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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Clostridium Difficile Infection

Intervention / Treatment
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* Drug: Cadazolid
* Drug: Vancomycin capsule
* Drug: Vancomycin solution


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A / Cohort A<br>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<br>* Granules for oral suspension to be administered twice daily<br>* Other names: ACT-179811;|
| Experimental: Part A / Cohort B<br>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<br>* Granules for oral suspension to be administered twice daily<br>* Other names: ACT-179811;|
| Experimental: Part A / Cohort C<br>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<br>* Granules for oral suspension to be administered twice daily<br>* Other names: ACT-179811;|
| Experimental: Part A/ Cohort D<br>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<br>* Granules for oral suspension to be administered twice daily<br>* Other names: ACT-179811;|
| Experimental: Part A/ Cohort E<br>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<br>* Granules for oral suspension to be administered twice daily<br>* Other names: ACT-179811;|
| Experimental: Part B / Cadazolid<br>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<br>* Granules for oral suspension to be administered twice daily<br>* Other names: ACT-179811;|
| Active Comparator: Part B / Vancomycin<br>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<br>* Capsule containing 125 mg of vancomycin to be administered orally 4 times a day<br>Drug: Vancomycin solution<br>* Vancomycin powder to be administered as oral solution at a dose of 40 mg/kg/day, 3 to 4 times a day<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vancomycin, children, cadazolid, clostridium difficile associated diarrhea