Clinical trial NCT03816176: A Study to Evaluate Isavuconazonium Sulfate for the Treatment of Invasive Aspergillosis (IA) or Invasive Mucormycosis (IM) in Pediatric Participants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Invasive Mucormycosis
Invasive Aspergillosis
Keywords: ASP9766
Cresemba
BAL8557
isavuconazonium sulfate
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2019-01-25
Enrollment: 31
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose to 30 days after the last dose (maximum 210 Days)
measure: Percentage of Participants With All - Cause Mortality Through Day 42
timeFrame: Baseline up to 42 days
Secondary outcomes:
measure: Percentage of Participants With All - Cause Mortality
timeFrame: Baseline up to day 84 and end of treatment (EOT) (up to a maximum of 180 days) (Average duration of treatment: 57.7 days)
measure: Percentage of Participants With Overall Response: Adjudication Committee (AC) Assessment
timeFrame: Baseline up to days 42, 84 and EOT (180 days)
measure: Percentage of Participants With Clinical Response: AC Assessment
timeFrame: Baseline up to days 42, 84 and EOT (180 days)
measure: Percentage of Participants With Clinical Response: Investigator Assessment
timeFrame: Baseline up to days 42, 84 and EOT (180 days)
measure: Percentage of Participants With Radiological Response: AC Assessment
timeFrame: Baseline up to days 42, 84 and EOT (180 days)
measure: Percentage of Participants With Radiological Response: Investigator Assessment
timeFrame: Baseline up to days 42, 84 and EOT (180 days)
measure: Percentage of Participants With Mycological Response: AC Assessment
timeFrame: Baseline up to days 42, 84 and EOT (180 days)
measure: Percentage of Participats With Mycological Response: Investigator Assessment
timeFrame: Baseline up to days 42, 84 and EOT (180 days)
measure: Pharmacokinetics of Isavuconazonium Sulphate in Plasma: Trough Concentration (Ctrough)
timeFrame: Predose on days 7, and 14
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital, Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Gent
country: Belgium
facility: Site BE32001
city: Leuven
country: Belgium
facility: Site BE32002
city: Barcelona
country: Spain
facility: Site ES34002
city: Madrid
country: Spain
facility: Site ES34003
city: Madrid
country: Spain
facility: Site ES34001
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Executive Director
role: STUDY_DIRECTOR
References: