Invasive Aspergillosis
Conditions
Keywords
Pediatrics voriconazole invasive fungal infection invasive aspergillosis immunocompromized
Brief summary
The purpose of this study is to evaluate the safety profile of voriconazole (an antifungal drug) when used in children who have invasive aspergillosis (IA) and other rare systemic fungal infections.
Interventions
DRUGVoriconazole
All subjects will receive voriconazole for a minimum of 6 weeks and a maximum of 12 weeks. All subjects must receive intravenous (IV) voriconazole for the first week of therapy. Group 1: Subjects 2 to 11 years old and subjects 12 to 14 years old with low body weight (\<50 kg) will receive 9 mg/kg IV every 12 hours (q12h) on day 1, then 8 mg/kg IV q12h starting day 2. If there is a significant clinical improvement after the first week of IV therapy, subjects may be switched to the step-down oral regimen (9 mg/kg PO q12h with a maximum dose of 350 mg PO q12h) at the discretion of the investigator. Group 2: Subjects 12 to 17 years old (excluding 12-14-year-olds weighing \<50 kg) will receive 6 mg/kg IV q12h on day 1, then 4 mg/kg IV q12h starting day 2. Similar to Group 1, subjects may be switched to the step-down oral regimen (200 mg PO q12h) at the discretion of the investigator. Oral voriconazole can be administered as tablet or oral suspension.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Immunocompromised with clinically compatible illness. * Diagnosis of proven or probable or possible Invasive Aspergillosis (based on a modified version of the revised EORTC/MSG consensus definitions). * Diagnosis of infection due to Scedosporium or Fusarium species. * Male and female from 2 to 17 years of age. * Females with childbearing potential must have negative pregnancy test and be using appropriate contraception.
Exclusion criteria
* Allergy or hypersensitivity to the azole drugs. * Female subjects who are pregnant or lactating. * Patients who received more than four days of antifungal drugs to treat the current episode of invasive aspergillosis or rare mold infection. * Received within 24 hours prior to enrollment drugs that may cause QT interval prolongation. * Significant liver, kidney or heart dysfunction. * Not expected to survive for at least 5 days.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Adverse Events (AEs) | Baseline, daily while hospitalized, Days 7, 14, 28, 42, 84, and 114, at end of treatment, and up to 1 month post treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Global Response of Success | Weeks 6 and End of Treatment (EOT; up to Week 12) | Percentage of participants with global response of success at Weeks 6 and at EOT (up to Week 12). Global response of success was defined as a participant who achieved a complete or partial global response per the investigator. Complete response was defined as resolution of all clinical signs and symptoms PLUS resolution of 90 percent (%) or more of the lesions visible on radiological studies and attributed to invasive aspergillosis (IA) at Baseline. Partial response was defined as clinical improvement PLUS 50% to \<90% resolution of the radiological lesions attributed to IA at Baseline. |
| All-Cause Mortality - Number of Participant Deaths | Week 6 and EOT (up to Week 12) | Number of participant deaths reported at Week 6 and at EOT (up to Week 12). |
| Attributable Mortality - Number of Participant Deaths | Weeks 6 and EOT (up to Week 12) | Number of participant deaths attributable to study drug reported at Week 6 and at EOT (up to Week 12). |
| Time to Death | Baseline up to 1 month post treatment | — |
Countries
Canada, Czechia, Netherlands, Poland, Singapore, Spain, Thailand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Voriconazole: 2 to <12 Years Participants aged 2 to less than (\<)12 years (and young adolescents aged 12 to 14 years weighing \<50 kilograms \[kg\]) received a loading dose of voriconazole of 9 milligrams per kg (mg/kg), intravenously (IV), every 12 hours (q12h) for the first 24 hours, followed by maintenance dosing of 8 mg/kg IV q12h for a minimum of 7 days of IV therapy. Once significant clinical improvement was observed, participants could have been switched or oral (PO) therapy and received 9 mg/kg PO voriconazole q12h for a maximum dose of 350 mg. | 11 |
| Voriconazole: 12 to <18 Years Participants aged 12 to \<18 years (excluding those aged 12-14 years weighing \<50 kg) received a loading dose of 6 mg/kg IV q12h for the first 24 hours followed by maintenance dosing of 4 mg/kg IV q12h for a minimum of 7 days of IV therapy. Once significant clinical improvement was observed, participants could have been switched or oral therapy and received 200-300 mg PO q12h. | 20 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Voriconazole: 2 to <12 Years | Voriconazole: 12 to <18 Years | Total |
|---|---|---|---|
| Age, Continuous | 7.9 years STANDARD_DEVIATION 2.3 | 14.1 years STANDARD_DEVIATION 1.7 | 11.9 years STANDARD_DEVIATION 3.5 |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 15 Participants |
| Sex: Female, Male Male | 7 Participants | 9 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 11 | 19 / 20 |
| serious Total, serious adverse events | 6 / 11 | 9 / 20 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs)
Time frame: Baseline, daily while hospitalized, Days 7, 14, 28, 42, 84, and 114, at end of treatment, and up to 1 month post treatment
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole: 2 to <12 Years | Number of Participants With Adverse Events (AEs) | With serious AEs | 6 participants |
| Voriconazole: 2 to <12 Years | Number of Participants With Adverse Events (AEs) | Discontinued treatment due to AEs | 1 participants |
| Voriconazole: 2 to <12 Years | Number of Participants With Adverse Events (AEs) | With severe AEs | 5 participants |
| Voriconazole: 2 to <12 Years | Number of Participants With Adverse Events (AEs) | Dose reduced or temporarily discontinued due to AE | 0 participants |
| Voriconazole: 2 to <12 Years | Number of Participants With Adverse Events (AEs) | With AEs | 11 participants |
| Voriconazole: 12 to <18 Years | Number of Participants With Adverse Events (AEs) | Dose reduced or temporarily discontinued due to AE | 4 participants |
| Voriconazole: 12 to <18 Years | Number of Participants With Adverse Events (AEs) | With AEs | 19 participants |
| Voriconazole: 12 to <18 Years | Number of Participants With Adverse Events (AEs) | With serious AEs | 9 participants |
| Voriconazole: 12 to <18 Years | Number of Participants With Adverse Events (AEs) | With severe AEs | 8 participants |
| Voriconazole: 12 to <18 Years | Number of Participants With Adverse Events (AEs) | Discontinued treatment due to AEs | 0 participants |
Secondary
All-Cause Mortality - Number of Participant Deaths
Number of participant deaths reported at Week 6 and at EOT (up to Week 12).
Time frame: Week 6 and EOT (up to Week 12)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole: 2 to <12 Years | All-Cause Mortality - Number of Participant Deaths | Week 6 | 3 participants |
| Voriconazole: 2 to <12 Years | All-Cause Mortality - Number of Participant Deaths | EOT | 0 participants |
| Voriconazole: 12 to <18 Years | All-Cause Mortality - Number of Participant Deaths | Week 6 | 1 participants |
| Voriconazole: 12 to <18 Years | All-Cause Mortality - Number of Participant Deaths | EOT | 1 participants |
Secondary
Attributable Mortality - Number of Participant Deaths
Number of participant deaths attributable to study drug reported at Week 6 and at EOT (up to Week 12).
Time frame: Weeks 6 and EOT (up to Week 12)
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Voriconazole: 2 to <12 Years | Attributable Mortality - Number of Participant Deaths | 0 participants |
| Voriconazole: 12 to <18 Years | Attributable Mortality - Number of Participant Deaths | 0 participants |
Secondary
Percentage of Participants With a Global Response of Success
Percentage of participants with global response of success at Weeks 6 and at EOT (up to Week 12). Global response of success was defined as a participant who achieved a complete or partial global response per the investigator. Complete response was defined as resolution of all clinical signs and symptoms PLUS resolution of 90 percent (%) or more of the lesions visible on radiological studies and attributed to invasive aspergillosis (IA) at Baseline. Partial response was defined as clinical improvement PLUS 50% to \<90% resolution of the radiological lesions attributed to IA at Baseline.
Time frame: Weeks 6 and End of Treatment (EOT; up to Week 12)
Population: Modified intent to treat (MITT) population: all participants receiving at least 1 dose of study drug and diagnosed with proven or probable aspergillosis (defined by modified European Organization for Research and Treatment of Cancer Mycoses Study Group \[EORTC/MSC\] criteria) or microbiologically confirmed scedosporium or fusarium infection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Voriconazole: 2 to <12 Years | Percentage of Participants With a Global Response of Success | Week 6 | 40.0 percentage of participants |
| Voriconazole: 2 to <12 Years | Percentage of Participants With a Global Response of Success | EOT | 40.0 percentage of participants |
| Voriconazole: 12 to <18 Years | Percentage of Participants With a Global Response of Success | Week 6 | 77.8 percentage of participants |
| Voriconazole: 12 to <18 Years | Percentage of Participants With a Global Response of Success | EOT | 77.8 percentage of participants |
Secondary
Time to Death
Time frame: Baseline up to 1 month post treatment
Population: Safety population; only participants who died were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Voriconazole: 2 to <12 Years | Time to Death | 30.0 days |
| Voriconazole: 12 to <18 Years | Time to Death | 47.5 days |