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

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)

This clinical study is conducted to assess the efficacy of cadazolid compared to vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD).

Study Overview

• Status: Completed
• Conditions: Clostridium Difficile Infection
• Intervention / Treatment: Drug: Cadazolid; Drug: Vancomycin-matching placebo; Drug: Vancomycin; Drug: Cadazolid-matching placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 632
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Geelong, Australia, 3217
    • Investigator site
  • Southport, Australia, 4215
    • Investigator site
• Brazil
  • Porto Alegre, Brazil, 90035-903
    • Investigator site
  • Sao Paulo, Brazil, 05651-901
    • Investigator site
  • Bahia
    • Salvador, Bahia, Brazil, 40110-160
      • Investigator site
• Canada
  • Calgary, Canada, T2N 2T9
    • Investigator site
  • Edmonton, Canada, T6G 2X8
    • Investigator site
  • Hamilton, Canada, L8N 4A6
    • Investigator site
  • Montreal, Canada, H1T 2M4
    • Investigator site
  • Saint-Jerome, Canada, J7Z 5T3
    • Investigator site
  • Ontario
    • Toronto, Ontario, Canada, M3N 2V6
      • Investigator site
• France
  • Dijon, France, 21079
    • Investigator site
  • Grenoble, France, 38043
    • Investigator site
  • Lille, France, 59037
    • Investigator site
  • Orleans, France, 45067
    • Investigator site
  • Paris, France, 75679
    • Investigator site
  • Paris, France, 75877
    • Investigator site
• Germany
  • Hamburg, Germany, 20246
    • Investigator site
  • Koln, Germany, 50937
    • Investigator site
• Italy
  • Bergamo, Italy, 24127
    • Investigator site
  • Monza, Italy, 20900
    • Investigator site
  • Roma, Italy, 00149
    • Investigator site
  • Roma, Italy, 00161
    • Investigator site
• Netherlands
  • Apeldoorn, Netherlands, 7334 DZ
    • Investigator site
  • Dordrecht, Netherlands, 3318 AT
    • Investigator site
• Peru
  • Lima, Peru, 01
    • Investigator site
• Poland
  • Lancut, Poland, 37-100
    • Investigator site
  • Lodz, Poland, 91-347
    • Investigator site
  • Myslowice, Poland, 41-400
    • Investigator site
  • Wroclaw, Poland, 51-149
    • Investigator site
• Romania
  • Bucharest, Romania, 050098
    • Investigator site
  • Craiova, Romania, 200515
    • Investigator site
• Spain
  • Barcelona, Spain, 08025
    • Investigator site
  • Barcelona, Spain, 08035
    • Investigator site
  • Barcelona, Spain, 08036
    • Investigator site
  • Boadilla del Monte, Spain, 28660
    • Investigator site
  • Lleida, Spain, 25198
    • Investigator site
  • Madrid, Spain, 28007
    • Investigator site
  • Majadahonda, Spain, 28222
    • Investigator site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Investigator site
  • California
    • Oceanside, California, United States, 92056
      • Investigator site
    • Sacramento, California, United States, 95817
      • Investigator site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Investigator site
  • Florida
    • Naples, Florida, United States, 34110
      • Investigator site
    • Port Orange, Florida, United States, 32127
      • Investigator site
    • West Palm Beach, Florida, United States, 33401
      • Investigator site
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Investigator site
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Investigator site
  • Indiana
    • Carmel, Indiana, United States, 46032
      • Investigator site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Investigator site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Investigator site
    • South Weymouth, Massachusetts, United States, 02190
      • Investigator site
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Investigator site
  • New York
    • Brooklyn, New York, United States, 11229
      • Investigator site
    • New York, New York, United States, 10016
      • Investigator site
    • New York, New York, United States, 10022
      • Investigator site
    • Syracuse, New York, United States, 13210
      • Investigator site
  • Ohio
    • Dayton, Ohio, United States, 45428
      • Investigator site
    • Lima, Ohio, United States, 45801
      • Investigator site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Investigator site
  • Texas
    • Dallas, Texas, United States, 75216
      • Investigator site
    • Houston, Texas, United States, 77030
      • Investigator site
  • Virginia
    • Lansdowne Town Center, Virginia, United States, 20176
      • Investigator site
    • Winchester, Virginia, United States, 22601
      • Investigator site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cadazolid; Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days	Drug: Cadazolid; Cadazolid 250 mg as oral suspension twice daily.; Other Names: ACT-179811; Drug: Vancomycin-matching placebo; Placebo capsules matching vancomycin and administered orally 4 times per day
Active Comparator: Vancomycin; Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days	Drug: Vancomycin; Vancomycin 125 mg as oral capsules 4 times daily.; Other Names: Vancocin; Drug: Cadazolid-matching placebo; Placebo matching cadazolid and administered orally twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to Day 12 on average (end-of-treatment + 2 days)
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.	Up to Day 12 on average (end-of-treatment + 2 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Between Day 38 and Day 42 on average (end-of-treatment + 28-32 days)
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.	Up to Day 10
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.	Day 1 (baseline) and Day 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigator's Assessment of Clinical Response (ICR) Rate at Visit 4 in the Modified Intent-to-treat Population	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.	Up to Day 12 on average (up to end-of-treatment + 2 to 4 days)
Investigator's Assessment of Clinical Response (ICR) Rate at Visit 4 in the Per-protocol Population	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.	Up to Day 12 on average (up to end-of-treatment + 2 to 4 days)
Investigator's Assessment of Sustained Response Rate (ISR Rate) at Visit 5	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).	Between Day 38 and Day 42 on average (end-of-treatment + 28 to 32 days)
Sustained Cure Rate (SCR) in the Per-protocol Population	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.	Between Day 38 and Day 42 on average (end-of-treatment + 28-32 days)
Recurrence Rate	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.	Between Day 13 and Day 40 on average (from end-of-treatment + 3 days and end-of-treatment + 30 days)

Collaborators and Investigators

• Sponsor: Actelion

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 27, 2014
• Primary Completion (Actual): February 26, 2017
• Study Completion (Actual): March 24, 2017

Study Registration Dates

• First Submitted: November 7, 2013
• First Submitted That Met QC Criteria: November 13, 2013
• First Posted (Estimate): November 20, 2013

Study Record Updates

• Last Update Posted (Actual): May 4, 2018
• Last Update Submitted That Met QC Criteria: May 3, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Clostridium difficile infection; Post-antibiotic diarrhea
• Additional Relevant MeSH Terms: Infections; Signs and Symptoms, Digestive; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Diarrhea; Clostridium Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Vancomycin; Oxazolidinones
• Other Study ID Numbers: AC-061A301

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No