	Estimation Parameter	Difference between 2 proportions
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -6.5 to 8.7
	Estimation Comments	CI for the difference between two proportions are estimated using the Wilson's score method

10. Other Pre-specified Outcome

Title	Recurrence Rate
Description	Recurrence is defined as the occurrence of a new episode of diarrhea (> 3 unformed bowel movements on any day between end-of-treatment + 3 days and end-of-treatment + 30 days ) Recurrence rates is the percentage of subjects assessed as having a recurrence out of subjects with Clinical Cure.
Time Frame	Between Day 13 and Day 40 on average (from end-of-treatment + 3 days and end-of-treatment + 30 days)

Outcome Measure Data

Analysis Population Description

Subjects from the modified intent-to-treat analysis set with clinical cure

Arm/Group Title	Cadazolid	Vancomycin
Arm/Group Description:	Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Overall Number of Participants Analyzed	253	271
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	15; (11.1 to 19.9)	21.4; (16.9 to 26.7)

Adverse Events

Time Frame	Serious and frequent adverse events are reported from study treatment initiation up to Day 17 on average (i.e., 7 days after end-of-treatment or study withdrawal) and all-cause mortality up to Day 40 on average (i.e. 28 to 32 days after end-of-treatment or study withdrawal)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Cadazolid		Vancomycin
Arm/Group Description	304 subjects received at least one dose of cadazolid and were included in the safety analysis. The median duration of treatment with cadazolid was 10 days.		322 subjects received at least one dose of vancomycin and were included in the safety analysis. The median duration of treatment with vancomycin was 10 days.
All-Cause Mortality
	Cadazolid		Vancomycin
	Affected / at Risk (%)		Affected / at Risk (%)
Total	7/304 (2.30%)		7/322 (2.17%)
Serious Adverse Events
	Cadazolid		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/304 (6.25%)		26/322 (8.07%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Thrombocytopenia † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Cardiac disorders
Acute myocardial infarction † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Atrioventricular block second degree † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Cardiac failure † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Cardiac failure chronic † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Cardiac failure congestive † 1	1/304 (0.33%)	1	1/322 (0.31%)	1
Cardio-respiratory arrest † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Myocardial infarction † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Gastrointestinal disorders
Ascites † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Gastrointestinal haemorrhage † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Megacolon † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Pancreatitis † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Rectal stenosis † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Small intestinal obstruction † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
General disorders
Oedema peripheral † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Hepatobiliary disorders
Cholangitis † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Cholangitis acute † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Hypertransaminasaemia † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Infections and infestations
Abdominal abscess † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Arthritis bacterial † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Cellulitis † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Cellulitis of male external genital organ † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Clostridium difficile infection † 1	2/304 (0.66%)	2	8/322 (2.48%)	8
Endocarditis † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Perineal abscess † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Peritonitis bacterial † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Pneumonia † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Pseudomembranous colitis † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Sepsis † 1	2/304 (0.66%)	2	2/322 (0.62%)	2
Septic shock † 1	1/304 (0.33%)	1	1/322 (0.31%)	1
Sinusitis † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Urinary tract infection † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Urinary tract infection pseudomonal † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Injury, poisoning and procedural complications
Anaemia postoperative † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Biliary anastomosis complication † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Metabolism and nutrition disorders
Dehydration † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Diabetic ketoacidosis † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Hyperglycaemia † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic cancer † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Metastases to central nervous system † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Metastatic carcinoma of the bladder † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Nervous system disorders
Cerebrovascular accident † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Chronic kidney disease † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Renal failure † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Acute pulmonary oedema † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Pulmonary embolism † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Pulmonary oedema † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Respiratory failure † 1	1/304 (0.33%)	1	1/322 (0.31%)	1
Skin and subcutaneous tissue disorders
Skin ulcer † 1	1/304 (0.33%)	1	0/322 (0.00%)	0
Vascular disorders
Deep vein thrombosis † 1	2/304 (0.66%)	2	0/322 (0.00%)	0
Hypotension † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
Peripheral vascular disorder † 1	0/304 (0.00%)	0	1/322 (0.31%)	1
1 Term from vocabulary, MedDRA 19.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Cadazolid		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/304 (10.86%)		49/322 (15.22%)
Gastrointestinal disorders
Abdominal pain † 1	14/304 (4.61%)	16	22/322 (6.83%)	24
Nausea † 1	12/304 (3.95%)	13	24/322 (7.45%)	27
Nervous system disorders
Headache † 1	14/304 (4.61%)	17	25/322 (7.76%)	28
1 Term from vocabulary, MedDRA 19.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

Any study-related publication written independently by investigators must be submitted to Actelion for review at least 30 days prior to submission for publication or presentation. Upon review, Actelion may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights.

Results Point of Contact

• Name/Title: Clinical Trial disclosure Desk
• Organization: Actelion Pharmaceuticals Ltd
• Phone: 0041615656565
• EMail: clinical-trials-disclosure@its.jnj.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gerding DN, Cornely OA, Grill S, Kracker H, Marrast AC, Nord CE, Talbot GH, Buitrago M, Gheorghe Diaconescu I, Murta de Oliveira C, Preotescu L, Pullman J, Louie TJ, Wilcox MH. Cadazolid for the treatment of Clostridium difficile infection: results of two double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. Lancet Infect Dis. 2019 Mar;19(3):265-274. doi: 10.1016/S1473-3099(18)30614-5. Epub 2019 Jan 29.

Kleinman L, Talbot GH, Hunsche E, Schuler R, Nord CE. The CDI-DaySyms: Content Development of a New Patient-Reported Outcome Questionnaire for Symptoms of Clostridium difficile Infection. Value Health. 2018 Apr;21(4):441-448. doi: 10.1016/j.jval.2017.08.3017. Epub 2017 Nov 7.

• Responsible Party: Actelion
• ClinicalTrials.gov Identifier: NCT01987895
• Other Study ID Numbers: AC-061A301
• First Submitted: November 7, 2013
• First Posted: November 20, 2013
• Results First Submitted: February 23, 2018
• Results First Posted: May 4, 2018
• Last Update Posted: May 4, 2018