Nausea and Vomiting, Unspecified Adult Solid Tumor, Protocol Specific
Conditions
Keywords
nausea and vomiting, unspecified adult solid tumor, protocol specific
Brief summary
RATIONALE: Gabapentin may prevent or reduce delayed nausea and vomiting caused by chemotherapy. It is not yet known whether gabapentin is more effective than a placebo in preventing nausea and vomiting. PURPOSE: This randomized phase III trial is studying the side effects of gabapentin and to see how well it works compared with a placebo in preventing nausea and vomiting in patients receiving chemotherapy.
Detailed description
OBJECTIVES: * To evaluate the effectiveness of gabapentin in controlling delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy as defined by the percentage of complete responders (no emetic episodes and no rescue medication) on days 2 through 6 (five days after receipt of highly emetogenic chemotherapy) compared to an effective prophylactic regimen. * To evaluate the effectiveness of gabapentin in controlling delayed CINV in patients receiving highly emetogenic chemotherapy as defined by the percentage of complete responders (no emetic episodes, no more than mild nausea, and no rescue medication) on days 2 through 6 compared to an effective prophylactic regimen. * To compare the effectiveness of these regimens in controlling acute CINV on day 1 of treatment in these patients. * To compare the use of rescue agents in these patients. * To determine the tolerability of gabapentin in these patients. * To evaluate the effect of gabapentin for delayed chemotherapy-induced nausea and vomiting on symptom distress and functional abilities in these patients. * To compare alternative endpoints and methods for assessing nausea and vomiting and to determine how these measures compare to patient's satisfaction with symptom control, distress and function. OUTLINE: This is a multicenter study. Patients are stratified according to gender, age (\< 50 years vs \> 50 years), history of alcoholism (yes vs no), and history of motion sickness or history of pregnancy induced nausea/vomiting (yes vs no). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive oral dexamethasone with 5HT3 receptor antagonist and oral gabapentin once daily on day 1 of chemotherapy. Patients then receive oral dexamethasone twice daily with or without 5HT3 receptor antagonist on days 2-4, and oral gabapentin either two or three times daily on days 2-5 of chemotherapy. * Arm II: Patients receive oral dexamethasone with 5HT3 receptor antagonist and oral placebo once daily on day 1 of chemotherapy. Patients then receive oral dexamethasone twice daily with or without 5HT3 receptor antagonist on days 2-4, and oral placebo either two or three times daily on days 2-5 of chemotherapy. Patients complete a Functional Living Index - Emesis questionnaire, an overall satisfaction survey, and a side effect experience diary at baseline and on day 6. Patients also complete a nausea and vomiting diary at baseline and periodically during study therapy.
Interventions
DRUGdexamethasone
Given orally
DRUGgabapentin
Given orally
OTHERplacebo
Given orally
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Scheduled to receive highly emetogenic chemotherapy * May be scheduled to receive prophylactic treatment for acute nausea and vomiting with a 5HT3 antagonist and dexamethasone 20 mg on day 1 of chemotherapy treatment * May be scheduled to receive multiple day chemotherapy regimens as long as the chemotherapy drugs given on the subsequent days have mild or no emetogenic potential * Chemotherapy schedules must allow at least 7 days rest between courses involving administration of highly emetogenic chemotherapy * No primary CNS malignancy and/or CNS metastasis PATIENT CHARACTERISTICS: * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Life expectancy ≥ 3 months * Creatinine ≤ 1.5 times upper limit of normal within the past 30 days * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Ability to complete questionnaire(s) by his/herself or with assistance * Able to swallow pills * No epilepsy or seizure history * No gastrointestinal obstruction, active peptic ulcer disease, or uncontrolled heartburn * No history of nausea and/or vomiting related to any kind of chemotherapy * No nausea or vomiting within the past 3 days * No history of allergic or other adverse reaction to gabapentin or pregabalin PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior moderate or highly emetogenic chemotherapy * No prior or concurrent aprepitant or any other NK-1 receptor antagonist * At least 1 months since prior and no concurrent gabapentin, pregabalin, or other anticonvulsants * At least 7 days since prior and no concurrent pelvic or abdominal radiotherapy * At least 3 days since prior antiemetics * No concurrent or planned use of lorazepam, diphenhydramine, eszopiclone, and/or dronabinol during the 6 days of this study, except for treatment of breakthrough nausea and vomiting
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Percentage of Complete Responders | Days 2 through 6 | Complete response being defined as no emetic episodes and no use of rescue therapy for days 2 through 6. If a patient does not complete the study or does not provide complete data, they will be assumed to be a non-responder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Days 1 through 6 | The percentages of complete responders on day 1, vs. days 1 through 6 vs. days 2 through 6 will be compared between arms. Complete response being defined as no emetic episodes and no use of rescue therapy. If a patient does not complete the study or does not provide complete data, they will be assumed to be a non-responder. |
| Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Days1 through 6 | The percentage of patients experiencing emetic episodes and the percentage needing rescue agents was compared between groups. |
| Complete Response | Days 2-6 | The primary analysis described above was repeated using a slightly different alternate definition of complete response: no emetic episodes, no more than a mean of 2.5 on the nausea numeric analogue scale (0 - 10 (As bad as it could be)), and no rescue agents. |
| Level of Satisfaction for the Control of Nausea. | Days 1 through 6 | Level of satisfaction for the control of nausea with the mean severity of nausea over the six days in the diary (on a 0 - 10 scale, higher the better) as well as the nausea subscale on the Functional Living Index - Emesis (FLIE) questionnaire ( 1-7 scale, lower the better) |
| Comparison of Daily Complete Response Endpoints | Days 1 through 6 | Daily complete response is defined as no emetic episodes and no use of rescue therapy. |
| Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | Days 1 through 6 | The sum of the daily distress questions as well as the individual daily responses from the Nausea and Vomiting Diary (NVD) on a 0-10 scale (Lower score is better) will be compared. |
Countries
United States
Participant flow
Recruitment details
430 patients were enrolled on this study. There are 17 cancelled patients, 7 on the gabapentin arm and 10 on the placebo arm.
Participants by arm
| Arm | Count |
|---|---|
| Gabapentin Patients receive oral dexamethasone with 5HT3 receptor antagonist and oral gabapentin once daily on day 1 of chemotherapy. Patients then receive oral dexamethasone twice daily with or without 5HT3 receptor antagonist on days 2-4, and oral gabapentin either two or three times daily on days 2-5 of chemotherapy.\> dexamethasone: Given orally\> gabapentin: Given orally | 207 |
| Placebo Patients receive oral dexamethasone with 5HT3 receptor antagonist and oral placebo once daily on day 1 of chemotherapy. Patients then receive oral dexamethasone twice daily with or without 5HT3 receptor antagonist on days 2-4, and oral placebo either two or three times daily on days 2-5 of chemotherapy.\> dexamethasone: Given orally\> placebo: Given orally | 206 |
| Total | 413 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 6 |
| Overall Study | Hospitalization/efficacy | 1 | 1 |
| Overall Study | Refused further treatment | 4 | 1 |
Baseline characteristics
| Characteristic | Gabapentin | Placebo | Total |
|---|---|---|---|
| Age, Customized <50 Years | 57 participants | 58 participants | 115 participants |
| Age, Customized >=50 Years | 150 participants | 148 participants | 298 participants |
| Region of Enrollment United States | 207 participants | 206 participants | 413 participants |
| Sex: Female, Male Female | 145 Participants | 145 Participants | 290 Participants |
| Sex: Female, Male Male | 62 Participants | 61 Participants | 123 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 95 / 207 | 96 / 206 |
| serious Total, serious adverse events | 0 / 207 | 0 / 206 |
Outcome results
Primary
Comparison of Percentage of Complete Responders
Complete response being defined as no emetic episodes and no use of rescue therapy for days 2 through 6. If a patient does not complete the study or does not provide complete data, they will be assumed to be a non-responder.
Time frame: Days 2 through 6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gabapentin | Comparison of Percentage of Complete Responders | Response Days 2-6: No | 53.1 percentage of participants |
| Gabapentin | Comparison of Percentage of Complete Responders | Response Days 2-6: Yes | 46.9 percentage of participants |
| Placebo | Comparison of Percentage of Complete Responders | Response Days 2-6: No | 59.2 percentage of participants |
| Placebo | Comparison of Percentage of Complete Responders | Response Days 2-6: Yes | 40.8 percentage of participants |
Comparison: Complete Responders by Arm - Days 2-6, the primary analysis utilizes Fisher's exact test to compare the percentage of complete responders in each group (dex/gabapentin vs. dex/placebo), with complete response being defined as no emetic episodes and no use of rescue therapy for days 2 through 6. If a patient does not complete the study or does not provide complete data, they will be assumed to be a non-responder.p-value: 0.2344Fisher Exact
Secondary
Comparison of Daily Complete Response Endpoints
Daily complete response is defined as no emetic episodes and no use of rescue therapy.
Time frame: Days 1 through 6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 3: Yes | 77.8 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 2: No | 26.6 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 4: No | 19.3 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 5: No | 32.9 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 4: Yes | 80.7 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 2: Yes | 73.4 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 5: Yes | 67.1 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 1: Yes | 67.6 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 6: No | 28.0 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 3: No | 22.2 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 6: Yes | 72.0 percentage of participants |
| Gabapentin | Comparison of Daily Complete Response Endpoints | Response Day 1: No | 32.4 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 6: Yes | 68.4 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 1: No | 33.5 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 1: Yes | 66.5 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 2: No | 36.4 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 2: Yes | 63.6 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 3: No | 34.5 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 3: Yes | 65.5 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 4: No | 30.1 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 5: No | 34.0 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 5: Yes | 66.0 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 6: No | 31.6 percentage of participants |
| Placebo | Comparison of Daily Complete Response Endpoints | Response Day 4: Yes | 69.9 percentage of participants |
Secondary
Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6.
The percentages of complete responders on day 1, vs. days 1 through 6 vs. days 2 through 6 will be compared between arms. Complete response being defined as no emetic episodes and no use of rescue therapy. If a patient does not complete the study or does not provide complete data, they will be assumed to be a non-responder.
Time frame: Days 1 through 6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gabapentin | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1: No | 32.4 percentage of participants |
| Gabapentin | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1: Yes | 67.6 percentage of participants |
| Gabapentin | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1-6: No | 60.4 percentage of participants |
| Gabapentin | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1-6: Yes | 39.6 percentage of participants |
| Gabapentin | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 2-6: No | 62.3 percentage of participants |
| Gabapentin | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 2-6: Yes | 37.7 percentage of participants |
| Placebo | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 2-6: No | 65 percentage of participants |
| Placebo | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1: No | 33.5 percentage of participants |
| Placebo | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1-6: Yes | 36.4 percentage of participants |
| Placebo | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1: Yes | 66.5 percentage of participants |
| Placebo | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 2-6: Yes | 35 percentage of participants |
| Placebo | Comparison of Percentages of Complete Responders on Day 1, vs. Days 1 Through 6 vs. Days 2 Through 6. | Response Day 1-6: No | 63.6 percentage of participants |
Secondary
Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses
The sum of the daily distress questions as well as the individual daily responses from the Nausea and Vomiting Diary (NVD) on a 0-10 scale (Lower score is better) will be compared.
Time frame: Days 1 through 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gabapentin | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 3 | 0.9 units on a scale | Standard Deviation 1.9 |
| Gabapentin | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 5 | 0.9 units on a scale | Standard Deviation 1.9 |
| Gabapentin | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 2 | 0.9 units on a scale | Standard Deviation 1.9 |
| Gabapentin | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 6 | 0.8 units on a scale | Standard Deviation 1.8 |
| Gabapentin | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 4 | 0.7 units on a scale | Standard Deviation 1.6 |
| Gabapentin | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Sum Days 1-6 | 5.1 units on a scale | Standard Deviation 8 |
| Gabapentin | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 1 | 1.1 units on a scale | Standard Deviation 2.3 |
| Placebo | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Sum Days 1-6 | 6.4 units on a scale | Standard Deviation 8.9 |
| Placebo | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 1 | 1.2 units on a scale | Standard Deviation 2.2 |
| Placebo | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 2 | 1.1 units on a scale | Standard Deviation 1.7 |
| Placebo | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 3 | 1.2 units on a scale | Standard Deviation 2.2 |
| Placebo | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 4 | 1.1 units on a scale | Standard Deviation 1.9 |
| Placebo | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 5 | 1.1 units on a scale | Standard Deviation 1.8 |
| Placebo | Comparison of Sum of the Daily Distress Questions as Well as the Individual Daily Responses | NVD Nausea Distress Day 6 | 0.9 units on a scale | Standard Deviation 1.7 |
Secondary
Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents
The percentage of patients experiencing emetic episodes and the percentage needing rescue agents was compared between groups.
Time frame: Days1 through 6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gabapentin | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Rescue Agent Status: No | 55 percentage of participants |
| Gabapentin | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Rescue Agent Status: Yes | 45 percentage of participants |
| Gabapentin | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Emetic Status: No | 70 percentage of participants |
| Gabapentin | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Emetic Status: Yes | 30 percentage of participants |
| Placebo | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Emetic Status: Yes | 30 percentage of participants |
| Placebo | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Rescue Agent Status: No | 47 percentage of participants |
| Placebo | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Emetic Status: No | 70 percentage of participants |
| Placebo | Comparison of the Percentage of Patients Experiencing Emetic Episodes and the Percentage Needing Rescue Agents | Rescue Agent Status: Yes | 53 percentage of participants |
Secondary
Complete Response
The primary analysis described above was repeated using a slightly different alternate definition of complete response: no emetic episodes, no more than a mean of 2.5 on the nausea numeric analogue scale (0 - 10 (As bad as it could be)), and no rescue agents.
Time frame: Days 2-6
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gabapentin | Complete Response | Response Days 2-6: No | 56 percentage of participants |
| Gabapentin | Complete Response | Response Days 2-6: Yes | 44 percentage of participants |
| Placebo | Complete Response | Response Days 2-6: No | 60.7 percentage of participants |
| Placebo | Complete Response | Response Days 2-6: Yes | 39.3 percentage of participants |
Comparison: The primary analysis described above was repeated using a slightly different alternate definition of complete response: no emetic episodes, no more than a mean of 2.5 on the nausea numeric analogue scale, and no rescue agents.p-value: 0.3694Fisher Exact
Secondary
Level of Satisfaction for the Control of Nausea.
Level of satisfaction for the control of nausea with the mean severity of nausea over the six days in the diary (on a 0 - 10 scale, higher the better) as well as the nausea subscale on the Functional Living Index - Emesis (FLIE) questionnaire ( 1-7 scale, lower the better)
Time frame: Days 1 through 6
Population: 203 patients in Gabapentin arm and 201 patients in Placebo arm submitted the data for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gabapentin | Level of Satisfaction for the Control of Nausea. | Satisfaction Nausea Control (0-10 scale) | 8.3 units on a scale | Standard Deviation 2.8 |
| Gabapentin | Level of Satisfaction for the Control of Nausea. | FLIE Nausea Subscale Day 6 | 2.8 units on a scale | Standard Deviation 1 |
| Placebo | Level of Satisfaction for the Control of Nausea. | Satisfaction Nausea Control (0-10 scale) | 8.1 units on a scale | Standard Deviation 2.9 |
| Placebo | Level of Satisfaction for the Control of Nausea. | FLIE Nausea Subscale Day 6 | 2.9 units on a scale | Standard Deviation 1 |