Fungal Infections
Conditions
Brief summary
The purpose of this dose-escalation study is to evaluate the pharmacokinetics, safety, and tolerability of oral posaconazole in immunocompromised children with neutropenia or expected neutropenia.
Interventions
DRUGPosaconazole 12 mg/kg/day BID
Posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) (maximum 800 mg/day)
DRUGPosaconazole 18 mg/kg/day BID
Posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) (maximum 1200 mg/day)
DRUGPosaconazole 18 mg/kg/day TID
Posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) (maximum 1200 mg/day)
DRUGPosaconazole 12 mg/kg/day TID
Posaconazole oral suspension 12 mg/kg/day divided into 3 doses (TID) (maximum 800 mg/day)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* Documented or anticipated neutropenia expected to last at least 7 days and only in the following clinical situations: acute leukemia; myelodysplasia; severe aplastic anemia; autologous hematopoietic stem cell transplantation (HSCT) recipients; high risk neuroblastoma; advanced stage non-Hodgkin's lymphoma; recipients of allogeneic HSCT during the pre-engraftment (neutropenia) period * Participants of child-bearing potential must use a medically accepted method of contraception throughout the study and for at least 30 days after stopping study medication, unless they are surgically or medically sterile or agree to remain abstinent.
Exclusion criteria
* Proven invasive fungal infection (IFI) before study entry * Severe nausea and/or vomiting at screening * Received posaconazole within 10 days before screening * Unable to receive study drug by mouth or via an intestinal (enteral) tube * Females who are pregnant, intend to become pregnant during the study, or are breastfeeding * History of anaphylaxis attributed to the azole class of antifungal agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | Up to 12 hours after the first dose (BID dose groups) or up to 8 hours after the first dose (TID dose (TID dose groups) | Blood samples for determination of plasma posaconazole concentration were collected predose and approximately 3, 5, 8, and 12 hours after the first dose on Day 1. The 12-hour sample was not obtained for the TID dose groups. Day 1 pharmacokinetic samples were not collected for participants 3 months to \<2 years of age weighing \<6.5 kg. |
| Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | Up to 12 hours after the first dose on Day 7 (BID dose groups) or up to 8 hours after the first dose on Day 7 (TID dose | Blood samples for determination of plasma posaconazole concentration were collected predose and approximately 3, 5, 8, and 12 hours after the first dose on Day 7 (steady state). The 12-hour sample was not obtained for the TID dose groups. The target Cavg range was 500 to \<2500 ng/mL. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Adverse Event | Up to Day 58 | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. |
| Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | Up to Day 28 | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. |
Participant flow
Pre-assignment details
A total of 160 participants were screened, 142 were randomized / enrolled, and 136 were treated. An arm planned for participants aged 3 months to \<2 years to receive posaconazole 18 mg/kg/day TID was never initiated.
Participants by arm
| Arm | Count |
|---|---|
| POS 12 BID 2 to <7 Years Participants aged 2 to \<7 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days. | 24 |
| POS 12 BID 7 to <18 Years Participants aged 7 to \<18 years received posaconazole oral suspension 12 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days. | 22 |
| POS 18 BID 2 to <7 Years Participants aged 2 to \<7 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days. | 20 |
| POS 18 BID 7 to <18 Years Participants aged 7 to \<18 years received posaconazole oral suspension 18 mg/kg/day divided into 2 doses (BID) until recovery from neutropenia or up to 28 days. | 28 |
| POS 18 TID 2 to <7 Years Participants aged 2 to \<7 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days. | 15 |
| POS 18 TID 7 to <18 Years Participants aged 7 to \<18 years received posaconazole oral suspension 18 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days. | 32 |
| POS 12 TID 3 Months to <2 Years Participants aged 3 months to \<2 years received posaconazole oral suspension 12 mg/kg/day divided into 3 doses (TID) until recovery from neutropenia or up to 28 days. | 1 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 10 | 2 | 8 | 3 | 6 | 0 |
| Overall Study | Did not meet protocol eligibility | 0 | 0 | 1 | 0 | 0 | 4 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 2 | 2 | 1 | 3 | 0 |
Baseline characteristics
| Characteristic | POS 12 BID 2 to <7 Years | POS 12 BID 7 to <18 Years | POS 18 BID 2 to <7 Years | POS 18 BID 7 to <18 Years | POS 18 TID 2 to <7 Years | POS 18 TID 7 to <18 Years | POS 12 TID 3 Months to <2 Years | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 4.0 Years STANDARD_DEVIATION 1.3 | 11.9 Years STANDARD_DEVIATION 3.5 | 4.4 Years STANDARD_DEVIATION 1.5 | 12.2 Years STANDARD_DEVIATION 3.2 | 4.1 Years STANDARD_DEVIATION 1.3 | 13.1 Years STANDARD_DEVIATION 3 | 0.9 Years STANDARD_DEVIATION 0 | 8.9 Years STANDARD_DEVIATION 4.9 |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 8 Participants | 9 Participants | 6 Participants | 14 Participants | 0 Participants | 59 Participants |
| Sex: Female, Male Male | 14 Participants | 10 Participants | 12 Participants | 19 Participants | 9 Participants | 18 Participants | 1 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 22 | 20 / 21 | 16 / 19 | 26 / 28 | 13 / 15 | 28 / 30 | 1 / 1 |
| serious Total, serious adverse events | 5 / 22 | 3 / 21 | 1 / 19 | 7 / 28 | 7 / 15 | 11 / 30 | 1 / 1 |
Outcome results
Primary
Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose)
Blood samples for determination of plasma posaconazole concentration were collected predose and approximately 3, 5, 8, and 12 hours after the first dose on Day 1. The 12-hour sample was not obtained for the TID dose groups. Day 1 pharmacokinetic samples were not collected for participants 3 months to \<2 years of age weighing \<6.5 kg.
Time frame: Up to 12 hours after the first dose (BID dose groups) or up to 8 hours after the first dose (TID dose (TID dose groups)
Population: The pharmacokinetic evaluable population included all treated participants with evaluable samples applicable to the endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 12 BID 2 to <7 Years | Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | 122 ng/mL | Standard Deviation 101 |
| POS 12 BID 7 to <18 Years | Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | 107 ng/mL | Standard Deviation 92.5 |
| POS 18 BID 2 to <7 Years | Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | 112 ng/mL | Standard Deviation 86.9 |
| POS 18 BID 7 to <18 Years | Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | 113 ng/mL | Standard Deviation 100 |
| POS 18 TID 2 to <7 Years | Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | 68.4 ng/mL | Standard Deviation 40.4 |
| POS 18 TID 7 to <18 Years | Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | 57.9 ng/mL | Standard Deviation 30.2 |
| POS 12 TID 3 Months to <2 Years | Average Concentration of Posaconazole (Cavg) on Day 1 (Single Dose) | 68.5 ng/mL | Standard Deviation 0 |
Primary
Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State)
Blood samples for determination of plasma posaconazole concentration were collected predose and approximately 3, 5, 8, and 12 hours after the first dose on Day 7 (steady state). The 12-hour sample was not obtained for the TID dose groups. The target Cavg range was 500 to \<2500 ng/mL.
Time frame: Up to 12 hours after the first dose on Day 7 (BID dose groups) or up to 8 hours after the first dose on Day 7 (TID dose
Population: The pharmacokinetic evaluable population included all treated participants with evaluable samples applicable to the endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| POS 12 BID 2 to <7 Years | Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | 604 ng/mL | Standard Deviation 779 |
| POS 12 BID 7 to <18 Years | Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | 1050 ng/mL | Standard Deviation 789 |
| POS 18 BID 2 to <7 Years | Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | 485 ng/mL | Standard Deviation 306 |
| POS 18 BID 7 to <18 Years | Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | 1240 ng/mL | Standard Deviation 1400 |
| POS 18 TID 2 to <7 Years | Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | 620 ng/mL | Standard Deviation 411 |
| POS 18 TID 7 to <18 Years | Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | 1150 ng/mL | Standard Deviation 750 |
| POS 12 TID 3 Months to <2 Years | Average Concentration of Posaconazole (Cavg) on Day 7 (Steady State) | 453 ng/mL | Standard Deviation 0 |
Secondary
Number of Participants With an Adverse Event
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions.
Time frame: Up to Day 58
Population: The population analyzed was all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| POS 12 BID 2 to <7 Years | Number of Participants With an Adverse Event | 21 Participants |
| POS 12 BID 7 to <18 Years | Number of Participants With an Adverse Event | 21 Participants |
| POS 18 BID 2 to <7 Years | Number of Participants With an Adverse Event | 16 Participants |
| POS 18 BID 7 to <18 Years | Number of Participants With an Adverse Event | 26 Participants |
| POS 18 TID 2 to <7 Years | Number of Participants With an Adverse Event | 13 Participants |
| POS 18 TID 7 to <18 Years | Number of Participants With an Adverse Event | 30 Participants |
| POS 12 TID 3 Months to <2 Years | Number of Participants With an Adverse Event | 1 Participants |
Secondary
Number of Participants With an Adverse Event Leading to Study Drug Discontinuation
An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions.
Time frame: Up to Day 28
Population: The population analyzed was all treated participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| POS 12 BID 2 to <7 Years | Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | 7 Participants |
| POS 12 BID 7 to <18 Years | Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | 9 Participants |
| POS 18 BID 2 to <7 Years | Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | 2 Participants |
| POS 18 BID 7 to <18 Years | Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | 9 Participants |
| POS 18 TID 2 to <7 Years | Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | 3 Participants |
| POS 18 TID 7 to <18 Years | Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | 6 Participants |
| POS 12 TID 3 Months to <2 Years | Number of Participants With an Adverse Event Leading to Study Drug Discontinuation | 0 Participants |