A Study to Evaluate Isavuconazonium Sulfate for the Treatment of Invasive Aspergillosis (IA) or Invasive Mucormycosis (IM) in Pediatric Participants

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the safety, tolerability, and efficacy of isavuconazonium sulfate in pediatric participants.

Detailed Description
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Treatment began on Day 1 and then participants were followed for 60 days post-last dose for safety. Treatment was administered until the participant had a successful outcome or for a maximum duration of 84 days (IA) or 180 days (IM), whichever occured first. Participants received a loading regimen of isavuconazonium sulfate (via intravenous or oral administration at the investigator's discretion), which consisted of a dose every 8 hours (± 2 hours) on Days 1 and 2 (for a total of 6 doses), followed by once daily maintenance dosing for up to 84 days (IA) or 180 days (IM) of dosing. The first maintenance dose started 12 to 24 hours after the administration of the last loading dose. Subsequent maintenance doses were administered once daily (24 hours ± 2 hours from the previous maintenance dose). The oral formulation could only be given to participants 6 years to < 18 years of age and with a body weight of at least 12 kg. Participants who were discharged from the hospital with oral capsules for at-home administration had to return weekly for study drug accountability and to receive new oral dosing supplies. Participants who began oral administration were to complete the oral dosing acceptability assessment after ingesting their first oral dose.

Official Title
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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

Conditions
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Invasive Mucormycosis, Invasive Aspergillosis

Intervention / Treatment
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* Drug: Isavuconazonium sulfate
* Drug: Isavuconazonium sulfate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject diagnosed with IA or IM. A positive diagnosis is defined as follows: Proven, probable or possible IFI per the European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG], 2008 criteria Note: Subjects with possible IFI will be eligible for enrollment; however, diagnostic tests to confirm the invasive fungal disease as probable or proven according to the EORTC/MSG criteria should be completed within 10 calendar days after the first dose of study drug Note: In addition to the criteria set for mycological criteria by the EORTC/MSG in 2008, and only for subjects with an underlying hematologic malignancy or recipients of hematopoietic stem cell transplant (HSCT) who also have clinical and radiologic features consistent with invasive fungal infection, the following are acceptable: Galactomannan (GM) levels (optical density index) meeting the below criteria are acceptable mycological evidence for enrollment or upgrading the diagnosis to probable IA: 1. A single value for serum or bronchoalveolar lavage (BAL) fluid of ≥ 1.0 or 2. Two serum GM values of ≥ 0.5 from two separate samples Subject has sufficient venous access to permit intravenous administration of study drug or the ability to swallow oral capsules A female subject is eligible to participate if not pregnant and at least one of the following conditions applies: Not a subject who is of childbearing potential, OR Subject who is of childbearing potential who agrees to follow a contraceptive guidance throughout the treatment period and for at least 30 days after the final study drug administration Subject and subject's parent(s) or legal guardian agree that the subject will not participate in another interventional study while on treatment with the exception of oncology trials Exclusion Criteria: Subject has familial short QT syndrome, is receiving medications that are known to shorten the QT interval, or has a clinically significant abnormal ECG Subject has evidence of hepatic dysfunction defined as any of the following: Total bilirubin (TBL) ≥ 3 times the upper limit of normal (ULN) Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 5 times the ULN Known cirrhosis or chronic hepatic failure Subject has used strong cytochrome P450 (CYP3A4) inhibitors or inducers such as ketoconazole, high dose ritonavir, rifampin/rifampicin, long acting barbiturates (e.g., phenytoin), carbamazepine and St. John's Wort in the 5 days prior to the first dose of study drug Subject has another IFI other than possible, probably or proven IA or IM Subject has chronic aspergillosis, aspergilloma or allergic bronchopulmonary aspergillosis Subject has received mould active systemic antifungal therapy, effective against the primary IMI, for more than four days during the seven days preceding the first dose Note: Prior use of prophylactic antifungal therapy is acceptable. In case of breakthrough IA while on prophylactic mould-active azole class drugs, additional documentation will be required to be submitted to the sponsor medical monitor or designee to approve subject enrollment Subject has known history of allergy, hypersensitivity or any serious reaction to any of the azole class antifungals, or any components of the study drug formulation Subject has any condition which makes the subject unsuitable for study participation Subject is unlikely to survive 30 days Subject has received investigational drug, with the exception of oncology drug trials, or trials with investigational drugs treating graft versus host disease, within 28 days or five half-lives, whichever is longer, prior to screening

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Isavuconazonium sulfate<br>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 IA or 180 days 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. | Drug: Isavuconazonium sulfate<br>* Intravenous (IV) infusion<br>* Other names: Cresemba;Drug: Isavuconazonium sulfate<br>* Oral capsule<br>* Other names: Cresemba;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 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. TEAE is defined as an AE observed after starting administration of the study drug through 30 days after the last dose. | From first dose to 30 days after the last dose (maximum 210 Days) | 
| Percentage of Participants With All - Cause Mortality Through Day 42 | All - Cause Mortality Through Day 42 | Baseline up to 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With All - Cause Mortality | EOT was defined as anytime from day 1 to a maximum of day 180. Data reported in the table below for each category, i.e., Day 84 represented data between Day 1 and Day 84 and for EOT, data represented between Day 1 to the EOT day for each individual. Participants who died after EOT assessment but before reaching Day 84 were included in the data for Day 84 category. Only those deaths that occurred after Day 84 would be included in EOT category if the death occurred during the treatment period (i.e. prior to the EOT). | Baseline up to day 84 and end of treatment (EOT) (up to a maximum of 180 days) (Average duration of treatment: 57.7 days) | 
| Percentage of Participants With Overall Response: Adjudication Committee (AC) Assessment | 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 | Baseline up to days 42, 84 and EOT (180 days) | 
| Percentage of Participants With Clinical Response: AC Assessment | 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 No assessment: Those participants that do not fall under any of the above criteria | Baseline up to days 42, 84 and EOT (180 days) | 
| Percentage of Participants With Clinical Response: Investigator Assessment | 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 No assessment: Those participants that do not fall under any of the above criteria | Baseline up to days 42, 84 and EOT (180 days) | 
| Percentage of Participants With Radiological Response: AC Assessment | 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 No assessment: Those participants that do not fall under any of the above criteria | Baseline up to days 42, 84 and EOT (180 days) | 
| Percentage of Participants With Radiological Response: Investigator Assessment | 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 No assessment: Those participants that do not fall under any of the above criteria | Baseline up to days 42, 84 and EOT (180 days) | 
| Percentage of Participants With Mycological Response: AC Assessment | 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 No assessment: Those participants that do not fall under any of the above criteria | Baseline up to days 42, 84 and EOT (180 days) | 
| Percentage of Participats With Mycological Response: Investigator Assessment | 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 No assessment: Those participants that do not fall under any of the above criteria | Baseline up to days 42, 84 and EOT (180 days) | 
| Pharmacokinetics of Isavuconazonium Sulphate in Plasma: Trough Concentration (Ctrough) | Ctrough was defined as the predose concentration at the end of dosing interval. | Predose on days 7, and 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASP9766, Cresemba, BAL8557, isavuconazonium sulfate