Clostridium Difficile Infection
Conditions
Keywords
vancomycin, children, cadazolid, clostridium difficile associated diarrhea
Brief summary
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
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.
Interventions
DRUGCadazolid
Granules for oral suspension to be administered twice daily
Capsule containing 125 mg of vancomycin to be administered orally 4 times a day
DRUGVancomycin solution
Vancomycin powder to be administered as oral solution at a dose of 40 mg/kg/day, 3 to 4 times a day
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Assessor masking in Part B only (no masking in Part A)
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Cure Rate During Part B | Day 10 (End of Treatment) + 2 days | 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 |
| Maximal Plasma Concentration (Cmax) of Cadazolid During Part A | Day 10 (End of Treatment) | Blood samples are collected at different timepoints on Day 10 for the determination of cadazolid Cmax after 10 days of treatment. |
| Time to Reach Cmax (Tmax) of Cadazolid During Part A | Day 10 (End of Treatment) | Blood samples are collected at different timepoints to determine the time when the maximal plasma concentration of cadazolid is reached. |
| Area Under the Plasma Concentration Time Curve (AUC) of Cadazolid During Part A | Day 10 (End of Treatment) | Blood samples are collected at different timepoints for the determination of the cadazolid AUC over one dosing interval (0-12h) on Day 10. |
| Fecal Concentrations of Cadazolid During Part A | Day 10 (End of Treatment) | A fecal sample is collected as the end-of-treatment visit in all participants in Part A. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events Leading to Premature Discontinuation of Study Treatment | Up to Day 10 | Number of participants who prematurely discontinued the study treatment due to an adverse event |
| Marked Abnormalities in Clinical Laboratory Parameters | Day 17 (on average) | Number of participants with any marked abnormalities in laboratory parameters up to 7 days after end of treatment |
| Clinical Cure Rate During Part A | Day 10 (End of Treatment) + 2 days | 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). |
| Treatment-emergent Adverse Events (TEAES) | Day 17 (on average) | 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. |
| Marked Abnormalities in Vital Signs | Day 17 (on average) | Number of subjects with any treatment-emergent abnormalities in vital signs (up to 7 days after end of treatment) |
| Sustained Clinical Cure Rate During Part A and Part B | Day 40 (on average) | 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). |
| Recurrence Rate During Part A and Part B | Day 40 (on average) | 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. |
| Time to Recurrence in Part B | Day 40 (on average) | 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) |
| Time to Resolution of Diarrhea in Part B | Day 10 | 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 |
Countries
Belgium, Canada, Czechia, Hungary, Italy, Poland, Romania, Spain, United States
Participant flow
Recruitment details
Due to early termination of the study after sponsor's decision to discontinue the development of cadazolid, only one patient was enrolled at one site in the US.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Part A / Cohort A | — |
|---|---|---|
| Age, Customized Adolescents (12 years to < 18 years) | 1 Participants | — |
| Age, Customized Children (2 years to < 12 years | 0 Participants | — |
| Age, Customized infants and toddlers (3 months to < 2 years | 0 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 1 Participants | — |
| Sex: Female, Male Male | 0 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
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.
Time frame: Day 10 (End of Treatment)
Population: Due to the premature study termination, cadazolid concentrations were obtained from only one subject and pharmacokineitc plasma profile was not analyzed because of lack of meaningful data.
Primary
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
Time frame: Day 10 (End of Treatment) + 2 days
Population: Due to the premature study termination, no subject was enrolled into Part B and consequently the percentage of subjects with a clinical cure could not be reported.
Primary
Fecal Concentrations of Cadazolid During Part A
A fecal sample is collected as the end-of-treatment visit in all participants in Part A.
Time frame: Day 10 (End of Treatment)
Population: Due to premature termination, fecal sample was collected from only one subject, consequently mean values cannot be provided and no statistical analyses can be performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part B | Fecal Concentrations of Cadazolid During Part A | 4520 mcg/g |
Primary
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.
Time frame: Day 10 (End of Treatment)
Population: Due to the premature study termination, cadazolid concentrations were obtained from only one subject and pharmacokineitc plasma profile was not analyzed because of lack of meaningful data.
Primary
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.
Time frame: Day 10 (End of Treatment)
Population: Due to the premature study termination, cadazolid concentrations were obtained from only one subject and pharmacokineitc plasma profile was not analyzed because of lack of meaningful data.
Secondary
Adverse Events Leading to Premature Discontinuation of Study Treatment
Number of participants who prematurely discontinued the study treatment due to an adverse event
Time frame: Up to Day 10
Population: Due to premature termination, no subject was enrolled in Part B. Consequently, no data can be reported during Part B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part B | Adverse Events Leading to Premature Discontinuation of Study Treatment | 0 Participants |
Secondary
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).
Time frame: Day 10 (End of Treatment) + 2 days
Population: Due to premature termination, data were collected from only one subject, consequently percentage of participants with clinical cure cannot be calculated and no statistical analyses can be performed
Secondary
Marked Abnormalities in Clinical Laboratory Parameters
Number of participants with any marked abnormalities in laboratory parameters up to 7 days after end of treatment
Time frame: Day 17 (on average)
Population: Due to premature termination, no subject was enrolled in Part B. Consequently, no data can be reported during Part B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part B | Marked Abnormalities in Clinical Laboratory Parameters | 0 Participants |
Secondary
Marked Abnormalities in Vital Signs
Number of subjects with any treatment-emergent abnormalities in vital signs (up to 7 days after end of treatment)
Time frame: Day 17 (on average)
Population: Due to premature termination, no subject was enrolled in Part B. Consequently, no data can be reported during Part B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part B | Marked Abnormalities in Vital Signs | 0 Participants |
Secondary
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.
Time frame: Day 40 (on average)
Population: Due to the premature termination of the study and consequent lack of meaningful data, no analyses were performed.
Secondary
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).
Time frame: Day 40 (on average)
Population: Due to the premature termination of the study and consequent lack of meaningful data, no analyses were performed.
Secondary
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)
Time frame: Day 40 (on average)
Population: Due to premature termination, no subject was enrolled in Part B. Consequently, no data can be reported during Part B
Secondary
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
Time frame: Day 10
Population: Due to premature termination, data were collected from only one subject, consequently KM estimates cannot be calculated and no statistical analyses can be performed
Secondary
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.
Time frame: Day 17 (on average)
Population: Due to premature termination, no subject was enrolled in Part B. Consequently, no data can be reported during Part B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part B | Treatment-emergent Adverse Events (TEAES) | 0 Participants |