Chemotherapy-Induced Nausea and Vomiting (CINV)
Conditions
Keywords
NK1-receptor occupancy
Brief summary
This study will evaluate if the mean value of brain neurokinin 1 (NK1)-receptor occupancy of participants treated with aprepitant is similar to that of participants treated with fosaprepitant at certain timepoints.
Detailed description
The third arm of the study (Aprepitant 250 mg) will only be conducted if the real-time assessment of the NK1-receptor occupancy data between fosaprepitant 150 mg & aprepitant 165 mg reveals that the primary hypothesis will not be supported.
Interventions
DRUGDexamethasone (12-8-16-16 mg)
Dexamethasone 12 mg will be administered orally 30 minutes after the start of fosaprepitant dimeglumine or 30 minutes after aprepitant on Day 1; Oral doses of dexamethasone will be administered on Day 2 (8 mg), Day 3 (8 mg twice daily), and Day 4 (8 mg twice daily) with or without a meal.
a single intravenous infusion of 150 mg fosaprepitant dimeglumine over 20 minutes on Day 1 15 minutes after consumption of a standard light breakfast meal
a single oral 165 mg aprepitant capsule 15 minutes after consumption of a standard light breakfast meal
DRUGAprepitant 250 mg
a single oral 250 mg dose achieved by administering two 125 mg aprepitant capsules 15 minutes after consumption of a standard light breakfast meal
DRUGDexamethasone (12-8-8-16 mg)
Dexamethasone 12 mg will be administered orally 30 minutes after after aprepitant on Day 1; Oral doses of dexamethasone will be administered on Day 2 (8 mg), Day 3 (8 mg), and Day 4 (8 mg twice daily) with or without a meal.
DRUGOndansetron
The intravenous (I.V.) infusion of ondansetron 32 mg will begin 30 minutes after the start of fosaprepitant dimeglumine or 30 minutes after aprepitant on Day 1 and will be administered as a 15-minute infusion
DRUGMK0999
I.V. infusion of MK0999 containing \ 100 MBq (\ 3 mCi) containing ≤ 5 ug of MK0999)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Generally healthy * Female participants must be of non-childbearing potential * Non-smoker or has not used nicotine or nicotine-containing products for at least 6 months
Exclusion criteria
* History of a clinically significant psychiatric disorder over the last 5 to 10 years * History of stroke, chronic seizures, or major neurological disorder * History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases * History of neoplastic disease * Excessive consumption of alcohol (3 drinks/day) or caffeinated beverages (6 servings/day) * Major surgery, donated or lost 1 unit of blood within 4 weeks * Participated in another investigational study within 4 weeks * History of significant drug allergy or any clinically significant adverse experiences related to EMEND™, dexamethasone, or ondansetron * History of significant multiple and/or severe allergies * History of anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food * Current drug/alcohol abuse, or history of such within 2 years * Participation in a PET study or other study involving administration of a radioactive substance or ionizing radiation within the prior 12 months * Extensive radiological examination within the prior 12 months * Magnetizable metal prostheses or devices (Magnetic Resonance Imaging (MRI) hazard) * History of claustrophobia
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Brain NK1-receptor Occupancy at 24 Hours Post Dose | 24 hours post dose |
| Brain NK1-receptor Occupancy at 48 Hours Post Dose | 48 hours post dose |
Secondary
| Measure | Time frame |
|---|---|
| Brain NK1-receptor Occupancy at 120 Hours Post Dose | 120 hours post dose |
| Brain NK1-receptor Occupancy at the Time of the Maximum Concentration (Tmax) | 30 minutes after the end of the 20-minute infusion of fosaprepitant or at 4 hours after oral dosing of aprepitant |
Participant flow
Pre-assignment details
Aprepitant 250 mg was not evaluated because the assessment of the positron emission tomography (PET) scan data (neurokinin 1 (NK1)-receptor occupancy values at 24 & 48 hours postdose) from fosaprepitant 150 mg & aprepitant 165 mg revealed that the protocol's hypothesis was met; therefore, it was not necessary to evaluate aprepitant 250 mg.
Participants by arm
| Arm | Count |
|---|---|
| Fosaprepitant 150 mg A single intravenous infusion of 150 mg fosaprepitant dimeglumine over 20 minutes, 15 minutes after consumption of a standard light breakfast meal on Day 1. | 8 |
| Aprepitant 165 mg A single oral 165 mg aprepitant capsule 15 minutes after consumption of a standard light breakfast meal on Day 1. | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | All planned PET scans were not obtained. | 2 | 0 |
Baseline characteristics
| Characteristic | Fosaprepitant 150 mg | Aprepitant 165 mg | Total |
|---|---|---|---|
| Age, Customized < = 18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized > = 55 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Between 18 and 55 years | 8 Participants | 8 Participants | 16 Participants |
| Region of Enrollment Belgium | 8 participants | 8 participants | 16 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 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 | 5 / 8 | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Brain NK1-receptor Occupancy at 24 Hours Post Dose
Time frame: 24 hours post dose
Population: All participants with at least 1 successful post dose PET~scan were included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fosaprepitant 150 mg | Brain NK1-receptor Occupancy at 24 Hours Post Dose | 100.40 Percent of occupancy |
| Aprepitant 165 mg | Brain NK1-receptor Occupancy at 24 Hours Post Dose | 100.20 Percent of occupancy |
90% CI: [0.99, 1.01]
Primary
Brain NK1-receptor Occupancy at 48 Hours Post Dose
Time frame: 48 hours post dose
Population: All participants with at least 1 successful postdose PET~scan were included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fosaprepitant 150 mg | Brain NK1-receptor Occupancy at 48 Hours Post Dose | 98.62 Percent of occupancy |
| Aprepitant 165 mg | Brain NK1-receptor Occupancy at 48 Hours Post Dose | 98.79 Percent of occupancy |
90% CI: [0.98, 1.02]
Secondary
Brain NK1-receptor Occupancy at 120 Hours Post Dose
Time frame: 120 hours post dose
Population: All participants with at least 1 successful postdose PET~scan were included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fosaprepitant 150 mg | Brain NK1-receptor Occupancy at 120 Hours Post Dose | 59.93 Percent of occupancy |
| Aprepitant 165 mg | Brain NK1-receptor Occupancy at 120 Hours Post Dose | 54.32 Percent of occupancy |
90% CI: [0.5, 1.66]
Secondary
Brain NK1-receptor Occupancy at the Time of the Maximum Concentration (Tmax)
Time frame: 30 minutes after the end of the 20-minute infusion of fosaprepitant or at 4 hours after oral dosing of aprepitant
Population: All participants with at least 1 successful postdose PET~scan were included in the analysis population.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Fosaprepitant 150 mg | Brain NK1-receptor Occupancy at the Time of the Maximum Concentration (Tmax) | 100.25 Percent of occupancy |
| Aprepitant 165 mg | Brain NK1-receptor Occupancy at the Time of the Maximum Concentration (Tmax) | 99.99 Percent of occupancy |
90% CI: [0.97, 1.03]