Comparison of Cadazolid Versus Vancomycin in Children With Clostridium Difficile-associated Diarrhea (CDAD)

A Prospective, Multicenter Study to Investigate the Pharmacokinetics, Safety, and Efficacy of Cadazolid Versus Vancomycin in Pediatric Subjects With Clostridium Difficile-associated Diarrhea

Cadazolid has demonstrated activity against a bacteria named Clostridium difficile in animal studies. The results of a first study conducted in adult patients have suggested efficacy of the new antibiotic, cadazolid, in the treatment of diarrhea caused by this bacteria. This is the first study of cadazolid in children. The overall purpose of this study is to provide reassurance on the safety and efficacy of cadazolid in children suffering from infection due to Clostridium difficile.

Study Overview

• Status: Terminated
• Conditions: Clostridium Difficile Infection
• Intervention / Treatment: Drug: Cadazolid; Drug: Vancomycin capsule; Drug: Vancomycin solution

Detailed Description

This multicenter, study will be run into two parts. Both parts will be run in consecutive age cohorts, starting from the oldest age categories(12 to < 18 years old) to the youngest (birth to < 3 months).

• Part A is an open-label, dose finding part to be conducted in at least 24 subjects.
• Part B follows a randomized, assessor-blinded, parallel-group design with vancomycin used as an active comparator. Part B will be conducted in about 176 children.

In both parts, the treatment period will be 10 days and will be followed by a Follow-up period of 28-32 days.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Jette, Belgium, 1090
    • Universitair Ziekenhuis Brussel - Kinderziekenhuis
• Canada
  • Calgary, Canada, T2N 2T9
    • Infection Prevention & Control, AGW5 Foothills Medical Center 1403 29th Street N.W.
• Czechia
  • Brno, Czechia, 62500
    • FN Brno
• Hungary
  • Budapest, Hungary, 1097
    • Egyesített Szent István és Szent László Kórház - Rendelőintézet / Gyermekinfektológiai Osztály
  • Gyula, Hungary, 5700
    • Pándy Kálmán Megyei Kórház
• Italy
  • Milano, Italy, 20154
    • Ospedale Buzzi
  • Roma, Italy, 00165
    • Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) - Ospedale Pediatrico Bambino Gesu
• Poland
  • Bydgoszcz, Poland, 85-030
    • Wojewodzki Szpital Obserwacyjno-Zakazny im. Tadeusza Browicza
  • Poznan, Poland, 61-734
    • Specjalistyczny Zespół Opieki Zdrowotnej nad Matką i Dzieckiem
  • Rzeszow, Poland, 35-302
    • Gabinet Lekarski Bartosz Korczowski
  • Warsaw, Poland, 04-730
    • Klinika Gastroenterologii, Hepatologii, Zaburzeń Odżywiania i Pediatrii, Instytut "Pomnik - Centrum Zdrowia Dziecka"
• Romania
  • Bucharest, Romania, 21105
    • Institutul National De Boli Infectioase "Prof. Dr. Matei Bals", sectia IX pediatrie
  • Iasi, Romania, 700116
    • Spitalul Clinic de Boli Infectioase "Sfanta Parascheva" Iasi, Clinica de Boli Infectioase I,
• Spain
  • Barcelona, Spain, 8950
    • Hospital Sant Joan de Déu, Esplugues
  • Madrid, Spain, 28046
    • Hospital Universitario Infantil la Paz
• United States
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Snake River Research, PLLC
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago, Dept. Of Medicine
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Sciences Center - Shreveport
  • Ohio
    • Syracuse, Ohio, United States, 13210
      • SUNY Upstate Medical University - Upstate Golisano Children's Hospital (GCH) - Pediatric Designated AIDS Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital Feigin Cente

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• Signed informed consent by parents or legally authorized representatives (LAR) and assent by the child according to local requirements prior to initiation of any study-mandated procedure.
• Male or female from birth to < 18 years of age, diagnosed with Clostridium Difficile-associated diarrhea (CDAD).
• Females of childbearing potential must have a negative pregnancy test at screening and must agree to use an adequate and reliable method of contraception.

Key Exclusion Criteria:

• Positive Rotavirus test for subjects < 5 years.
• Fulminant or life-threatening CDAD.
• More than one previous episode of CDAD in the 3 month period prior to enrollment / randomization.
• Antimicrobial treatment active against CDAD administered within 24 h prior to screening except for metronidazole treatment failures (MTF).
• Subjects with body weight < 3 kg.
• Inflammatory bowel disease, chronic abdominal pain, or chronic diarrhea of any etiology.
• Fecal microbiota transplant (FMT), immunoglobulin therapy, or any investigational drug to prevent or treat CDAD within 1 month period (or 5 half-lives in case of investigational drug, whichever is longer) prior to enrollment / randomization.
• Monoclonal antibodies against C. difficile within 6 months prior to enrollment / randomization.
• Previous vaccination against C. difficile.
• Known mental disorders.
• Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's 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: Single

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A / Cohort A; Subjects from 12 years to 18 years old (exclusive) will receive cadazolid 500 mg per day for 10 days. The dose may be adjusted based on the pharmacokinetic (PK) and safety data reviewed for the first 3 subjects.	Drug: Cadazolid; Granules for oral suspension to be administered twice daily; Other Names: ACT-179811
Experimental: Part A / Cohort B; Subjects from 6 years to 12 years old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort A reviewed by the Independent Data Monitoring Committee (IDMC).	Drug: Cadazolid; Granules for oral suspension to be administered twice daily; Other Names: ACT-179811
Experimental: Part A / Cohort C; Subjects from 2 years to 6 years old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort B reviewed by the IDMC.	Drug: Cadazolid; Granules for oral suspension to be administered twice daily; Other Names: ACT-179811
Experimental: Part A/ Cohort D; Subjects from 3 months to 2 years old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort C reviewed by the IDMC.	Drug: Cadazolid; Granules for oral suspension to be administered twice daily; Other Names: ACT-179811
Experimental: Part A/ Cohort E; Subjects from birth to 3 months old (exclusive) will receive cadazolid for 10 days. The dose will depend on the PK and safety data from cohort D reviewed by the IDMC.	Drug: Cadazolid; Granules for oral suspension to be administered twice daily; Other Names: ACT-179811
Experimental: Part B / Cadazolid; Subjects from birth to 18 years old (exclusive) will receive cadazolid for 10 days, at the dose defined in the corresponding age cohort in Part A.	Drug: Cadazolid; Granules for oral suspension to be administered twice daily; Other Names: ACT-179811
Active Comparator: Part B / Vancomycin; Subjects from birth to 18 years old (exclusive) will receive vancomycin capsule (for subjects able to swallow) or vancomycin solution (for the others) during 10 days .	Drug: Vancomycin capsule; Capsule containing 125 mg of vancomycin to be administered orally 4 times a day; Drug: Vancomycin solution; Vancomycin powder to be administered as oral solution at a dose of 40 mg/kg/day, 3 to 4 times a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Cure Rate During Part B	This is the percentage of participants in part B reported as with a clinical cure. Clinical Cure is defined as: • <3 unformed bowel movement (UBM) per day (or no water diarrhea if subjects < 2 years of age), for at least 2 consecutive days between first dose of study treatment up to end of treatment (EOT) (inclusive) AND • Subject remains well up to EOT + 2 days (inclusive) based on investigator judgment AND • No need for additional antimicrobial treatment active against Clostridium difficile-associated diarrhea (CDAD) between first dose of study treatment up to EOT + 2 days (inclusive). percentage of subjects with a clinical cure	Day 10 (End of Treatment) + 2 days
Maximal Plasma Concentration (Cmax) of Cadazolid During Part A	Blood samples are collected at different timepoints on Day 10 for the determination of cadazolid Cmax after 10 days of treatment.	Day 10 (End of Treatment)
Time to Reach Cmax (Tmax) of Cadazolid During Part A	Blood samples are collected at different timepoints to determine the time when the maximal plasma concentration of cadazolid is reached.	Day 10 (End of Treatment)
Area Under the Plasma Concentration Time Curve (AUC) of Cadazolid During Part A	Blood samples are collected at different timepoints for the determination of the cadazolid AUC over one dosing interval (0-12h) on Day 10.	Day 10 (End of Treatment)
Fecal Concentrations of Cadazolid During Part A	A fecal sample is collected as the end-of-treatment visit in all participants in Part A.	Day 10 (End of Treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Cure Rate During Part A	This is the percentage of participants in Part A reported as with a clinical cure. Clinical Cure is defined as: • <3 unformed bowel movement (UBM) per day (or no water diarrhea if subjects < 2 years of age), for at least 2 consecutive days between first dose of study treatment up to end of treatment (EOT) (inclusive) AND • Subject remains well up to EOT + 2 days (inclusive) based on investigator judgment AND • No need for additional antimicrobial treatment active against Clostridium difficile-associated diarrhea (CDAD) between first dose of study treatment up to EOT + 2 days (inclusive).	Day 10 (End of Treatment) + 2 days
Sustained Clinical Cure Rate During Part A and Part B	This is the percentage of participants in Parts A and B reported as with sustained clinical cure. Sustained clinical cure is defined as • Clinical Cure and no Recurrence until 30 days after the last study drug intake (end of study).	Day 40 (on average)
Recurrence Rate During Part A and Part B	This is the percentage of participants in Parts A and B assessed as having a recurrence out of subjects meeting the criteria for Clinical Cure. Recurrence is defined as: • Clinical Cure AND New episode of diarrhea with ≥ 3 UBMs (or watery diarrhea if subject < 2 years) on any day between EOT + 3 days and end of study AND • Stool test showing positive C. difficile (as defined in Inclusion Criterion 4), AND •Antimicrobial treatment active against CDAD started between EOT + 3 days and end of study.	Day 40 (on average)
Time to Recurrence in Part B	This it the time (in days) elapsed between the last dose of study drug and the onset day of new episode of diarrhea reported as Kaplan-Meier estimates (KM estimates)	Day 40 (on average)
Time to Resolution of Diarrhea in Part B	This is the time (in days) elapsed between the first dose of study treatment and the resolution of diarrhea and reported as Kaplan-Meier estimates (KM estimates). The date of resolution of Diarrhea (ROD) is defined as the date of the first day of the 2 consecutive days on treatment with < 3 UBM (or no watery diarrhea for subjects < 2 years of age). Time to ROD is the time (in days) elapsed between the first dose of study treatment and the ROD	Day 10
Adverse Events Leading to Premature Discontinuation of Study Treatment	Number of participants who prematurely discontinued the study treatment due to an adverse event	Up to Day 10
Marked Abnormalities in Clinical Laboratory Parameters	Number of participants with any marked abnormalities in laboratory parameters up to 7 days after end of treatment	Day 17 (on average)
Marked Abnormalities in Vital Signs	Number of subjects with any treatment-emergent abnormalities in vital signs (up to 7 days after end of treatment)	Day 17 (on average)
Treatment-emergent Adverse Events (TEAES)	Number of subjects with any TEAEs. A TEAE is any adverse event temporally associated with the use of study treatment (from study treatment initiation until 7 days after study treatment discontinuation) whether or not considered by the investigator as related to study treatment.	Day 17 (on average)

Collaborators and Investigators

• Sponsor: Actelion

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2017
• Primary Completion (Actual): April 17, 2018
• Study Completion (Actual): April 17, 2018

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: April 3, 2017
• First Posted (Actual): April 10, 2017

Study Record Updates

• Last Update Posted (Actual): April 3, 2019
• Last Update Submitted That Met QC Criteria: March 14, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: children; vancomycin; cadazolid; clostridium difficile associated diarrhea
• Additional Relevant MeSH Terms: Infections; Signs and Symptoms, Digestive; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Diarrhea; Clostridium Infections; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin
• Other Study ID Numbers: AC-061A303; 2015-004805-17 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No