Chemotherapy-Induced Nausea and Vomiting (CINV)
Conditions
Keywords
NK-1 Receptor Antagonist, CINV, Emesis, MEC
Brief summary
This study aims to demonstrate that, when given concomitantly with a 5-hydroxytryptamine 3 (5-HT3) antagonist and a corticosteroid, a single 150 mg intravenous (IV) dose of fosaprepitant given on Day 1 is superior to the control regimen of 5-HT3 antagonist and corticosteroid only, in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC).
Interventions
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has a histologically or cytologically confirmed malignant disease * Is naive to moderately and highly emetogenic chemotherapy * Is scheduled to receive a single IV dose of one or more MEC agents on Day 1, except for the combination of anthracycline and cyclophosphamide * Has a predicted life expectancy of at least 4 months, and a Karnofsky score of at least 60 indicating that the participant requires occasional assistance, but is able to care for most of his/her needs. * Female of childbearing potential demonstrates a negative urine pregnancy test, and agrees to remain abstinent or use two acceptable forms of birth control for at least 14 days prior to study, throughout the study, and at least 1 month following last dose of study drug.
Exclusion criteria
* Has vomited in the 24 hours prior to treatment Day 1 * Has symptomatic primary or metastatic symptomatic central nervous system malignancy causing nausea and/or vomiting * Is scheduled to receive chemotherapy agent classified as highly emetogenic * Has received or will receive total body irradiation, or radiation therapy to the abdomen, pelvis, head and neck in the week prior to Treatment Days 1 through Day 6 of the Treatment Period * Has illness or history of illness which might confound study results or pose unwarranted risk * Known history of QT interval prolongation * Uses illicit drugs or abuses alcohol * Mentally incapacitated or has a significant emotional or psychiatric disorder * History of hypersensitivity to aprepitant, ondansetron or dexamethasone * Pregnant or breast-feeding * Has participated in a study with aprepitant or taken a non-approved (investigational) drug within the last 4 weeks * Has concurrent condition, such as systemic fungal infection or uncontrolled diabetes, that precludes administration of dexamethasone.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response From 25 to 120 Hours After Initiation of Moderately Emetogenic Chemotherapy (MEC) | 25 to 120 hours after initiation of MEC | A Complete Response was defined as no vomiting and no use of rescue medication. |
| Percentage of Participants With Infusion-site Thrombophlebitis | Day 1 through Day 17, inclusive | The percentages of participants with infusion-site thrombophlebitis are presented. Thrombophlebitis was defined as a condition affecting a superficial vein used for an IV infusion, associated with red color, hardness upon palpation, and the presence of a tender cord and possible fever. |
| Percentage of Participants With Severe Infusion-site Reactions | Day 1 through Day 17, inclusive | The percentages of participants with severe infusion-site reactions, including severe site pain, or severe site redness (erythema) or severe site hardness (induration) are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response From 0 to 120 Hours After Initiation of MEC | 0 to 120 hours after initiation of MEC | A Complete Response was defined as no vomiting and no use of rescue medication. |
| Percentage of Participants With Complete Response From 0 to 24 Hours After Initiation of MEC | 0 to 24 hours after initiation of MEC | A Complete Response was defined as no vomiting and no use of rescue medication. |
| Percentage of Participants With No Vomiting From 0 to 120 Hours After Initiation of MEC | 0 to 120 hours after initiation of MEC | No Vomiting was defined as no emetic (vomiting) episodes, including no vomiting and no retching or dry heaves (attempts to vomit that are not productive of stomach contents), regardless of use of rescue medication. |
Participant flow
Pre-assignment details
A total of 14 participants did not receive any study drug: 4 in the Fosaprepitant Regimen and 10 in the Control Regimen. One participant who was randomized to the Control Regimen received the Fosaprepitant Regimen.
Participants by arm
| Arm | Count |
|---|---|
| Fosaprepitant Regimen On Day 1, participants received fosaprepitant, 150 mg IV infusion, \
30 minutes prior to chemotherapy PLUS dexamethasone 12 mg, PO \
30 minutes prior to chemotherapy PLUS ondansetron 16 mg total dose: 8 mg PO \
30-60 minutes prior to chemotherapy, followed by 8 mg PO, 8 hours after first dose PLUS dexamethasone placebo, PO \
30 minutes prior to chemotherapy. On Days 2 and 3, participants received ondansetron placebo, PO every 12 hours. Rescue Therapy: For established cases of nausea or vomiting, medications may have been prescribed from these permitted choices: 5-HT3 antagonists (granisetron, dolasetron, tropisetron or ondansetron); phenothiazines (e.g. prochlorperazine, fluphenazine, perphenazine, thiethylperazine, or chlorpromazine); butyrophenones (e.g. haloperidol or droperidol); benzamides (e.g. metoclopramide or alizapride); benzodiazepines; corticosteroids; domperidone. | 502 |
| Control Regimen On Day 1, participants received fosaprepitant placebo, 150 mL IV infusion, \
30 minutes prior to chemotherapy PLUS dexamethasone 20 mg, PO \
30 minutes prior to chemotherapy PLUS ondansetron 16 mg total dose: 8 mg PO \
30-60 minutes prior to chemotherapy; followed by 8 mg PO, 8 hours after the first dose. On Days 2-3, participants received ondansetron 8 mg, PO every 12 hours. Rescue Therapy: For established cases of nausea or vomiting, medications may have been prescribed from these permitted choices: 5-HT3 antagonists (granisetron, dolasetron, tropisetron or ondansetron); phenothiazines (e.g. prochlorperazine, fluphenazine, perphenazine, thiethylperazine, or chlorpromazine); butyrophenones (e.g. haloperidol or droperidol); benzamides (e.g. metoclopramide or alizapride); benzodiazepines; corticosteroids; domperidone. | 498 |
| Total | 1,000 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 9 | 3 |
| Overall Study | Lost Source Documentation | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Non-compliance with Protocol | 0 | 1 |
| Overall Study | Not Treated | 4 | 10 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Fosaprepitant Regimen | Control Regimen | Total |
|---|---|---|---|
| Age, Continuous | 60.0 Years STANDARD_DEVIATION 11.8 | 59.1 Years STANDARD_DEVIATION 12.3 | 59.6 Years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 298 Participants | 293 Participants | 591 Participants |
| Sex: Female, Male Male | 204 Participants | 205 Participants | 409 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 190 / 504 | 193 / 497 |
| serious Total, serious adverse events | 39 / 504 | 35 / 497 |
Outcome results
Primary
Percentage of Participants With Complete Response From 25 to 120 Hours After Initiation of Moderately Emetogenic Chemotherapy (MEC)
A Complete Response was defined as no vomiting and no use of rescue medication.
Time frame: 25 to 120 hours after initiation of MEC
Population: The ITT population consisted of all randomized participants who received ≥1 dose of study drug within the assigned treatment regimen. One participant in the Fosaprepitant Regimen was excluded from the ITT population due to missing source documentation. One participant in the Control Regimen was treated with fosaprepitant in error.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fosaprepitant Regimen | Percentage of Participants With Complete Response From 25 to 120 Hours After Initiation of Moderately Emetogenic Chemotherapy (MEC) | 78.9 Percentage of Participants |
| Control Regimen | Percentage of Participants With Complete Response From 25 to 120 Hours After Initiation of Moderately Emetogenic Chemotherapy (MEC) | 68.5 Percentage of Participants |
Comparison: Percentage difference in Fosaprepitant Regimen vs. Control Regimenp-value: <0.001Cochran-Mantel-Haenszel
Primary
Percentage of Participants With Infusion-site Thrombophlebitis
The percentages of participants with infusion-site thrombophlebitis are presented. Thrombophlebitis was defined as a condition affecting a superficial vein used for an IV infusion, associated with red color, hardness upon palpation, and the presence of a tender cord and possible fever.
Time frame: Day 1 through Day 17, inclusive
Population: The Safety population consisted of all randomized participants who received study drug as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fosaprepitant Regimen | Percentage of Participants With Infusion-site Thrombophlebitis | 0.6 Percentage of Participants |
| Control Regimen | Percentage of Participants With Infusion-site Thrombophlebitis | 0.0 Percentage of Participants |
p-value: 0.08595% CI: [-0.2, 1.7]Miettinen & Nurminen method
Primary
Percentage of Participants With Severe Infusion-site Reactions
The percentages of participants with severe infusion-site reactions, including severe site pain, or severe site redness (erythema) or severe site hardness (induration) are presented.
Time frame: Day 1 through Day 17, inclusive
Population: The Safety population consisted of all randomized participants who received study drug as treated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fosaprepitant Regimen | Percentage of Participants With Severe Infusion-site Reactions | 0.0 Percentage of Participants |
| Control Regimen | Percentage of Participants With Severe Infusion-site Reactions | 0.0 Percentage of Participants |
Secondary
Percentage of Participants With Complete Response From 0 to 120 Hours After Initiation of MEC
A Complete Response was defined as no vomiting and no use of rescue medication.
Time frame: 0 to 120 hours after initiation of MEC
Population: The ITT population consisted of all randomized participants who received ≥1 dose of study drug within the assigned treatment regimen. One participant in the Fosaprepitant Regimen was excluded from the ITT population due to missing source documentation. One participant in the Control Regimen was treated with fosaprepitant in error.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fosaprepitant Regimen | Percentage of Participants With Complete Response From 0 to 120 Hours After Initiation of MEC | 77.1 Percentage of Participants |
| Control Regimen | Percentage of Participants With Complete Response From 0 to 120 Hours After Initiation of MEC | 66.9 Percentage of Participants |
Comparison: Percentage difference in Fosaprepitant Regimen vs. Control Regimenp-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Complete Response From 0 to 24 Hours After Initiation of MEC
A Complete Response was defined as no vomiting and no use of rescue medication.
Time frame: 0 to 24 hours after initiation of MEC
Population: The ITT population consisted of all randomized participants who received ≥1 dose of study drug within the assigned treatment regimen. One participant in the Fosaprepitant Regimen was excluded from the ITT population due to missing source documentation. One participant in the Control Regimen was treated with fosaprepitant in error.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fosaprepitant Regimen | Percentage of Participants With Complete Response From 0 to 24 Hours After Initiation of MEC | 93.2 Percentage of Participants |
| Control Regimen | Percentage of Participants With Complete Response From 0 to 24 Hours After Initiation of MEC | 91.0 Percentage of Participants |
Comparison: Percentage difference in Fosaprepitant Regimen vs. Control Regimenp-value: 0.184Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With No Vomiting From 0 to 120 Hours After Initiation of MEC
No Vomiting was defined as no emetic (vomiting) episodes, including no vomiting and no retching or dry heaves (attempts to vomit that are not productive of stomach contents), regardless of use of rescue medication.
Time frame: 0 to 120 hours after initiation of MEC
Population: The ITT population consisted of all randomized participants who received ≥1 dose of study drug within the assigned treatment regimen. One participant in the Fosaprepitant Regimen was excluded from the ITT population due to missing source documentation. One participant in the Control Regimen was treated with fosaprepitant in error.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fosaprepitant Regimen | Percentage of Participants With No Vomiting From 0 to 120 Hours After Initiation of MEC | 82.7 Percentage of participants |
| Control Regimen | Percentage of Participants With No Vomiting From 0 to 120 Hours After Initiation of MEC | 72.9 Percentage of participants |
Comparison: Percentage difference in Fosaprepitant Regimen vs. Control Regimenp-value: <0.001Cochran-Mantel-Haenszel