Postoperative Nausea and Vomiting
Conditions
Brief summary
This two part study will determine the appropriate dosing regimen of aprepitant for the prevention of postoperative nausea and vomiting (PONV) in pediatric participants 6 months to 17 years of age, by assessing pharmacokinetic parameters and monitoring safety and tolerability of administered doses. Part I will be an open label investigation of a single dose of aprepitant measuring pharmacokinetics at specified time points up to 48 hours after aprepitant dosing. Part II will be a double blind trial of participants randomized to receive either aprepitant or ondansetron.
Interventions
DRUGAprepitant
Aprepitant administered orally or intraveously.
DRUGOndansetron
Ondansetron administered intravenously.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* Participant is scheduled to have surgery requiring a 48 hour (Part I) or 24 hour (Part II) hospital stay * Participant is scheduled to receive general anesthesia * Participant is scheduled to receive opioids (e.g. morphine or fentanyl) * Female participants of childbearing potential must have negative pregnancy test prior to drug administration * A female participant who is of reproductive potential must agree to remain abstinent or use a barrier form of contraception for at least 14 days prior to, throughout, and for at least one month following the last dose of study medication * Participant weighs 6 kg or more
Exclusion criteria
* Participant is undergoing surgery for a life-threatening condition * Participant is pregnant or breast feeding * Participant has vomited within 24 hours prior to surgery * Participant has a known history of QT prolongation or is currently taking other medicinal products that lead to QT prolongation * Participant has an active infection (e.g., pneumonia), congestive heart failure, bradyarrythmia, any uncontrolled disease (e.g., diabetic ketoacidosis, gastrointestinal obstruction), evidence of any clinically significant respiratory, metabolic, hepatic, renal dysfunction, or a history of any illness, including morbid obesity, that might pose unwarranted risk
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Discontinuing Study Treatment Due to AEs | Day 1 | — |
| Maximum Plasma Concentration (Cmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 48 Hours Post-Dose | Blood samples were collected from participants for the analysis of Cmax up to 48 hours after dosing. |
| Time to Maximum Plasma Concentration (Tmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 48 Hours Post-Dose | Blood samples were collected from participants for the analysis of Tmax up to 48 hours after dosing. |
| Plasma Concentration of Aprepitant at 24 Hours (C24 hr) Following a Single Oral Dose in Study Part 1 | 24 Hours Post-Dose | Blood samples were collected from participants for the analysis of C24 hr at 24 hours after dosing. N/A indicates that \>50% of measurements were below the lower level of quantitaion (LLOQ). |
| Plasma Concentration of Aprepitant at 48 Hours (C48 hr) Following a Single Oral Dose in Study Part 1 | 48 Hours Post-Dose | The mean plasma concentration of aprepitant was evaluated in participants at 48 hours following a single oral dose. |
| Number of Participants Experiencing Adverse Events (AEs) | Up to 21 Days Post-Surgery | — |
| Area Under the Curve From 0-48 (AUC0-48) of Aprepitant Following a Single Oral Dose in Study Part 1 | Pre-dose, and 1, 2, 3, 4, 8, 12, 24, and 48 hours post-dose | Blood samples of 0.5 mL were collected from participants for the analysis of AUC0-48 at specified time points: pre-dose, and 1, 2, 3, 4, 8, 12, 24, and 48 hours post aprepitant single dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With No Vomiting Up to 24 Hours Following Surgery in Study Part 2 | Up to 24 Hours | — |
| Number of Participants With Complete Response Up to 24 Hours Following Surgery in Study Part 2 | Up to 24 Hours | Complete response was defined as no vomiting and no use of rescue medication in 0-24 hours post-surgery. |
| Number of Participants With No Vomiting Up to 48 Hours Following Surgery Ini Study Part 2 | Up to 48 Hours | — |
| Number of Participants With Complete Response Up to 48 Hours Following Surgery in Study Part 2 | Up to 48 Hours | Complete response was defined as no vomiting and no use of rescue medication in 0-48 hours post-surgery. |
| Number of Participants With Vomiting Frequency in Study Part 2 | Up to 24 Hours | — |
Countries
Brazil, Mexico, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
This trial was conducted at 18 trial centers: 2 in Brazil, 1 in Finland, 1 in Russia, 1 in Mexico, 4 in Spain, 6 in Turkey, and 3 in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Oral Aprepitant In Study Part 1, participants aged 6 months to 17 years received a single oral dose of aprepitant for the treatment of post-operative nausea and vomiting (PONV) on Day 1. | 46 |
| Part 2: Oral Aprepitant In Study Part 2, participants aged 6 months to 17 years received a single oral dose of aprepitant for the treatment of post-operative nausea and vomiting (PONV) on Day 1. | 27 |
| Part 2: Intravenous Ondansetron In Study Part 2, particpants aged 6 months to 17 years received a single intravenous dose of ondansetron for the treatment of post-operative nausea and vomiting (PONV) on Day 1. | 25 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part 1: Oral Aprepitant | Part 2: Oral Aprepitant | Part 2: Intravenous Ondansetron | Total |
|---|---|---|---|---|
| Age, Customized 0.5 to <2 years | 14 Participants | 8 Participants | 5 Participants | 27 Participants |
| Age, Customized 12 to 17 years | 10 Participants | 7 Participants | 7 Participants | 24 Participants |
| Age, Customized 2 to <6 years | 11 Participants | 7 Participants | 7 Participants | 25 Participants |
| Age, Customized 6 to <12 years | 11 Participants | 5 Participants | 6 Participants | 22 Participants |
| Sex: Female, Male Female | 13 Participants | 6 Participants | 12 Participants | 31 Participants |
| Sex: Female, Male Male | 33 Participants | 21 Participants | 13 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 46 | 5 / 27 | 4 / 25 |
| serious Total, serious adverse events | 3 / 46 | 2 / 27 | 0 / 25 |
Outcome results
Primary
Area Under the Curve From 0-48 (AUC0-48) of Aprepitant Following a Single Oral Dose in Study Part 1
Blood samples of 0.5 mL were collected from participants for the analysis of AUC0-48 at specified time points: pre-dose, and 1, 2, 3, 4, 8, 12, 24, and 48 hours post aprepitant single dose.
Time frame: Pre-dose, and 1, 2, 3, 4, 8, 12, 24, and 48 hours post-dose
Population: The population consisted of all participants that received at least one dose of study medication and for which AUC0-48 data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Oral Aprepitant | Area Under the Curve From 0-48 (AUC0-48) of Aprepitant Following a Single Oral Dose in Study Part 1 | 6 months to <2 years (n=11) | 5.97 hr*ug/ml | Standard Deviation 4.44 |
| Part 1: Oral Aprepitant | Area Under the Curve From 0-48 (AUC0-48) of Aprepitant Following a Single Oral Dose in Study Part 1 | 2 years to <6 years (n=11) | 4.76 hr*ug/ml | Standard Deviation 3.55 |
| Part 1: Oral Aprepitant | Area Under the Curve From 0-48 (AUC0-48) of Aprepitant Following a Single Oral Dose in Study Part 1 | 6 years to <12 years (n=11) | 6.16 hr*ug/ml | Standard Deviation 2.27 |
| Part 1: Oral Aprepitant | Area Under the Curve From 0-48 (AUC0-48) of Aprepitant Following a Single Oral Dose in Study Part 1 | 12 years to 17 years (n=10) | 6.01 hr*ug/ml | Standard Deviation 2.53 |
Primary
Maximum Plasma Concentration (Cmax) of Aprepitant Following a Single Oral Dose in Study Part 1
Blood samples were collected from participants for the analysis of Cmax up to 48 hours after dosing.
Time frame: 48 Hours Post-Dose
Population: The population consisted of all participants that received at least one dose of study medication and for which Cmax data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Oral Aprepitant | Maximum Plasma Concentration (Cmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 6 months to <2 years (n=11) | 715 ng/mL | Standard Deviation 445 |
| Part 1: Oral Aprepitant | Maximum Plasma Concentration (Cmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 2 years to <6 years (n=11) | 586 ng/mL | Standard Deviation 462 |
| Part 1: Oral Aprepitant | Maximum Plasma Concentration (Cmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 6 years to <12 years (n=11) | 913 ng/mL | Standard Deviation 294 |
| Part 1: Oral Aprepitant | Maximum Plasma Concentration (Cmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 12 years to 17 years (n=10) | 520 ng/mL | Standard Deviation 230 |
Primary
Number of Participants Discontinuing Study Treatment Due to AEs
Time frame: Day 1
Population: The population consists of all participants that received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Oral Aprepitant | Number of Participants Discontinuing Study Treatment Due to AEs | 0 Participants |
| Part 2: Oral Aprepitant | Number of Participants Discontinuing Study Treatment Due to AEs | 0 Participants |
| Part 2: Intravenous Ondansetron | Number of Participants Discontinuing Study Treatment Due to AEs | 0 Participants |
Primary
Number of Participants Experiencing Adverse Events (AEs)
Time frame: Up to 21 Days Post-Surgery
Population: The population consists of all participants that received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Oral Aprepitant | Number of Participants Experiencing Adverse Events (AEs) | 20 Participants |
| Part 2: Oral Aprepitant | Number of Participants Experiencing Adverse Events (AEs) | 12 Participants |
| Part 2: Intravenous Ondansetron | Number of Participants Experiencing Adverse Events (AEs) | 7 Participants |
Primary
Plasma Concentration of Aprepitant at 24 Hours (C24 hr) Following a Single Oral Dose in Study Part 1
Blood samples were collected from participants for the analysis of C24 hr at 24 hours after dosing. N/A indicates that \>50% of measurements were below the lower level of quantitaion (LLOQ).
Time frame: 24 Hours Post-Dose
Population: The population consisted of all participants that received at least one dose of study medication and for which C24 hr data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 24 Hours (C24 hr) Following a Single Oral Dose in Study Part 1 | 6 months to <2 years (n=11) | 31.0 ng/mL | Standard Deviation 39.5 |
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 24 Hours (C24 hr) Following a Single Oral Dose in Study Part 1 | 2 years to <6 years (n=11) | 58.6 ng/mL | Standard Deviation 54.3 |
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 24 Hours (C24 hr) Following a Single Oral Dose in Study Part 1 | 6 years to <12 years (n=11) | 51.1 ng/mL | Standard Deviation 35.6 |
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 24 Hours (C24 hr) Following a Single Oral Dose in Study Part 1 | 12 years to 17 years (n=10) | 81.1 ng/mL | Standard Deviation 59.8 |
Primary
Plasma Concentration of Aprepitant at 48 Hours (C48 hr) Following a Single Oral Dose in Study Part 1
The mean plasma concentration of aprepitant was evaluated in participants at 48 hours following a single oral dose.
Time frame: 48 Hours Post-Dose
Population: The population consisted of all participants that received at least one dose of study medication and for which C48 hr data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 48 Hours (C48 hr) Following a Single Oral Dose in Study Part 1 | 6 months to <2 years (n=11) | NA ng/mL | — |
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 48 Hours (C48 hr) Following a Single Oral Dose in Study Part 1 | 2 years to <6 years (n=11) | NA ng/mL | — |
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 48 Hours (C48 hr) Following a Single Oral Dose in Study Part 1 | 6 years to <12 years (n=11) | NA ng/mL | — |
| Part 1: Oral Aprepitant | Plasma Concentration of Aprepitant at 48 Hours (C48 hr) Following a Single Oral Dose in Study Part 1 | 12 years to 17 years (n=10) | 7.25 ng/mL | Standard Deviation 8.9 |
Primary
Time to Maximum Plasma Concentration (Tmax) of Aprepitant Following a Single Oral Dose in Study Part 1
Blood samples were collected from participants for the analysis of Tmax up to 48 hours after dosing.
Time frame: 48 Hours Post-Dose
Population: The population consisted of all participants that received at least one dose of study medication and for which Tmax data were available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Oral Aprepitant | Time to Maximum Plasma Concentration (Tmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 6 months to <2 years (n=11) | 3.00 Hours |
| Part 1: Oral Aprepitant | Time to Maximum Plasma Concentration (Tmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 2 years to <6 years (n=11) | 3.00 Hours |
| Part 1: Oral Aprepitant | Time to Maximum Plasma Concentration (Tmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 6 years to <12 years (n=11) | 2.00 Hours |
| Part 1: Oral Aprepitant | Time to Maximum Plasma Concentration (Tmax) of Aprepitant Following a Single Oral Dose in Study Part 1 | 12 years to 17 years (n=10) | 3.50 Hours |
Secondary
Number of Participants With Complete Response Up to 24 Hours Following Surgery in Study Part 2
Complete response was defined as no vomiting and no use of rescue medication in 0-24 hours post-surgery.
Time frame: Up to 24 Hours
Population: The Full Analysis Set (FAS) population was used for all efficacy evaluations and included those participants who received a full dose of active study therapy, had surgery, and had at least one post-treatment efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Oral Aprepitant | Number of Participants With Complete Response Up to 24 Hours Following Surgery in Study Part 2 | 19 Participants |
| Part 2: Oral Aprepitant | Number of Participants With Complete Response Up to 24 Hours Following Surgery in Study Part 2 | 20 Participants |
Secondary
Number of Participants With Complete Response Up to 48 Hours Following Surgery in Study Part 2
Complete response was defined as no vomiting and no use of rescue medication in 0-48 hours post-surgery.
Time frame: Up to 48 Hours
Population: The Full Analysis Set (FAS) population was used for all efficacy evaluations and included those participants who received a full dose of active study therapy, had surgery, and had at least one post-treatment efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Oral Aprepitant | Number of Participants With Complete Response Up to 48 Hours Following Surgery in Study Part 2 | 17 Participants |
| Part 2: Oral Aprepitant | Number of Participants With Complete Response Up to 48 Hours Following Surgery in Study Part 2 | 20 Participants |
Secondary
Number of Participants With No Vomiting Up to 24 Hours Following Surgery in Study Part 2
Time frame: Up to 24 Hours
Population: The Full Analysis Set (FAS) population was used for all efficacy evaluations and included those participants who received a full dose of active study therapy, had surgery, and had at least one post-treatment efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Oral Aprepitant | Number of Participants With No Vomiting Up to 24 Hours Following Surgery in Study Part 2 | 20 Participants |
| Part 2: Oral Aprepitant | Number of Participants With No Vomiting Up to 24 Hours Following Surgery in Study Part 2 | 20 Participants |
Secondary
Number of Participants With No Vomiting Up to 48 Hours Following Surgery Ini Study Part 2
Time frame: Up to 48 Hours
Population: The Full Analysis Set (FAS) population was used for all efficacy evaluations and included those participants who received a full dose of active study therapy, had surgery, and had at least one post-treatment efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Oral Aprepitant | Number of Participants With No Vomiting Up to 48 Hours Following Surgery Ini Study Part 2 | 18 Participants |
| Part 2: Oral Aprepitant | Number of Participants With No Vomiting Up to 48 Hours Following Surgery Ini Study Part 2 | 20 Participants |
Secondary
Number of Participants With Vomiting Frequency in Study Part 2
Time frame: Up to 24 Hours
Population: The Full Analysis Set (FAS) population was used for all efficacy evaluations and included those participants who received a full dose of active study therapy, had surgery, and had at least one post-treatment efficacy assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | 1 Vomiting Episode | 5 Participants |
| Part 1: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | 3 Vomiting Episodes | 0 Participants |
| Part 1: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | 2 Vomiting Episodes | 0 Participants |
| Part 1: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | >3 Vomiting Episodes | 0 Participants |
| Part 1: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | No Vomiting | 20 Participants |
| Part 2: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | >3 Vomiting Episodes | 1 Participants |
| Part 2: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | No Vomiting | 20 Participants |
| Part 2: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | 1 Vomiting Episode | 3 Participants |
| Part 2: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | 2 Vomiting Episodes | 1 Participants |
| Part 2: Oral Aprepitant | Number of Participants With Vomiting Frequency in Study Part 2 | 3 Vomiting Episodes | 0 Participants |