Chemotherapy Induced Nausea and Vomiting
Conditions
Brief summary
This study will compare the safety and efficacy of a three-day oral aprepitant regimen (aprepitant plus ondansetron) to ondansetron alone in the prevention of chemotherapy-induced nausea and vomiting (CINV) in the 120 hours following the initiation of chemotherapy in pediatric participants. Those who complete this first cycle of treatment and meet certain eligibility criteria will have the option of continuing for 5 additional cycles of open-label aprepitant.
Interventions
On the morning of Day 1: one 125 mg capsule PO 60 minutes prior to chemotherapy for participants 12 to 17 years of age
DRUGAprepitant 80 mg
On the morning of Days 2 and 3: one 80 mg capsule PO for participants 12 to 17 years of age
DRUGAprepitant powder for suspension (PFS)
On the morning of Day 1: 3.0 mg/kg (up to 125 mg) PO 60 minutes prior to chemotherapy for participants 6 months to \<12 years of age. On the morning of Days 2 and 3: 2.0 mg/kg (up to 80 mg) PO 60 minutes prior to chemotherapy (if applicable) for participants 6 months to \<12 years of age
DRUGOndansetron
Day 1: Administered according to product label for pediatric usage or local standard of care
DRUGPlacebo for Aprepitant 125 mg
On the morning of Day 1: one 125 mg capsule PO 60 minutes prior to chemotherapy for participants 12 to 17 years of age
DRUGPlacebo for Aprepitant 80 mg
On the morning of Days 2 and 3: one 80 mg capsule PO for participants 12 to 17 years of age
DRUGPlacebo for Aprepitant PFS
On the morning of Day 1: 3.0 mg/kg (up to 125 mg) PO 60 minutes prior to chemotherapy for participants 6 months to \<12 years of age. On the morning of Days 2 and 3: 2.0 mg/kg (up to 80 mg) PO 60 minutes prior to chemotherapy (if applicable) for participants 6 months to \<12 years of age
DRUGEmetogenic chemotherapy
Any moderately or highly emetic chemotherapeutic agent such as cyclophosphamide, doxorubicin, methotrexate, carboplatin, cisplatin, irinotecan, carmustine, ifosfamide, and streptozocin, or chemotherapeutics of a lower emetogenicity that were not previously tolerated. No chemotherapeutic agents were specified by the protocol, and many could potentially have been used.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
Cycle 1: * Is 6 months to 17 years of age at time of study entry * Is scheduled to receive chemotherapeutic agent(s) associated with moderate, high risk or very high risk of vomiting for a documented malignancy, or a chemotherapy regimen not previously tolerated due to vomiting * Is expected to receive ondansetron as part of their antiemetic regimen * If female and has begun menses, must has a negative urine pregnancy test prior to randomization. A female who is of reproductive potential agrees 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 * If \>10 years old, have a Karnofsky score ≥ 60; if ≤ 10 years have a Lansky Play Performance score ≥ 60 * Have a predicted life expectancy of ≥ 3 months Optional Cycles 2-6: * Participant has, in the opinion of the investigator, completed the preceding cycle of chemotherapy and related study procedures satisfactorily
Exclusion criteria
Cycle 1: * Has vomited in the 24 hours prior to Treatment Day 1 * Is scheduled to receive stem cell rescue therapy in conjunction with study related course(s) of emetogenic chemotherapy * Has received or will receive radiation therapy to the abdomen or pelvis within a week prior to Treatment Day 1 or during the course of the study * Is pregnant or breast feeding * Is allergic to aprepitant, ondansetron, or any other 5-hydroxytryptamine type-3 receptor (5-HT3) antagonist * Has a symptomatic primary or metastatic CNS malignancy causing nausea and/or vomiting * History of QT prolongation or taking other medicinal products that lead to QT prolongation * Has an active infection (e.g., pneumonia), congestive heart failure, bradyarrhythmia, or any uncontrolled disease (e.g., diabetic ketoacidosis, gastrointestinal obstruction) except for malignancy, which in the opinion of the investigator, might confound the results of the study or pose unwarranted risk in administering study drug to the participant * Has had benzodiazepine or opioid therapy initiated within 48 hours of study drug administration, except for single daily doses of triazolam, temazepam, or midazolam * Has been started on systemic corticosteroid therapy within 72 hours prior to study drug administration or is planned to receive a corticosteroid as part of the chemotherapy regimen * Is currently taking warfarin Optional Cycles 2-6: * All
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Complete Response in the Delayed Phase of Cycle 1 | 25 to 120 hours after the start of chemotherapy | Delayed Phase was defined as 25-120 hours after the start of chemotherapy. Complete response was defined as no vomiting or retching and no use of rescue medication in the delayed phase of Cycle 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Complete Response in the Acute Phase of Cycle 1 | 0 to 24 hours after initiation of chemotherapy | Acute phase was defined as 0 to 24 hours after the start of chemotherapy. Complete response was defined as no vomiting or retching and no use of rescue medication in the acute phase of Cycle 1. |
| Percentage of Participants With a Complete Response in the Overall Phase of Cycle 1 | 0 to 120 hours after initiation of chemotherapy | Overall phase was defined as 0 to 120 hourse after the start of chemotherapy. Complete response was defined as no vomiting or retching and no use of rescue medication in the overall phase of Cycle 1. |
| Percentage of Participants With No Vomiting in the Overall Phase of Cycle 1 | 0 to 120 hours after initiation of chemotherapy | Overall phase was defined as 0 to 120 hourse after the start of chemotherapy. No vomiting was defined as no emesis or retching or dry heaves in the overall phase of Cycle 1. |
Participant flow
Pre-assignment details
The base study consisted of once cycle of treatment (Cycle 1). Participants in either treatment group who met the eligibility criteria were eligible to participate in optional open-label aprepitant treatment for an additional 5 cycles (Cycles 2-6).
Participants by arm
| Arm | Count |
|---|---|
| Aprepitant Regimen Cycle 1: Participants 12 to 17 years of age, Day 1: aprepitant 125 mg capsule orally (PO) + ondansetron, Days 2 to 3: aprepitant 80 mg capsule PO. Participants 6 months to \<12 years of age, Day 1: aprepitant powder for suspension (PFS), 3.0 mg/kg (up to 125 mg) + ondansetron, Days 2 to 3: aprepitant PFS, 2.0 mg/kg (up to 80 mg). Optional Cycles 2-6: Open-label aprepitant administered in the same manner as in Cycle 1. | 152 |
| Control Regimen Cycle 1: Participants 12 to 17 years of age, Day 1: matching placebo for aprepitant 125 mg capsule oral (PO) + ondansetron Days 2 to 3: matching placebo for aprepitant 80 mg capsule PO. Participants 6 months to \<12 years of age, Day 1: matching placebo PFS: 3.0 mg/kg (up to 125 mg) + ondansetron, Days 2 to 3: matching placebo PFS: 2.0 mg/kg (up to 80 mg). Optional Cycles 2-6: Open-label aprepitant administered in the same manner as in Cycle 1. | 150 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Base Study (Cycle 1) | Adverse Event | 2 | 0 |
| Base Study (Cycle 1) | Physician Decision | 0 | 1 |
| Base Study (Cycle 1) | Protocol Violation | 2 | 0 |
| Base Study (Cycle 1) | Withdrawal by Subject | 1 | 2 |
| Optional Extension (Cycles 2-6) | Adverse Event | 2 | 0 |
| Optional Extension (Cycles 2-6) | Completed Chemotherapy Regimen | 51 | 0 |
| Optional Extension (Cycles 2-6) | Did Not Meet Additional Criteria | 25 | 0 |
| Optional Extension (Cycles 2-6) | Did Not Respond To Chemotherapy Regimen | 4 | 0 |
| Optional Extension (Cycles 2-6) | Lack of Efficacy | 1 | 0 |
| Optional Extension (Cycles 2-6) | Lost to Follow-up | 1 | 0 |
| Optional Extension (Cycles 2-6) | Physician Decision | 19 | 0 |
| Optional Extension (Cycles 2-6) | Protocol Violation | 4 | 0 |
| Optional Extension (Cycles 2-6) | Withdrawal by Subject | 18 | 0 |
Baseline characteristics
| Characteristic | Aprepitant Regimen | Control Regimen | Total |
|---|---|---|---|
| Age, Continuous | 97.7 Months STANDARD_DEVIATION 63.2 | 99.4 Months STANDARD_DEVIATION 60.9 | 98.5 Months STANDARD_DEVIATION 62 |
| Sex: Female, Male Female | 68 Participants | 71 Participants | 139 Participants |
| Sex: Female, Male Male | 84 Participants | 79 Participants | 163 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 | 88 / 152 | 84 / 150 | 136 / 170 |
| serious Total, serious adverse events | 46 / 152 | 41 / 150 | 84 / 170 |
Outcome results
Primary
Percentage of Participants With a Complete Response in the Delayed Phase of Cycle 1
Delayed Phase was defined as 25-120 hours after the start of chemotherapy. Complete response was defined as no vomiting or retching and no use of rescue medication in the delayed phase of Cycle 1.
Time frame: 25 to 120 hours after the start of chemotherapy
Population: Intent-to-treat (ITT) population: all randomized participants who received study medication. Results for Cycles 2-6 were not included because this outcome measure is for Cycle 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aprepitant Regimen | Percentage of Participants With a Complete Response in the Delayed Phase of Cycle 1 | 50.7 Percentage of participants |
| Control Regimen | Percentage of Participants With a Complete Response in the Delayed Phase of Cycle 1 | 26.0 Percentage of participants |
p-value: <0.01Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Complete Response in the Acute Phase of Cycle 1
Acute phase was defined as 0 to 24 hours after the start of chemotherapy. Complete response was defined as no vomiting or retching and no use of rescue medication in the acute phase of Cycle 1.
Time frame: 0 to 24 hours after initiation of chemotherapy
Population: ITT population: all randomized participants who received study medication. Results for Cycles 2-6 were not included because this outcome measure is for Cycle 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aprepitant Regimen | Percentage of Participants With a Complete Response in the Acute Phase of Cycle 1 | 66.4 Percentage of participants |
| Control Regimen | Percentage of Participants With a Complete Response in the Acute Phase of Cycle 1 | 52.0 Percentage of participants |
p-value: <0.05Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Complete Response in the Overall Phase of Cycle 1
Overall phase was defined as 0 to 120 hourse after the start of chemotherapy. Complete response was defined as no vomiting or retching and no use of rescue medication in the overall phase of Cycle 1.
Time frame: 0 to 120 hours after initiation of chemotherapy
Population: ITT population: all randomized participants who received study medication. Results for Cycles 2-6 were not included because this outcome measure is for Cycle 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aprepitant Regimen | Percentage of Participants With a Complete Response in the Overall Phase of Cycle 1 | 40.1 Percentage of participants |
| Control Regimen | Percentage of Participants With a Complete Response in the Overall Phase of Cycle 1 | 20.0 Percentage of participants |
p-value: <0.01Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With No Vomiting in the Overall Phase of Cycle 1
Overall phase was defined as 0 to 120 hourse after the start of chemotherapy. No vomiting was defined as no emesis or retching or dry heaves in the overall phase of Cycle 1.
Time frame: 0 to 120 hours after initiation of chemotherapy
Population: ITT population: all randomized participants who received study medication. Results for Cycles 2-6 were not included because this outcome measure is for Cycle 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aprepitant Regimen | Percentage of Participants With No Vomiting in the Overall Phase of Cycle 1 | 46.7 Percentage of participants |
| Control Regimen | Percentage of Participants With No Vomiting in the Overall Phase of Cycle 1 | 21.3 Percentage of participants |
p-value: <0.01Cochran-Mantel-Haenszel