Clinical Trial Results:
A Phase 2, Open-Label, Non-Comparative, Multicenter Study to Evaluate the Safety and Tolerability, Efficacy and Pharmacokinetics of Isavuconazonium Sulfate for the Treatment of Invasive Aspergillosis (IA) or Invasive Mucormycosis (IM) in Pediatric Subjects
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Summary
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EudraCT number |
2018-003975-36 |
Trial protocol |
GB BE DE ES Outside EU/EEA |
Global end of trial date |
14 Dec 2022
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Results information
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Results version number |
v1 |
This version publication date |
16 Jun 2023
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First version publication date |
16 Jun 2023
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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 |
9766-CL-0107
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03816176 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Astellas Pharma Global Development, Inc
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Sponsor organisation address |
1 Astellas Way, Northbrook, IL, United States, 60062
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Public contact |
Clinical Transparency, Astellas Pharma Global Development, Inc, astellas.resultsdisclosure@astellas.com
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Scientific contact |
Clinical Transparency, 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-001301-PIP02-12 | ||
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 |
14 Dec 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Dec 2022
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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 purpose of this study was to evaluate the safety and tolerability of isavuconazonium sulfate in pediatric participants. and to assess the efficacy of isavuconazonium sulfate for the treatment of invasive aspergillosis (IA) or invasive mucormycosis (IM) in pediatric subjects. Also to evaluate the pharmacokinetics of isavuconazole by monitoring the plasma concentrations in pediatric subjects during treatment with isavuconazonium sulfate.
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Protection of trial subjects |
This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (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 |
22 Aug 2019
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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 |
Belgium: 11
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
United States: 16
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Worldwide total number of subjects |
31
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EEA total number of subjects |
15
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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) |
2
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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 |
A total of 31 pediatric participants diagnosed with IA or IM were enrolled and received isavuconazonium sulfate. Safety Analysis Set (SAF) | ||||||||||||||
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Pre-assignment
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Screening details |
Male or female participant 1 year to < 18 years of age diagnosed with IA or IM. A positive diagnosis was defined as proven, probable or possible invasive fungal infection (IFI) per the European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG], 2008 criteria. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Period
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||
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Arms
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Arm title
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Isavuconazonium Sulfate | ||||||||||||||
Arm description |
Participants received 10 milligrams/kilograms (mg/kg) dose of isavuconazonium sulfate every 8 hours (± 2 hours) on days 1 and 2 for a total of 6 doses (via intravenous or oral administration at the investigator's discretion) followed by once-daily maintenance dose of 10 mg/kg for up to 84 days for invasive aspergillosis (IA) or 180 days for invasive mucormycosis (IM) or until the participant had a successful outcome as judged by the investigator, whichever occurred first. The route of administration could have been changed per the investigator’s discretion. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Isavuconazonium Sulfate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, Infusion
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Participants received 10 milligrams/killograms (mg/kg) dose of isavuconazonium sulfate every 8 hours (± 2 hours) on days 1 and 2 for a total of 6 doses (via intravenous or oral administration at the investigator's discretion)followed by once-daily maintenance dose of 10 mg/kg for up to 84 days invasive aspergillosis (IA) or 180 days invasive mucormycosis (IM) or until the participant had a successful outcome as judged by the investigator, whichever occured first. The route of administration could have been changed per the investigator’s discretion
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Baseline characteristics reporting groups
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Reporting group title |
Isavuconazonium Sulfate
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Reporting group description |
Participants received 10 milligrams/kilograms (mg/kg) dose of isavuconazonium sulfate every 8 hours (± 2 hours) on days 1 and 2 for a total of 6 doses (via intravenous or oral administration at the investigator's discretion) followed by once-daily maintenance dose of 10 mg/kg for up to 84 days for invasive aspergillosis (IA) or 180 days for invasive mucormycosis (IM) or until the participant had a successful outcome as judged by the investigator, whichever occurred first. The route of administration could have been changed per the investigator’s discretion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Isavuconazonium Sulfate
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Reporting group description |
Participants received 10 milligrams/kilograms (mg/kg) dose of isavuconazonium sulfate every 8 hours (± 2 hours) on days 1 and 2 for a total of 6 doses (via intravenous or oral administration at the investigator's discretion) followed by once-daily maintenance dose of 10 mg/kg for up to 84 days for invasive aspergillosis (IA) or 180 days for invasive mucormycosis (IM) or until the participant had a successful outcome as judged by the investigator, whichever occurred first. The route of administration could have been changed per the investigator’s discretion. | ||
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End point title |
Number of Participants with Treatment Emergent Adverse Events (TEAEs) [1] | ||||||
End point description |
An AE is any untoward medical occurrence in a participant administered a study drug, which does not have to have a causal relationship with this treatment. It can be any unfavorable sign, symptom, or disease temporally associated with the use of a medicinal product. Treatment Emergent Adverse Event defined as an AE observed after starting administration of the study drug through 30 days after the last dose.
The safety analysis set (SAF) consisted of all participant who were enrolled and 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 to 30 days after the last dose (maximum 210 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: statistical analysis were not prespecified for this endpoint |
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| Notes [2] - SAF (enrolled participants, who received 1 dose of study drug) with available data were analyzed. |
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| No statistical analyses for this end point | |||||||
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End point title |
Percentage of Participants with All - Cause Mortality Through Day 42 [3] | ||||||||
End point description |
Percentage of participants with All Cause Mortality through Day 42
Full analysis set (FAS) (included all participants who were enrolled and received at least 1 dose of study drug)
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End point type |
Primary
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End point timeframe |
Baseline up to 42 days
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| Notes [3] - 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: statistical analysis were not prespecified for this endpoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants with All - Cause Mortality | ||||||||||||
End point description |
Percentage of participants with All - Cause Mortality
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to day 84 and end of treatment (EOT) (180 Days)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Participants with Overall Response: Adjudication Committee (AC) Assessment | ||||||||||||||
End point description |
Overall response was based on a composite of clinical, mycological, and radiological responses with success criteria assessed. Success criteria as assessed by AC in:
Clinical response:
• Complete: Resolution of all attributable clinical symptoms and physical findings
• Partial: Resolution of at Least some of the clinical symptoms and physical findings associated with IFD
Mycological response:
• Eradication: No growth of the original (at baseline) causative organism on culture or identified by histology/cytology on post baseline (after day 7) cultures and/or histology/cytology
• Presumed eradication: Missing post baseline documentation of eradication of the original causative organism at baseline PLUS resolution of all or some clinical symptoms/physical finding
Radiological response:
• Complete: ≥ 90% improvement
• Partial: At least < 25% response at day 42 and at least 50% by Day 84
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to days 42, 84 and EOT (180 days)
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Participants with Clinical Response: AC Assessment | ||||||||||||||||||||||||||
End point description |
AC Assessed Clinical response was defined as follows:
•Success: Complete (if resolution of all attributable clinical symptoms and physical findings occurs); Partial (if resolution of at least some of the clinical symptoms and physical findings associated with IFD)
•Failure: Stable (if minor of no change in clinical symptoms and physical findings associated with IFD); Progression (if worsening or new clinical symptoms and physical findings associated with IFD, or if alternative systemic antifungal treatment is required)
•Not Evaluable: If not assessed or no clinical signs or symptoms at baseline.
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to days 42, 84 and EOT (180 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Percentage of Participants With Clinical Response: Investigator Assessment | ||||||||||||||||||||||||||
End point description |
Investigator-assessed Clinical Response was defined as follows:
• Success: if resolution of all attributable signs and symptoms or resolution of attributable clinical symptoms and physical findings
• Failure: if no resolution of any attributable signs and symptoms or no resolution of any attributable signs and symptoms (no change) or worsening of any attributable signs and symptoms
• Not Evaluable: if results not available /participant unevaluable or if no attributable signs and symptoms
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to days 42, 84 and EOT (180 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Percentage of Participants with Radiological Response: AC Assessment | ||||||||||||||||||||||||||
End point description |
AC-assessed Radiological Response was defined as follows:
•Success: Complete (if ≥ 90% improvement); Partial (if at least < 25% response at day 42 and at least 50% response by Day 84)
•Failure: Stable (if minor or no change in radiographic abnormalities associated with IFD, but no signs of progression); Progression (if worsening or new radiological abnormalities associated with IRD)
•Not Evaluable: if no post baseline radiology available with baseline evidence of radiolical disease Or Radiology not applicable at baseline
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to days 42, 84 and EOT (180 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Percentage of Participants With Radiological Response: Investigator Assessment | ||||||||||||||||||||||||||
End point description |
Investigator’s assessed radiological response was defined as follows:
•Success: if ≥ 90% improvement, ≥ 50% to < 90% improvement, ≥ 25% to 50% improvement (for Day 42 only)
•Failure if < 25% improvement at any time or no signs or radiological Images
•Not Evaluable if results not evaluable or no radiological data available.
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to days 42, 84 and EOT (180 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Percentage of Participants with Mycological Response: AC Assessment | ||||||||||||||||||||||||||
End point description |
AC assessed mycological response was defined as follows:
•Success: Eradicated (no growth of the original [at baseline] causative organism on culture or identified by histology/cytology on post baseline [after day 7] cultures and/or histology/cytology); Presumed Eradicated (missing post baseline documentation of eradication of the original causative organism at baseline PLUS resolution of all or some clinical symptoms/physical finding)
•Failure: Persistence (persistence of the original causative organism cultured or identified by histological /cytology at baseline); Presumed Persistence (missing post baseline documentation of the persistence of the original causative organism at baseline PLUS no resolution or worsening of any clinical symptoms/physical findings)
•Not Evaluable - no mycological evidence
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to days 42, 84 and EOT (180 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Percentage of Participants With Mycological Response: Investigator Assessment | ||||||||||||||||||||||||||
End point description |
Investigator’s assessed mycological response was defined as follows:
•Success: Eradicated (no growth of the original [at baseline] causative organism on culture or identified by histology/cytology on post baseline [after day 7] cultures and/or histology/cytology); Presumed Eradicated (missing post baseline documentation of eradication of the original causative organism at baseline PLUS resolution of all or some clinical symptoms/physical finding)
•Failure: Persistence (persistence of the original causative organism cultured or identified by histological /cytology at baseline); Presumed Persistence (missing post baseline documentation of the persistence of the original causative organism at baseline PLUS no resolution or worsening of any clinical symptoms/physical findings)
•Not Evaluable: Indeterminate/no mycological follow-up or results available.
FAS population
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End point type |
Secondary
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End point timeframe |
Baseline up to days 42, 84 and EOT (180 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Pharmacokinetics of Isavuconazonium Sulphate in Plasma: Trough Concentration (Ctrough) | ||||||||||||||||||||
End point description |
Ctrough was defined as the predose concentration at the end of dosing interval.
The pharmacokinetic analysis set (PKAS) consisted of all participants who took at least one dose of study drug and who had at least one plasma concentration
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End point type |
Secondary
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End point timeframe |
Predose on days 7, and 14
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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 to 30 days after the last dose (maximum 210 days)
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
v23.0
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Reporting groups
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Reporting group title |
Isavuconazonium sulfate
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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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12 Feb 2019 |
• An additional 24-hour pharmacokinetic sample was added to the pharmacokinetic assessment. This 24-hour sample was obtained between days 21 and 42, while the subject was still receiving study drug. Total Amount of Blood Drawn was updated with the 4 mL of blood required for these new samples.
• Added acceptable galactomannan levels for recipients of hematopoietic stem cell transplant who also had clinical and radiologic features consistent with invasive fungal infection. |
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08 May 2019 |
• An oral dose of isavuconazonium sulfate in 74.5 mg capsules was added to the study. Oral administration was for participants from 12 to < 18 years of age. Study results for oral isavuconazonium sulfate were added to the dose rationale.
• Clarification was added for the intermittently changing administration routes at any time during the loading and/or treatment period.
• Times of the 24-hour pharmacokinetic samples were added for oral dosing.
• Section 5.1.3 was updated with instructions for participants who were discharged while continuing treatment with either intravenous or oral dosing.
• The stopping rule for infusion-related reactions was updated to state that if the infusion-related reactions event was mild and self-limiting, the participants could continue the study at the discretion of the investigator. |
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05 Sep 2019 |
• Additional text was added to specify that no additional vital signs were needed on dosing days for oral administration other than screening and end of treatment.
• Additional text was added to footnote 12 (Table 1) to clarify that the pregnancy test may be either urine or serum.
• Text was added to specify that the return visit should occur on days when study-related assessments were required.
• The lower limit on the age requirement for oral dosing was changed from “12 years of age” to “6 years of age and with a body weight of at least 12 kg.” The dose rationale was updated with additional data from Part 2 of Study 9766-CL-0046 (6 to < 11 years of age) to support this change.
• A table was added to provide guidance to the investigator defining the elements of a successful outcome.
• Inclusion criterion No. 2 was updated to extend the timing of diagnostic tests to confirm invasive fungal disease to 10 calendar days after the first dose of study drug.
• Inclusion criterion No. 3 was updated to clarify that the administration would be intravenous and to specify that the sparticipant had to be able to swallow oral capsules.
• Inclusion criterion No. 7 was updated to include allergy, hypersensitivity or serious reaction to “any component of the study drug formulation.”
• Text was added to state that participants who developed serious hypersensitivity adverse reactions without alternative etiology would be discontinued from treatment |
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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 | |||
