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

• ClinicalTrials.gov Identifier: NCT03816176
• Recruitment Status: Completed
• First Posted: January 25, 2019
• Results First Posted: September 21, 2023
• Last Update Posted: March 21, 2024
• Sponsor: Astellas Pharma Global Development, Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Invasive Mucormycosis; Invasive Aspergillosis	Drug: Isavuconazonium sulfate	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 22, 2019
• Actual Primary Completion Date: December 14, 2022
• Actual Study Completion Date: December 14, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Isavuconazonium sulfate; 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; Intravenous (IV) infusion; Other Name: Cresemba; Drug: Isavuconazonium sulfate; Oral capsule; Other Name: Cresemba

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From first dose to 30 days after the last dose (maximum 210 Days) ]

   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.

2. Percentage of Participants With All - Cause Mortality Through Day 42 [ Time Frame: Baseline up to 42 days ]
   All - Cause Mortality Through Day 42

Secondary Outcome Measures :

1. Percentage of Participants With All - Cause Mortality [ Time Frame: Baseline up to day 84 and end of treatment (EOT) (up to a maximum of 180 days) (Average duration of treatment: 57.7 days) ]
   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).
2. Percentage of Participants With Overall Response: Adjudication Committee (AC) Assessment [ Time Frame: Baseline up to days 42, 84 and EOT (180 days) ]

   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
3. Percentage of Participants With Clinical Response: AC Assessment [ Time Frame: Baseline up to days 42, 84 and EOT (180 days) ]

   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
4. Percentage of Participants With Clinical Response: Investigator Assessment [ Time Frame: Baseline up to days 42, 84 and EOT (180 days) ]

   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
5. Percentage of Participants With Radiological Response: AC Assessment [ Time Frame: Baseline up to days 42, 84 and EOT (180 days) ]

   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
6. Percentage of Participants With Radiological Response: Investigator Assessment [ Time Frame: Baseline up to days 42, 84 and EOT (180 days) ]

   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
7. Percentage of Participants With Mycological Response: AC Assessment [ Time Frame: Baseline up to days 42, 84 and EOT (180 days) ]

   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
8. Percentage of Participats With Mycological Response: Investigator Assessment [ Time Frame: Baseline up to days 42, 84 and EOT (180 days) ]

   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
9. Pharmacokinetics of Isavuconazonium Sulphate in Plasma: Trough Concentration (Ctrough) [ Time Frame: Predose on days 7, and 14 ]
   Ctrough was defined as the predose concentration at the end of dosing interval.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Children's Hospital, Los Angeles

Los Angeles, California, United States, 90027

University of California - Los Angeles

Los Angeles, California, United States, 90095

Children's Hospital of Orange County

Orange, California, United States, 92868

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Illinois

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States, 60611

Belgium

Site BE32001

Gent, Belgium, 9000

Site BE32002

Leuven, Belgium, 3000

Spain

Site ES34002

Barcelona, Spain, 8035

Site ES34003

Madrid, Spain, 28009

Site ES34001

Madrid, Spain, 28041

Sponsors and Collaborators

Astellas Pharma Global Development, Inc.

Investigators

• Study Director: Executive Director; Astellas Pharma Global Development, Inc.

  Study Documents (Full-Text)

Documents provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):

Study Protocol  [PDF] September 5, 2019

Statistical Analysis Plan  [PDF] October 17, 2019

More Information

Additional Information:

Link to results and other applicable study documents on the Astellas Clinical Trials website 

Link to plain language summary of the study on the Trial Results Summaries website 

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT03816176
• Other Study ID Numbers: 9766-CL-0107; 2018-003975-36 ( EudraCT Number )
• First Posted: January 25, 2019
• Results First Posted: September 21, 2023
• Last Update Posted: March 21, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):

ASP9766; Cresemba; BAL8557; isavuconazonium sulfate

Additional relevant MeSH terms:

Aspergillosis; Mucormycosis; Zygomycosis; Mycoses; Bacterial Infections and Mycoses; Infections; Isavuconazole; Antifungal Agents; Anti-Infective Agents