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

Primary Purpose

Clostridium Difficile Infection

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Cadazolid
Vancomycin
Cadazolid-matching placebo
Vancomycin-matching placebo
Sponsored by
Actelion
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Clostridium Difficile Infection focused on measuring Post-antibiotic diarrhea, Clostridium difficile infection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed Informed Consent.
  • Male or female ≥ 18 years of age. Females of childbearing potential must agree to use an adequate and reliable method of contraception.
  • Subject with a diagnosis of mild-moderate or severe CDAD (first occurrence or first recurrence within 3 months) with: Diarrhea: a change in bowel habits with > 3 liquid or unformed bowel movements (UBM) within 24 hours prior to randomization, AND Positive C. difficile toxin test on a stool sample produced within 72 hours prior to randomization.

Exclusion Criteria:

  • More than one previous episode of CDAD in the 3-month period prior to randomization.
  • Evidence of life-threatening or fulminant CDAD.
  • Likelihood of death within 72 hours from any cause.
  • History of inflammatory colitides, chronic abdominal pain, or chronic diarrhea.
  • Antimicrobial treatment active against CDAD administered for > 24 hours except for metronidazole treatment failures (MTF)
  • Known hypersensitivity or contraindication to study drugs, oxazolidinones, or quinolones.
  • Unable or unwilling to comply with all protocol requirements.
  • Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol

Sites / Locations

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Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Cadazolid

Vancomycin

Arm 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

Outcomes

Primary Outcome Measures

Clinical Cure Rate (CCR) in the Modified Intent-to-treat Population
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.
Clinical Cure Rate (CCR) in the Per-protocol Population
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.

Secondary Outcome Measures

Sustained Cure Rate (SCR) in the Modified Intent-to-treat Population
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).
Kaplan-Meier Estimates for Resolution of Diarrhea
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.
Change From Baseline to Day 3 in Clostridium Difficile Infection (CDI) Daily Symptoms Patient-Reported Outcome (CDI-DaySyms PRO) Domain Scores
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.

Full Information

First Posted
November 7, 2013
Last Updated
May 3, 2018
Sponsor
Actelion
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1. Study Identification

Unique Protocol Identification Number
NCT01987895
Brief Title
Efficacy and Safety of Cadazolid Versus Vancomycin in Subjects With Clostridium Difficile - Associated Diarrhea
Official Title
A Multi-center, Randomized, Double-blind Study to Compare the Efficacy and Safety of Cadazolid Versus Vancomycin in Subjects With Clostridium Difficile-associated Diarrhea (CDAD)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
March 27, 2014 (Actual)
Primary Completion Date
February 26, 2017 (Actual)
Study Completion Date
March 24, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Actelion

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This clinical study is conducted to assess the efficacy of cadazolid compared to vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD).
Detailed Description
Subjects selected to participate in the study are treated either with cadazolid or vancomycin for 10 days. At the end of treatment, clinical cure is assessed; subjects are then followed-up to assess any disease recurrence.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clostridium Difficile Infection
Keywords
Post-antibiotic diarrhea, Clostridium difficile infection

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
632 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cadazolid
Arm Type
Experimental
Arm Description
Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days
Arm Title
Vancomycin
Arm Type
Active Comparator
Arm Description
Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
Intervention Type
Drug
Intervention Name(s)
Cadazolid
Other Intervention Name(s)
ACT-179811
Intervention Description
Cadazolid 250 mg as oral suspension twice daily.
Intervention Type
Drug
Intervention Name(s)
Vancomycin
Other Intervention Name(s)
Vancocin
Intervention Description
Vancomycin 125 mg as oral capsules 4 times daily.
Intervention Type
Drug
Intervention Name(s)
Cadazolid-matching placebo
Intervention Description
Placebo matching cadazolid and administered orally twice daily
Intervention Type
Drug
Intervention Name(s)
Vancomycin-matching placebo
Intervention Description
Placebo capsules matching vancomycin and administered orally 4 times per day
Primary Outcome Measure Information:
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)
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)
Secondary Outcome Measure Information:
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)
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
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
Other Pre-specified Outcome Measures:
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)
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)
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)
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)
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed Informed Consent. Male or female ≥ 18 years of age. Females of childbearing potential must agree to use an adequate and reliable method of contraception. Subject with a diagnosis of mild-moderate or severe CDAD (first occurrence or first recurrence within 3 months) with: Diarrhea: a change in bowel habits with > 3 liquid or unformed bowel movements (UBM) within 24 hours prior to randomization, AND Positive C. difficile toxin test on a stool sample produced within 72 hours prior to randomization. Exclusion Criteria: More than one previous episode of CDAD in the 3-month period prior to randomization. Evidence of life-threatening or fulminant CDAD. Likelihood of death within 72 hours from any cause. History of inflammatory colitides, chronic abdominal pain, or chronic diarrhea. Antimicrobial treatment active against CDAD administered for > 24 hours except for metronidazole treatment failures (MTF) Known hypersensitivity or contraindication to study drugs, oxazolidinones, or quinolones. Unable or unwilling to comply with all protocol requirements. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anne Claire Marrast, MD
Organizational Affiliation
Actelion
Official's Role
Study Director
Facility Information:
Facility Name
Investigator Site
City
Mobile
State/Province
Alabama
ZIP/Postal Code
36608
Country
United States
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Investigator Site
City
Oceanside
State/Province
California
ZIP/Postal Code
92056
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United States
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Investigator Site
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
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United States
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Investigator Site
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Aurora
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Colorado
ZIP/Postal Code
80045
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United States
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Investigator Site
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Naples
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Florida
ZIP/Postal Code
34110
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United States
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Investigator Site
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Port Orange
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Florida
ZIP/Postal Code
32127
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United States
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Investigator Site
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West Palm Beach
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Florida
ZIP/Postal Code
33401
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United States
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Investigator Site
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Decatur
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Georgia
ZIP/Postal Code
30033
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United States
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Idaho Falls
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Idaho
ZIP/Postal Code
83404
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United States
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Carmel
State/Province
Indiana
ZIP/Postal Code
46032
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United States
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Investigator Site
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Chevy Chase
State/Province
Maryland
ZIP/Postal Code
20815
Country
United States
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Investigator Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
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United States
Facility Name
Investigator Site
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South Weymouth
State/Province
Massachusetts
ZIP/Postal Code
02190
Country
United States
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Investigator Site
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68114
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United States
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Investigator Site
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Brooklyn
State/Province
New York
ZIP/Postal Code
11229
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United States
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Investigator Site
City
New York
State/Province
New York
ZIP/Postal Code
10016
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United States
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New York
State/Province
New York
ZIP/Postal Code
10022
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United States
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Investigator Site
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Syracuse
State/Province
New York
ZIP/Postal Code
13210
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United States
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Dayton
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Ohio
ZIP/Postal Code
45428
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United States
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Lima
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Ohio
ZIP/Postal Code
45801
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United States
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Pittsburgh
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Pennsylvania
ZIP/Postal Code
15213
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United States
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Dallas
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Texas
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75216
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United States
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Houston
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Texas
ZIP/Postal Code
77030
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United States
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Lansdowne Town Center
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Virginia
ZIP/Postal Code
20176
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United States
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Investigator Site
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Winchester
State/Province
Virginia
ZIP/Postal Code
22601
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United States
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Geelong
ZIP/Postal Code
3217
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Australia
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Investigator Site
City
Southport
ZIP/Postal Code
4215
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Australia
Facility Name
Investigator Site
City
Salvador
State/Province
Bahia
ZIP/Postal Code
40110-160
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Brazil
Facility Name
Investigator Site
City
Porto Alegre
ZIP/Postal Code
90035-903
Country
Brazil
Facility Name
Investigator Site
City
Sao Paulo
ZIP/Postal Code
05651-901
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Brazil
Facility Name
Investigator Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M3N 2V6
Country
Canada
Facility Name
Investigator Site
City
Calgary
ZIP/Postal Code
T2N 2T9
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Canada
Facility Name
Investigator Site
City
Edmonton
ZIP/Postal Code
T6G 2X8
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Canada
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Investigator Site
City
Hamilton
ZIP/Postal Code
L8N 4A6
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Canada
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Investigator Site
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Montreal
ZIP/Postal Code
H1T 2M4
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Canada
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Saint-Jerome
ZIP/Postal Code
J7Z 5T3
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Canada
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Dijon
ZIP/Postal Code
21079
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France
Facility Name
Investigator Site
City
Grenoble
ZIP/Postal Code
38043
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France
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Investigator Site
City
Lille
ZIP/Postal Code
59037
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France
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Investigator Site
City
Orleans
ZIP/Postal Code
45067
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France
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Investigator Site
City
Paris
ZIP/Postal Code
75679
Country
France
Facility Name
Investigator Site
City
Paris
ZIP/Postal Code
75877
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France
Facility Name
Investigator Site
City
Hamburg
ZIP/Postal Code
20246
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Germany
Facility Name
Investigator Site
City
Koln
ZIP/Postal Code
50937
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Germany
Facility Name
Investigator Site
City
Bergamo
ZIP/Postal Code
24127
Country
Italy
Facility Name
Investigator Site
City
Monza
ZIP/Postal Code
20900
Country
Italy
Facility Name
Investigator Site
City
Roma
ZIP/Postal Code
00149
Country
Italy
Facility Name
Investigator Site
City
Roma
ZIP/Postal Code
00161
Country
Italy
Facility Name
Investigator Site
City
Apeldoorn
ZIP/Postal Code
7334 DZ
Country
Netherlands
Facility Name
Investigator Site
City
Dordrecht
ZIP/Postal Code
3318 AT
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Netherlands
Facility Name
Investigator Site
City
Lima
ZIP/Postal Code
01
Country
Peru
Facility Name
Investigator Site
City
Lancut
ZIP/Postal Code
37-100
Country
Poland
Facility Name
Investigator Site
City
Lodz
ZIP/Postal Code
91-347
Country
Poland
Facility Name
Investigator Site
City
Myslowice
ZIP/Postal Code
41-400
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Poland
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Investigator Site
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Wroclaw
ZIP/Postal Code
51-149
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Poland
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Bucharest
ZIP/Postal Code
050098
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Romania
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Investigator Site
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Craiova
ZIP/Postal Code
200515
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Romania
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Barcelona
ZIP/Postal Code
08025
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Spain
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City
Barcelona
ZIP/Postal Code
08035
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Spain
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Investigator Site
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
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Investigator Site
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Boadilla del Monte
ZIP/Postal Code
28660
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Spain
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Investigator Site
City
Lleida
ZIP/Postal Code
25198
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Spain
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Investigator Site
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Madrid
ZIP/Postal Code
28007
Country
Spain
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Investigator Site
City
Majadahonda
ZIP/Postal Code
28222
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
30709665
Citation
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.
Results Reference
derived
PubMed Identifier
29680101
Citation
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.
Results Reference
derived

Learn more about this trial

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

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