Invasive Aspergillosis
Conditions
Brief summary
This study will evaluate the safety, efficacy, and pharmacokinetics of posaconazole (POS) intravenous (IV) and oral formulations in pediatric participants 2 to \<18 years of age with invasive aspergillosis (IA).
Interventions
DRUGPosaconazole IV
Posaconazole (POS) 6 mg/kg body weight by IV infusion
DRUGPosaconazole PFS
Dosing based on weight-band taken orally
POS tablet 300 mg taken orally
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Has a diagnosis of possible, probable, or proven IA per modified 2008/2020 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) disease definitions * Has one or more of pre-defined risks as per modified 2008 EORTC/MSG disease definitions * Has a central line (e.g., central venous catheter, peripherally-inserted central catheter) in place or planned to be in place prior to beginning IV study treatment. * Has clinical symptoms consistent with an acute episode of IA, defined as duration of clinical syndrome of \<30 days. * Participants weigh at least 10 kg, and may be of any race/ethnicity. * During the intervention period and for at least 30 days after the last dose of study treatment, males agree to be abstinent from heterosexual intercourse or use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause). * Female is not pregnant or breastfeeding, and is not a woman of child bearing potential (WOCBP) or is a WOCBP using a highly effective contraceptive method. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
Exclusion criteria
* Has chronic (≥30 days' duration) IA, relapsed/recurrent IA, or refractory IA that has not responded to prior antifungal treatment. * Has cystic fibrosis, pulmonary sarcoidosis, aspergilloma, or allergic bronchopulmonary aspergillosis * Has a known hypersensitivity or other serious adverse reaction to any azole antifungal therapy, or to any other ingredient of the study treatment used. * Has any known history of torsade de pointes, unstable cardiac arrhythmia or proarrhythmic conditions, a history of recent myocardial infarction, congenital or acquired QT prolongation, or cardiomyopathy in the context of cardiac failure within 90 days of time of first dose of study treatment. * Has known hereditary fructose intolerance. * Has a known hereditary problem of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. * Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study. * Is on artificial ventilation at the time of first dose of study treatment. * Has received any treatment prohibited by the protocol. * Has enrolled previously in the current study and been discontinued. * Is not expected, in the opinion of the investigator, to survive for at least 1 month after the initiation of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experience One or More Treatment-related Adverse Events (AEs) | Up to 14 days after treatment (up to Day 102) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Treatment-related AEs were determined by the investigator to be related to the drug. The 95% confidence interval (CI) was based on the exact binomial method by Clopper- Pearson. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 12 | Up to Week 12 | A global clinical response is assessed by the investigator as favorable if the participant is alive and has a complete response (CR) or partial response (PR). CR is defined as survival within the prespecified period of observation, resolution of all attributable symptoms and signs of disease, resolution of radiological lesion(s), and documented clearance of infected sites that are accessible to repeated sampling. PR is defined as survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease, improvement of radiological lesion(s), and evidence of clearance of infected sites that are accessible to repeated sampling. |
| Percentage of Participants Who Have a Relapse of Invasive Aspergillosis (IA) at Any Point After Achieving Favorable Global Clinical Response | Up to 28 days post-treatment (up to Day 116) | In participants who achieved favorable global clinical response, relapse of IA is defined as the re-emergence of clinical, radiographic, or other relevant abnormalities indicating IA. |
| Average Plasma Concentration (Cavg) of POS by Age Cohorts | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady state Cavg was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cavg parameter values (1 for IV dosing, 1 for oral dosing). |
| Minimum Plasma Concentration (Cmin) of POS by Age Cohorts | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady state Cmin was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cmin parameter values (1 for IV dosing, 1 for oral dosing). |
| Maximum Plasma Concentration (Cmax) of POS by Age Cohorts | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady state Cmax was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cmax parameter values (1 for IV dosing, 1 for oral dosing). |
| Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Age Cohorts | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady state AUCtau was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 AUCtau parameter values (1 for IV dosing, 1 for oral dosing). |
| Time to Reach Cmax (Tmax) of POS by Age Cohorts | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady state Tmax was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Tmax parameter values (1 for IV dosing, 1 for oral dosing). |
| Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 6 | Up to week 6 | A global clinical response is assessed by the investigator as favorable if the participant is alive and has a complete response (CR) or partial response (PR). CR is defined as survival within the prespecified period of observation, resolution of all attributable symptoms and signs of disease, resolution of radiological lesion(s), and documented clearance of infected sites that are accessible to repeated sampling. PR is defined as survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease, improvement of radiological lesion(s), and evidence of clearance of infected sites that are accessible to repeated sampling. |
| Minimum Plasma Concentration (Cmin) of POS by Formulation | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady-state Cmin was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2. |
| Maximum Plasma Concentration (Cmax) of POS by Formulation | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady-state Cmax was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2. |
| Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady-state AUCtau was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2. |
| Time to Reach Cmax (Tmax) of POS by Formulation | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady-state Tmax was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2. |
| Percentage of Participants With Different Categories of Palatability After First Day of Treatment With the POS PFS Formulation | First day of PFS treatment (Day 8) | Palatability was categorized on the first day (Day 8) on PFS based on responses by participants to a palatability questionnaire. Per protocol participants were pooled into a single treatment group. Palatability categories for taste are as follows: Very good; Good; Very bad; Neither good nor bad. |
| Percentage of Participants With Different Categories of Palatability After Last Day of Treatment With the POS PFS Formulation | Last day of PFS treatment (Day 85) | Palatability was categorized on the last day (Day 85) on PFS based on responses by participants to a palatability questionnaire. Per protocol participants were pooled into a single treatment group Palatability categories for taste are as follows: Very good; Good; Very bad; Neither good nor bad. |
| Average Plasma Concentration (Cavg) of POS by Formulation | Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12 | Steady-state Cavg was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2. |
Countries
Belgium, Greece, Hungary, Israel, Italy, Mexico, Peru, Russia, South Korea, United States
Participant flow
Pre-assignment details
Male or female participants with a diagnosis of possible, probable, or proven invasive aspergillosis (IA) aged 2 to \<18 years were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Age Cohort 1 (2 -< 12 Years Old) On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation. | 14 |
| Age Cohort 2 (12 -< 18 Years Old) On Day 1 participants receive 2 administrations of posaconazole (POS) 6 mg/kg body weight by intravenous (IV) infusion. On Days 2 through 7, participants receive POS 6 mg/kg body weight once daily by IV infusion. Beginning at Day 8 up to Day 84, participants may transition to receiving an oral formulation, or they may remain on the IV formulation. | 17 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 3 |
Baseline characteristics
| Characteristic | Total | Age Cohort 1 (2 -< 12 Years Old) | Age Cohort 2 (12 -< 18 Years Old) |
|---|---|---|---|
| Age, Continuous | 11.1 years STANDARD_DEVIATION 4.4 | 6.9 years STANDARD_DEVIATION 2.7 | 14.5 years STANDARD_DEVIATION 1.7 |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 17 Participants | 0 Participants | 17 Participants |
| Age, Customized Adults (18-64 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Children (2-11 years) | 14 Participants | 14 Participants | 0 Participants |
| Age, Customized From 65-84 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 12 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 9 Participants | 8 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 1 Participants |
| Sex: Female, Male Male | 23 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 14 | 4 / 17 |
| other Total, other adverse events | 12 / 14 | 14 / 17 |
| serious Total, serious adverse events | 4 / 14 | 8 / 17 |
Outcome results
Primary
Percentage of Participants Who Experience One or More Treatment-related Adverse Events (AEs)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Treatment-related AEs were determined by the investigator to be related to the drug. The 95% confidence interval (CI) was based on the exact binomial method by Clopper- Pearson.
Time frame: Up to 14 days after treatment (up to Day 102)
Population: All enrolled participants who received at least 1 dose of study treatment, regardless of their IA classification.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants Who Experience One or More Treatment-related Adverse Events (AEs) | 14.3 Percentage of participants | 95% Confidence Interval 1.8 |
| Age Cohort 2 (12 -< 18 Years Old) | Percentage of Participants Who Experience One or More Treatment-related Adverse Events (AEs) | 29.4 Percentage of participants | 95% Confidence Interval 10.3 |
Secondary
Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Age Cohorts
Steady state AUCtau was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 AUCtau parameter values (1 for IV dosing, 1 for oral dosing).
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Age Cohorts | 62200 ng*h/mL | Geometric Coefficient of Variation 50.8 |
| Age Cohort 2 (12 -< 18 Years Old) | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Age Cohorts | 66400 ng*h/mL | Geometric Coefficient of Variation 55.4 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Age Cohorts | 64700 ng*h/mL | Geometric Coefficient of Variation 53 |
Secondary
Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation
Steady-state AUCtau was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2.
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation | 69600 ng*h/mL | Geometric Coefficient of Variation 51.6 |
| Age Cohort 2 (12 -< 18 Years Old) | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation | 49700 ng*h/mL | Geometric Coefficient of Variation 38 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation | NA ng*h/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): IV Formulation | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation | 68600 ng*h/mL | Geometric Coefficient of Variation 45.8 |
| Age Cohort 2 (12 -< 18 Years Old): PFS Formulation | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation | NA ng*h/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): Tablet Formulation | Area Under the Concentration Time Curve Over the Dosing Interval (AUCtau) of POS by Formulation | 60100 ng*h/mL | Geometric Coefficient of Variation 72.7 |
Secondary
Average Plasma Concentration (Cavg) of POS by Age Cohorts
Steady state Cavg was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cavg parameter values (1 for IV dosing, 1 for oral dosing).
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Average Plasma Concentration (Cavg) of POS by Age Cohorts | 2590 ng/mL | Geometric Coefficient of Variation 50.8 |
| Age Cohort 2 (12 -< 18 Years Old) | Average Plasma Concentration (Cavg) of POS by Age Cohorts | 2770 ng/mL | Geometric Coefficient of Variation 55.4 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Average Plasma Concentration (Cavg) of POS by Age Cohorts | 2700 ng/mL | Geometric Coefficient of Variation 53 |
Secondary
Average Plasma Concentration (Cavg) of POS by Formulation
Steady-state Cavg was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2.
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Average Plasma Concentration (Cavg) of POS by Formulation | 2900 ng/mL | Geometric Coefficient of Variation 51.6 |
| Age Cohort 2 (12 -< 18 Years Old) | Average Plasma Concentration (Cavg) of POS by Formulation | 2070 ng/mL | Geometric Coefficient of Variation 38 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Average Plasma Concentration (Cavg) of POS by Formulation | NA ng/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): IV Formulation | Average Plasma Concentration (Cavg) of POS by Formulation | 2860 ng/mL | Geometric Coefficient of Variation 45.8 |
| Age Cohort 2 (12 -< 18 Years Old): PFS Formulation | Average Plasma Concentration (Cavg) of POS by Formulation | NA ng/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): Tablet Formulation | Average Plasma Concentration (Cavg) of POS by Formulation | 2500 ng/mL | Geometric Coefficient of Variation 72.7 |
Secondary
Maximum Plasma Concentration (Cmax) of POS by Age Cohorts
Steady state Cmax was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cmax parameter values (1 for IV dosing, 1 for oral dosing).
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Maximum Plasma Concentration (Cmax) of POS by Age Cohorts | 3620 ng/mL | Geometric Coefficient of Variation 48.5 |
| Age Cohort 2 (12 -< 18 Years Old) | Maximum Plasma Concentration (Cmax) of POS by Age Cohorts | 3610 ng/mL | Geometric Coefficient of Variation 53.7 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Maximum Plasma Concentration (Cmax) of POS by Age Cohorts | 3610 ng/mL | Geometric Coefficient of Variation 51 |
Secondary
Maximum Plasma Concentration (Cmax) of POS by Formulation
Steady-state Cmax was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2.
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Maximum Plasma Concentration (Cmax) of POS by Formulation | 4530 ng/mL | Geometric Coefficient of Variation 39.2 |
| Age Cohort 2 (12 -< 18 Years Old) | Maximum Plasma Concentration (Cmax) of POS by Formulation | 2510 ng/mL | Geometric Coefficient of Variation 36.3 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Maximum Plasma Concentration (Cmax) of POS by Formulation | NA ng/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): IV Formulation | Maximum Plasma Concentration (Cmax) of POS by Formulation | 4180 ng/mL | Geometric Coefficient of Variation 38.8 |
| Age Cohort 2 (12 -< 18 Years Old): PFS Formulation | Maximum Plasma Concentration (Cmax) of POS by Formulation | NA ng/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): Tablet Formulation | Maximum Plasma Concentration (Cmax) of POS by Formulation | 2880 ng/mL | Geometric Coefficient of Variation 69.3 |
Secondary
Minimum Plasma Concentration (Cmin) of POS by Age Cohorts
Steady state Cmin was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Cmin parameter values (1 for IV dosing, 1 for oral dosing).
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Minimum Plasma Concentration (Cmin) of POS by Age Cohorts | 1610 ng/mL | Geometric Coefficient of Variation 66.3 |
| Age Cohort 2 (12 -< 18 Years Old) | Minimum Plasma Concentration (Cmin) of POS by Age Cohorts | 1920 ng/mL | Geometric Coefficient of Variation 63.9 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Minimum Plasma Concentration (Cmin) of POS by Age Cohorts | 1790 ng/mL | Geometric Coefficient of Variation 64.7 |
Secondary
Minimum Plasma Concentration (Cmin) of POS by Formulation
Steady-state Cmin was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2.
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Minimum Plasma Concentration (Cmin) of POS by Formulation | 1680 ng/mL | Geometric Coefficient of Variation 74.8 |
| Age Cohort 2 (12 -< 18 Years Old) | Minimum Plasma Concentration (Cmin) of POS by Formulation | 1410 ng/mL | Geometric Coefficient of Variation 44.8 |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Minimum Plasma Concentration (Cmin) of POS by Formulation | NA ng/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): IV Formulation | Minimum Plasma Concentration (Cmin) of POS by Formulation | 1820 ng/mL | Geometric Coefficient of Variation 56.5 |
| Age Cohort 2 (12 -< 18 Years Old): PFS Formulation | Minimum Plasma Concentration (Cmin) of POS by Formulation | NA ng/mL | — |
| Age Cohort 2 (12 -< 18 Years Old): Tablet Formulation | Minimum Plasma Concentration (Cmin) of POS by Formulation | 1910 ng/mL | Geometric Coefficient of Variation 80.5 |
Secondary
Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 12
A global clinical response is assessed by the investigator as favorable if the participant is alive and has a complete response (CR) or partial response (PR). CR is defined as survival within the prespecified period of observation, resolution of all attributable symptoms and signs of disease, resolution of radiological lesion(s), and documented clearance of infected sites that are accessible to repeated sampling. PR is defined as survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease, improvement of radiological lesion(s), and evidence of clearance of infected sites that are accessible to repeated sampling.
Time frame: Up to Week 12
Population: Participants who have possible, probable, or proven IA; receive at least 1 dose of study treatment; have at least 1 post-allocation observation subsequent to at least 1 dose of study treatment; and have baseline data for those analyses that require baseline data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 12 | Success, Complete Response | 57.1 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 12 | Success, Partial Response | 21.4 Percentage of participants |
| Age Cohort 2 (12 -< 18 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 12 | Success, Complete Response | 41.2 Percentage of participants |
| Age Cohort 2 (12 -< 18 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 12 | Success, Partial Response | 35.3 Percentage of participants |
Secondary
Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 6
A global clinical response is assessed by the investigator as favorable if the participant is alive and has a complete response (CR) or partial response (PR). CR is defined as survival within the prespecified period of observation, resolution of all attributable symptoms and signs of disease, resolution of radiological lesion(s), and documented clearance of infected sites that are accessible to repeated sampling. PR is defined as survival within the prespecified period of observation, improvement in attributable symptoms and signs of disease, improvement of radiological lesion(s), and evidence of clearance of infected sites that are accessible to repeated sampling.
Time frame: Up to week 6
Population: Participants who have possible, probable, or proven IA; receive at least 1 dose of study treatment; have at least 1 post-allocation observation subsequent to at least 1 dose of study treatment; and have baseline data for those analyses that require baseline data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 6 | Success, Complete Response | 42.9 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 6 | Success, Partial Response | 21.4 Percentage of participants |
| Age Cohort 2 (12 -< 18 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 6 | Success, Complete Response | 17.6 Percentage of participants |
| Age Cohort 2 (12 -< 18 Years Old) | Percentage of Participants Who Have a Favorable Global Clinical Response Through Week 6 | Success, Partial Response | 52.9 Percentage of participants |
Secondary
Percentage of Participants Who Have a Relapse of Invasive Aspergillosis (IA) at Any Point After Achieving Favorable Global Clinical Response
In participants who achieved favorable global clinical response, relapse of IA is defined as the re-emergence of clinical, radiographic, or other relevant abnormalities indicating IA.
Time frame: Up to 28 days post-treatment (up to Day 116)
Population: Participants who have possible, probable, or proven IA; receive at least 1 dose of study treatment; have at least 1 post-allocation observation subsequent to at least 1 dose of study treatment; have baseline data for those analyses that require baseline data; and who have achieved a favorable global clinical response at the end of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants Who Have a Relapse of Invasive Aspergillosis (IA) at Any Point After Achieving Favorable Global Clinical Response | 0 Percentage of participants |
| Age Cohort 2 (12 -< 18 Years Old) | Percentage of Participants Who Have a Relapse of Invasive Aspergillosis (IA) at Any Point After Achieving Favorable Global Clinical Response | 0 Percentage of participants |
Secondary
Percentage of Participants With Different Categories of Palatability After First Day of Treatment With the POS PFS Formulation
Palatability was categorized on the first day (Day 8) on PFS based on responses by participants to a palatability questionnaire. Per protocol participants were pooled into a single treatment group. Palatability categories for taste are as follows: Very good; Good; Very bad; Neither good nor bad.
Time frame: First day of PFS treatment (Day 8)
Population: Participants who completed the palatability questionnaire. Per protocol participants were pooled into a single treatment group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After First Day of Treatment With the POS PFS Formulation | Very good | 20 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After First Day of Treatment With the POS PFS Formulation | Good | 40 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After First Day of Treatment With the POS PFS Formulation | Very bad | 10 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After First Day of Treatment With the POS PFS Formulation | Neither good nor bad | 30 Percentage of participants |
Secondary
Percentage of Participants With Different Categories of Palatability After Last Day of Treatment With the POS PFS Formulation
Palatability was categorized on the last day (Day 85) on PFS based on responses by participants to a palatability questionnaire. Per protocol participants were pooled into a single treatment group Palatability categories for taste are as follows: Very good; Good; Very bad; Neither good nor bad.
Time frame: Last day of PFS treatment (Day 85)
Population: Participants who completed the palatability questionnaire. Per protocol participants were pooled into a single treatment group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After Last Day of Treatment With the POS PFS Formulation | Very good | 10 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After Last Day of Treatment With the POS PFS Formulation | Good | 40 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After Last Day of Treatment With the POS PFS Formulation | Very bad | 10 Percentage of participants |
| Age Cohort 1 (2 -< 12 Years Old) | Percentage of Participants With Different Categories of Palatability After Last Day of Treatment With the POS PFS Formulation | Neither good nor bad | 40 Percentage of participants |
Secondary
Time to Reach Cmax (Tmax) of POS by Age Cohorts
Steady state Tmax was determined by population PK analysis of plasma concentrations obtained pre-dose up to Week 12 for each of Cohorts 1 and 2, as well as the pooled Cohorts 1 and 2. Some participants had 2 Tmax parameter values (1 for IV dosing, 1 for oral dosing).
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each age cohort, as well as the pooled age cohorts.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Time to Reach Cmax (Tmax) of POS by Age Cohorts | 1.68 hr. |
| Age Cohort 2 (12 -< 18 Years Old) | Time to Reach Cmax (Tmax) of POS by Age Cohorts | 1.63 hr. |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Time to Reach Cmax (Tmax) of POS by Age Cohorts | 1.63 hr. |
Secondary
Time to Reach Cmax (Tmax) of POS by Formulation
Steady-state Tmax was determined by population PK analysis from plasma concentration obtained pre-dose up to Week 12 for each of the POS formulations: IV, PFS and tablet. Some participants may have received more than 1 formulation, and results were only reported when N \> 2.
Time frame: Pre-dose, Day 1, Weeks 1, 2, 4, 6, 9 and 12
Population: All treated participants who had at least 1 postdose plasma concentration obtained after receiving at least 5 days of treatment. Per protocol PK results were analyzed for each POS formulation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Age Cohort 1 (2 -< 12 Years Old) | Time to Reach Cmax (Tmax) of POS by Formulation | 1.50 hr |
| Age Cohort 2 (12 -< 18 Years Old) | Time to Reach Cmax (Tmax) of POS by Formulation | 7.00 hr |
| Age Cohorts 1 and 2 (2 -< 18 Years Old) | Time to Reach Cmax (Tmax) of POS by Formulation | NA hr |
| Age Cohort 2 (12 -< 18 Years Old): IV Formulation | Time to Reach Cmax (Tmax) of POS by Formulation | 1.50 hr |
| Age Cohort 2 (12 -< 18 Years Old): PFS Formulation | Time to Reach Cmax (Tmax) of POS by Formulation | NA hr |
| Age Cohort 2 (12 -< 18 Years Old): Tablet Formulation | Time to Reach Cmax (Tmax) of POS by Formulation | 7.20 hr |