Clinical Trial Results:
A Phase 2A, Multi-Center, Open-Label, Uncontrolled Study to Determine the Safety, Tolerability, and Pharmacokinetics of fidaxomicin Oral Suspension or Tablets in Pediatric Subjects With Clostridium difficile-associated Diarrhea
Summary
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EudraCT number |
2013-001448-75 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
07 Mar 2014
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Results information
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Results version number |
v1 |
This version publication date |
01 Jun 2016
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First version publication date |
13 Jun 2015
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
OPT-80-206
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01591863 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Optimer Pharmaceuticals (a Cubist company)
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Sponsor organisation address |
4747 Executive Dr. Ste 1100, San Diego, CA, United States, 92121
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Public contact |
Clinical Trial Disclosure, Astellas Pharma Global Developmnet, Inc., Astellas.resultsdisclosure@astellas.com
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Scientific contact |
Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000636-PIP01-09 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
07 Mar 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Mar 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Mar 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to investigate the safety, tolerability, and pharmacokinetics of fidaxomicin oral suspension or tablets in pediatric subjects, aged 6 months to 17 years, 11 months, with Clostridium difficile-associated diarrhea (CDAD), following the administration of doses given every 12 hours for 10 consecutive days. Both plasma and fecal PK analyses were performed.
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Protection of trial subjects |
This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki.
Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Oct 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 3
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Country: Number of subjects enrolled |
United States: 35
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Worldwide total number of subjects |
38
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
9
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Children (2-11 years) |
17
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Adolescents (12-17 years) |
12
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Participants diagnosed with CDAD, defined by (1) a positive stool C.difficile Toxin A and/or Toxin B assay result within 48 hours of enrollment; (2) in the 24 hours prior to enrollment: participants 6-23 months: >3 episodes of watery diarrhea; participants 2 years-17 years 11 months: A change in bowel habits, with >3 unformed bowel movements. | ||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Fidaxomicin 6-23 Months | ||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fidaxomicin
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Investigational medicinal product code |
OPT-80, ASP2819
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Other name |
Dificid, Dificlir
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Pharmaceutical forms |
Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Participants aged 6 months to 23 months were dosed with weight-based doses of open-label fidaxomicin oral suspension 32 mg/kg/day, with a maximum dose of 400 mg/day, divided into 2 doses (every 12 hours), with or without food each day for 10 days.
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Arm title
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Fidaxomicin 2-5 Years, 11 Months | ||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fidaxomicin
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Investigational medicinal product code |
OPT-80, ASP2819
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Other name |
Dificid, Dificlir
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Pharmaceutical forms |
Oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Participants aged 2-5 years, 11 months were dosed with weight-based doses of open-label fidaxomicin oral suspension 32 mg/kg/day, with a maximum dose of 400 mg/day, divided into 2 doses (every 12 hours), with or without food each day for 10 days.
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Arm title
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Fidaxomicin 6-11 Years, 11 Months | ||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fidaxomicin
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Investigational medicinal product code |
OPT-80, ASP2819
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Other name |
Dificid, Dificlir
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants aged 6 years to 11 years, 11 months were dosed with open-label fidaxomicin 200 mg tablets by mouth every 12 hours, with or without food, each day for 10 days. Participants aged 6 years to 11 years, 11 months who were unable to swallow tablets received fidaxomicin oral suspension, with a maximum dose of 400 mg/day, divided in 2 doses of 200 mg, with approval by the sponsor on a case-by-case basis and after consultation with the medical monitor.
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Arm title
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Fidaxomicin 12-17 Years, 11 Months | ||||||||||||||||||||||||||||||||||||||||
Arm description |
- | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fidaxomicin
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Investigational medicinal product code |
OPT-80, ASP2819
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Other name |
Dificid, Dificlir
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Participants aged 12 years to 17 years, 11 months were dosed with open-label fidaxomicin 200 mg tablets by mouth every 12 hours, with or without food, each day for 10 days. Participants aged 12 years to 17 years, 11 months who were unable to swallow tablets received fidaxomicin oral suspension, with a maximum dose of 400 mg/day, divided in 2 doses of 200 mg, with approval by the sponsor on a case-by-case basis and after consultation with the medical monitor.
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Baseline characteristics reporting groups
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Reporting group title |
Fidaxomicin 6-23 Months
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fidaxomicin 2-5 Years, 11 Months
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fidaxomicin 6-11 Years, 11 Months
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fidaxomicin 12-17 Years, 11 Months
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Fidaxomicin 6-23 Months
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Reporting group description |
- | ||
Reporting group title |
Fidaxomicin 2-5 Years, 11 Months
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Reporting group description |
- | ||
Reporting group title |
Fidaxomicin 6-11 Years, 11 Months
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Reporting group description |
- | ||
Reporting group title |
Fidaxomicin 12-17 Years, 11 Months
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Reporting group description |
- |
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End point title |
Safety as assessed by incidence of adverse events (AEs), clinical laboratory test results, vital sign measurements, physical examinations, and electrocardiogram (ECG) results [1] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not it is considered related to the medicinal product. A serious AE (SAE) is any untoward medical occurrence that at any dose: Was fatal; Was life threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect. A treatment-emergent adverse event (TEAE) is an adverse event with an onset date/time on or after first dose date/time of study drug. The analysis population was the safety analysis set, which included all patients with any evaluable safety data who have received at least one dose of study drug.
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End point type |
Primary
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End point timeframe |
From first dose of study drug to 30 days after last dose of study drug (up to 41 days)
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design and purposes of the study. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic plasma concentration levels of fidaxomicin [2] | |||||||||||||||||||||||||||||||||||
End point description |
The analysis population was the plasma pharmacokinetic (PK) analysis set which included all dosed participants with evaluable plasma PK data, and excluded concentrations for which a problem occurred during sampling or laboratory analysis that invalidates the concentration measurements.
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End point type |
Primary
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End point timeframe |
Days 5-10
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design and purposes of the study. |
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Notes [3] - Participants with plasma concentrations above the lower limit of quantification. [4] - Participants with plasma concentrations above the lower limit of quantification. [5] - Participants with plasma concentrations above the lower limit of quantification. [6] - Participants with plasma concentrations above the lower limit of quantification. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic plasma concentration levels of fidaxomicin metabolite OP-1118 [7] | |||||||||||||||||||||||||||||||||||
End point description |
The analysis population was the PK analysis set.
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End point type |
Primary
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End point timeframe |
Days 5-10
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Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design and purposes of the study. |
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Notes [8] - Participants with plasma concentrations above the lower limit of quantification. [9] - Participants with plasma concentrations above the lower limit of quantification. [10] - Participants with plasma concentrations above the lower limit of quantification. [11] - Participants with plasma concentrations above the lower limit of quantification. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic fecal concentration levels of fidaxomicin [12] | |||||||||||||||||||||||||
End point description |
The analysis population was the fecal PK analysis set which included all dosed participants with evaluable fecal data, and excluded concentrations for which a problem occurred during collection or laboratory analysis that invalidates the concentration measurements.
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End point type |
Primary
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End point timeframe |
End of therapy (Day 10)
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Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design and purposes of the study. |
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Notes [13] - Participants with fecal concentrations above the lower limit of quantification. [14] - Participants with fecal concentrations above the lower limit of quantification. [15] - Participants with fecal concentrations above the lower limit of quantification. [16] - Participants with fecal concentrations above the lower limit of quantification. |
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No statistical analyses for this end point |
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End point title |
Pharmacokinetic fecal concentration levels of fidaxomicin metabolite OP-1118 [17] | |||||||||||||||||||||||||
End point description |
The analysis population was the fecal PK analysis set.
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End point type |
Primary
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End point timeframe |
End of therapy (Day 10)
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Notes [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design and purposes of the study. |
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Notes [18] - Participants with fecal concentrations above the lower limit of quantification. [19] - Participants with fecal concentrations above the lower limit of quantification. [20] - Participants with fecal concentrations above the lower limit of quantification. [21] - Participants with fecal concentrations above the lower limit of quantification. |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with clinical response (cure) | ||||||||||||||||||||
End point description |
Positive clinical response (cure) was determined as follows: 6 to 23 months: who no longer had watery diarrhea for 2 consecutive days during treatment, who remained well before the time of study drug discontinuation, and who did not require further CDAD therapy within 2 days after completion of study drug were considered to have a positive clinical response; 2 years to 17 years, 11 months: who had improvement in the number and character of bowel movements as determined by 3 or fewer unformed bowel movements for 2 consecutive days during treatment, who remained well before the time of study drug discontinuation, and who did not require further CDAD therapy within 2 days after completion of study drug were considered to have a positive clinical response. The analysis population was the modified intent-to-treat (mITT) analysis set which included all participants with CDAD confirmed by a positive toxin assay within 24 hours prior to enrollment who received at least one dose of study drug.
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End point type |
Secondary
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End point timeframe |
End of therapy (Day 10)
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No statistical analyses for this end point |
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End point title |
Percentage of participants with recurrence of CDAD | ||||||||||||||||||||
End point description |
Recurrence was defined as the the re-establishment of diarrhea after a positive clinical response, where the number of unformed bowel movements (UBMs) was greater than that noted on the last day of study drug and toxin A and/or B was present, and the investigator considered that retreatment of CDAD was necessary. Only participants who achieved a positive clinical response by end of therapy visit were included. Participants who withdrew from the study during the follow-up period were considered to have a recurrence. The analysis population was the mITT analysis set.
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End point type |
Secondary
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End point timeframe |
From end of therapy to 28 days post-treatment
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No statistical analyses for this end point |
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End point title |
Time to recurrence of CDAD | ||||||||||||||||||||||||||||||
End point description |
Time to recurrence of CDAD was defined as the time in days from date of cure to the date of recurrence. Only participants who achieved a positive clinical response by end of therapy visit were included. The survival function for time to recurrence (in days) will be estimated using the Kaplan-Meier method using LIFETEST procedure in SAS. Participants who never recurred during the follow-up period were censored at 30 days after last dose. The analysis population was the mITT analysis set. Confidence Interval (CI) limit that could not be calculated is denoted as "99999" as applicable.
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End point type |
Secondary
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End point timeframe |
From end of therapy to 28 days post-treatment
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Notes [22] - Participants with recurrence. [23] - Participants with recurrence. [24] - Participants with recurrence. [25] - Participants with recurrence. |
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No statistical analyses for this end point |
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End point title |
Percentage of participants with sustained clinical response | ||||||||||||||||||||
End point description |
Sustained clinical response was defined as positive clinical response at the end of treatment without proven or suspected CDAD recurrence through 28 days post treatment. Only participants who achieved a positive clinical response by end of therapy visit were included.The analysis population was the mITT analysis set.
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End point type |
Secondary
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End point timeframe |
From end of therapy to 28 days post-treatment
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No statistical analyses for this end point |
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End point title |
Time to resolution of diarrhea | |||||||||||||||||||||||||||||||||||
End point description |
Time to resolution of diarrhea was defined as the time elapsed (in hours rounded up from minutes ≥30) from the start of treatment (time of first dose of study drug) to resolution of diarrhea (time of the last UBM the day before the first of 2 consecutive days of ≤3 UBMs that were sustained through the end of therapy). The survival function for time to recurrence (in days) was estimated using the Kaplan-Meier method using LIFETEST procedure in SAS. Participants were censored at time of discontinuation, except for those subjects who completed End of Therapy and did not have resolution of diarrhea were censored at 240 hours. The analysis population was the mITT analysis set. Confidence Interval (CI) limit that could not be calculated is denoted as "99999" as applicable.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug to last dose of study drug (up to Day 10)
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Notes [26] - Participants with resolved diarrhea. [27] - Participants with resolved diarrhea. [28] - Participants with resolved diarrhea. [29] - Participants with resolved diarrhea. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From first dose of study drug to 30 days after last dose of study drug
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
Fidaxomicin 6-23 Months
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Reporting group description |
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Reporting group title |
Fidaxomicin 2-5 Years, 11 Months
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Reporting group description |
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Reporting group title |
Fidaxomicin 6-11 Years, 11 Months
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Reporting group description |
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Reporting group title |
Fidaxomicin 12-17 Years, 11 Months
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Reporting group description |
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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25 Jan 2012 |
Major changes to the conduct of the study are summarized: (1) Revised the timing of the CDAD signs and symptoms evaluation to address redundancy with this assessment and the participant/legal guardian interview (CDAD status); (2) Revised the timing of the investigator’s determination of clinical response as was
noted in the schedule of events; (3) Revised AE language for clarity and consistency. |
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04 Apr 2012 |
Major changes to the conduct of the study are summarized: (1) Clarified the age limit to 17 years, 11 months; (2) Changed “mother or legal guardian” to “parent or legal guardian”; (3) Updated sponsor contact information; (4) Updated study design to include interviews of the participant/legal guardian on CDAD status to be conducted daily and 2 to 3 days after the last dose of study medication and then weekly through 28 days after treatment; (5) Study assessments were updated to include fecal sample collection at the end of therapy visit to determine concentrations of fidaxomicin and its main metabolite, OP-1118; (6) Clarified that dose preparations and administration based on the participant’s weight were calculated at enrollment and remained consistent throughout the treatment period; (7) Updated the facsimile number for AE reports and pregnancy data collection form to be sent; (8) Removed efficacy from data that was to be reviewed by the Safety Moitorig Committee (SMC). |
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13 Jun 2012 |
Major changes to the conduct of the study are summarized: (1) Clarified that dose preparation and administration could not be changed during the course of the 10-day treatment; (2) Updated study evaluations on clinical laboratory tests and pregnancy tests; (3) Updated recording and reporting of AEs. |
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11 Oct 2012 |
Major changes to the conduct of the study are summarized: (1) Added “Informed consent/assent was provided” as an inclusion criterion; (2) Removed exclusion of participants with >24 hours of prior treatment with oral vancomycin and/or metronidazole; (3) Restricted the list of excluded P-glycoprotein inhibitors to cyclosporine, itraconazole and ketoconazole, erythromycin, azithromycin, and clarithromycin, verapamil, dronedarone and amiodarone, captopril, carvedilol, conivaptan, diltiazem, felodipine, lopinavir and ritonavir, quercetin, quinidine, and ranolazine; (4) Updated exclusion criteria to include: (a) Need for concurrent use of oral vancomycin, metronidazole or any other effective treatments for CDAD during therapy with fidaxomicin, (b) pregnant or breast-feeding an infant, (c) Fulminant colitis, (d) a history of inflammatory bowel disease (ulcerative colitis or Crohn’s disease), (e) need for concurrent use of the following P-glycoprotein inhibitors during therapy with fidaxomicin: cyclosporine, itraconazole, and ketoconazole; erythromycin, azithromycin, and clarithromycin; verapamil, dronedarone, and amiodarone; captopril, carvedilol, conivaptan, diltiazem, felodipine, lopinavir, and ritonavir; quercetin, quinidine, and ranolazine; topical ointments were not excluded, nor was administration of any P-glycoprotein inhibitors during the follow-up period, (f) updated concomitant therapy for consistency with exclusion criteria for P-glycoprotein inhibitors, (g) updated the protocol to Dificid package insert dated October 2012. |
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12 Dec 2013 |
Major changes to the conduct of the study are summarized: (1) Added that Optimer is now a Cubist company and updated signatory and contact personnel; (2) Updated sample size to at least 32 and up to 35 evaluable subjects and stipulated that with Amendment 5, further enrollment should only consist of subjects in stratum 2 (2 years to 5 years, 11 months); (3) Updated exposure margin in dogs to 117×; (4) Clarified that to be included in the plasma PK population, participants must have had 1 predose and at least 1 of the postdose PK blood samples collected at the PK visit (within the time of maximal concentration window, 1–5 hours after dosing); (5) Updated dose preparation and administration to allow a subject who could not swallow a tablet to receive a crushed tablet if the oral formulation was not available and if the subject met weight requirements to receive the full adult dose of 400 mg/day. Instructions for crushing the tablet were provided in the appendix of the amendment; the following instruction was added: If the subject was not of sufficient weight (12.5 kg) to receive the full adult dose and the oral suspension was no longer available, the subject should not have been enrolled; (6) Clarified that pregnancy tests were only to be conducted in females of childbearing potential; (7) Updated medical monitor and associated contact information; (8) Updated Difficid package insert to current version (March 2013); (9) Added an appendix in protocol, crushed tablet preparation. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |