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

Tracking Information

• First Submitted Date: November 7, 2013
• First Posted Date: November 20, 2013
• Results First Submitted Date: February 23, 2018
• Results First Posted Date: May 4, 2018
• Last Update Posted Date: May 4, 2018
• Actual Study Start Date: March 27, 2014
• Actual Primary Completion Date: February 26, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 3, 2018)

• Clinical Cure Rate (CCR) in the Modified Intent-to-treat Population [ Time Frame: Up to Day 12 on average (end-of-treatment + 2 days) ]
  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 [ Time Frame: Up to Day 12 on average (end-of-treatment + 2 days) ]
  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.

Original Primary Outcome Measures (submitted: November 13, 2013)

Clinical Cure at End of Treatment [ Time Frame: End of Treatment(10 days after starting study drug) +2days ]

Resolution of Diarrhea AND No additional CDAD treatment.

Current Secondary Outcome Measures (submitted: May 3, 2018)

• Sustained Cure Rate (SCR) in the Modified Intent-to-treat Population [ Time Frame: Between Day 38 and Day 42 on average (end-of-treatment + 28-32 days) ]
  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 [ Time Frame: Up to Day 10 ]
  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 [ Time Frame: Day 1 (baseline) and Day 3 ]
  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.

Original Secondary Outcome Measures (submitted: November 13, 2013)

• Sustained Cure [ Time Frame: End of Treatment(10 days after starting study drug) +28-32 days ]
  Clinical Cure AND No Recurrence.
• Time to Resolution of Diarrhea [ Time Frame: Baseline to End of Treatment(10 days after starting study drug) ]
  The time between the first dose of study drug and Resolution of Diarrhea.
• CDAD Symptoms [ Time Frame: Baseline to End of Treamtent(10 days after starting study drug) +2 days ]
  Change from baseline to End of Treatment +2days in CDAD Symptoms as measured by the DaySyms Patient Reported Outcome (PRO).

Current Other Pre-specified Outcome Measures (submitted: May 3, 2018)

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

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Clostridium Difficile Infection

Intervention

• Drug: Cadazolid
  Cadazolid 250 mg as oral suspension twice daily.
  Other Name: ACT-179811
• Drug: Vancomycin
  Vancomycin 125 mg as oral capsules 4 times daily.
  Other Name: Vancocin
• Drug: Cadazolid-matching placebo
  Placebo matching cadazolid and administered orally twice daily
• Drug: Vancomycin-matching placebo
  Placebo capsules matching vancomycin and administered orally 4 times per day

Study Arms

• Experimental: Cadazolid
  Subjects receive oral cadazolid 250 mg twice daily (bid) and oral vancomycin-matching placebo 4 times per day (qid) for 10 days
  Interventions:

  • Drug: Cadazolid
  • Drug: Vancomycin-matching placebo
• Active Comparator: Vancomycin
  Subjects receive oral vancomycin 125 mg qid and oral cadazolid-matching placebo bid for 10 days
  Interventions:

  • Drug: Vancomycin
  • Drug: Cadazolid-matching placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 28, 2017): 632
• Original Estimated Enrollment (submitted: November 13, 2013): 640
• Actual Study Completion Date: March 24, 2017
• Actual Primary Completion Date: February 26, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Canada, France, Germany, Italy, Netherlands, Peru, Poland, Romania, Spain, United States

Administrative Information

• NCT Number: NCT01987895
• Other Study ID Numbers: AC-061A301
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Actelion
• Original Responsible Party: Same as current
• Current Study Sponsor: Actelion
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Anne Claire Marrast, MD; Actelion

• PRS Account: Actelion
• Verification Date: May 2018