E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chemotherapy-Induced Nausea and Vomiting (CINV) in Subjects Receiving Moderately Emetogenic Chemotherapy (MEC) |
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E.1.1.1 | Medical condition in easily understood language |
Nausea and Vomiting in Subjects Receiving Moderately Emetogenic Chemotherapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049091 |
E.1.2 | Term | Chemotherapy antiemetic prophylaxis |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10054133 |
E.1.2 | Term | Prophylaxis of nausea and vomiting |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether administration of rolapitant with granisetron and
dexamethasone improves CINV in the delayed phase (>24 to 120 hours) of CINV
compared with administration of placebo with granisetron and dexamethasone in
subjects receiving MEC. The primary outcome will be based on complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (>24 to 120 hours). |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
-To determine the effect of rolapitant on the incidence of complete response in the acute (0-24 hours) and overall (0-120 hours) phases of CINV.
- To determine if rolapitant is safe and well tolerated in subjects receiving MEC.
-To determine the effect of rolapitant treatment on the incidences of no emesis in the acute, delayed and overall phases of CINV.
- To determine the effect of rolapitant treatment on the incidence of no significant nausea in the overall phase of CINV.
- To determine the effect of rolapitant treatment on the time to first emesis or use of rescue medication. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is 18 years of age or older, of either gender, and of any race.
2. Subject is naïve to moderately or highly emetogenic chemotherapy, and is to receive a first course of MEC including one or more of the following agents: cyclophosphamide IV (<1500 mg/m2), doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin, cytarabine IV (>1 g/m2).
The length of each chemotherapy cycle should be no less than 2 weeks.
3. Subject has a Karnofsky performance score of ≥60.
4. Subject has a predicted life expectancy of ≥ 4 months.
5. Subject has adequate bone marrow, kidney, and liver function as evidenced by:
a. Absolute neutrophil count ≥1500/mm3.
b. Platelet count ≥100,000/mm3.
c. Aspartate aminotransferase (AST) ≤2.5 x upper limit of normal range (ULN). For subjects with known liver metastases ≤5 x ULN.
d. Alanine aminotransferase (ALT) ≤2.5 x ULN. For subjects with known liver metastases ≤5 x ULN.
e. Bilirubin ≤1.5 x ULN, except for subjects with Gilbert‘s syndrome.
f. Creatinine ≤1.5 x ULN.
If a single or multiple screening laboratory test value exceeds, but is close to, the limit(s) of the reference range(s) as defined in the protocol inclusion criteria, subjects will be allowed to repeat these out-of-range tests once. If the repeated test results meet the study requirement, these subjects can be enrolled.
6. Female subjects of childbearing potential must agree to use a medically accepted method of birth control prior to Visit 1 and to continue its use during the study and for at least 30 days after the study. Acceptable methods of contraception include condoms (male or female) with or without a spermicidal agent, hormonal contraception, diaphragm or cervical cap with spermicide, medically prescribed intrauterine device (IUD), and surgical sterilization (e.g., vasectomy, hysterectomy or tubal ligation). Female subjects who are postmenopausal (i.e., have amenorrhea for 12 months) or surgically sterile are exempted from the use of contraception during the study.
7. Subject is able to read, understand, and complete all study-related documents.
8. Subject provides written informed consent. |
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E.4 | Principal exclusion criteria |
1. Any current treatment, medical history, or uncontrolled condition, other than malignancy, (e.g., alcoholism or signs of alcohol abuse, seizure disorder, medical or psychiatric condition) that, in the opinion of the investigator, would confound the results of the study or pose any unwarranted risk in administering study drug to the subject.
2. Subject has a contraindication to the administration of prescribed MEC agent, granisetron, or dexamethasone including, but not limited to, a history of hypersensitivity to the drugs or their components, severe renal impairment, severe bone marrow suppression, or systemic infection.
3. Subject is a woman of childbearing potential with a positive urine or serum pregnancy test within 3 days prior to study drug administration or is breast-feeding.
4. Subject has taken the following agents within the last 48 hours prior to the start of treatment with study drug:
a. 5-HT3 antagonists (ondansetron, granisetron, dolasetron, tropisetron, etc.). Palonosetron is not permitted within 7 days prior to administration of investigational product.
b. Phenothiazines (prochlorperazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine, etc.)
c. Benzamides (metoclopramide, alizapride, etc.)
d. Domperidone
e. Cannabinoids
f. NK1 antagonist (aprepitant)
g. Benzodiazepines (lorazepam, alprazolam, etc)
5. Subject is scheduled to receive any other chemotherapeutic agent with an emetogenicity level of 3 or above (Hesketh Scale) from Day -2 through Day 6, except on Day 1. (There is no restriction for Day 1.)
6. Subject is scheduled to receive any radiation therapy to the abdomen or pelvis from Day -5 through Day 6.
7. Subject has received systemic corticosteroids or sedative antihistamines (dimenhydrinate, diphenhydramine, etc.) within 72 hours of Day 1 of the study except as premedication for chemotherapy (e.g., taxanes). Subjects who are receiving inhaled steroids for respiratory conditions or topical steroids for skin disorders can be enrolled.
8. Subject has symptomatic primary or metastatic CNS disease.
9. Subject has ongoing vomiting, retching, or clinically severe nausea caused by any etiology or has a history of anticipatory nausea and vomiting.
10. Subject has vomited and/or has had dry heaves/retching within 24 hours prior to the start of MEC on Day 1 in Cycle 1.
11. Subject who has used any investigational drugs within 30 days of randomization.
12. Subject who is participating in any other clinical study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is the complete response rate in
the delayed phase of CINV, from >24 through 120 hours following initiation of
moderately emetogenic chemotherapy. Complete response is defined as no emetic
episodes and no rescue medication |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
>24 through 120 hours following initiation of moderately emetogenic chemotherapy.
For Cycle 1, telephone contact will be made with each subject every morning
on Days 2 to 5 at approximately the same time each day to assess the subject‘s status and to ensure that the subject is appropriately recording any nausea and vomiting episodes, use of rescue medication, and daily nausea ratings in the NV Subject Diary. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints for this study include:
•The incidence of complete response during the acute (0-24 hours) and overall (0 120 hours) phases of CINV following the initiation of MEC.
-No emesis (no vomiting, retching, or dry heaves; includes subjects who received
rescue medication) in the acute, delayed and overall phases of CINV.
- No significant nausea (maximum VAS <25 mm) in the overall phase of CINV.
- Time to first emesis or to use of rescue medication.
The tertiary efficacy endpoints for this study include:
- No significant nausea in the acute and delayed phases of CINV.
- No nausea (maximum VAS <5 mm) and Complete protection (no emesis, no
rescue medication, and maximum nausea VAS <25 mm on a 0- to 100 mm
scale) in the acute, delayed and overall phases of CINV.
- No impact on daily life (total score >108) as assessed by the FLIE Questionnaire |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall:
- 0 to 120 hours following initiation of MEC.
- Acute: 0 to 24 hours following initiation of MEC.
- Delayed: >24 to 120 hours following initiation of MEC.
For Cycle 1, telephone contact every morning on Days 2 to 5 to assess the subject‘s status and to ensure that the subject is appropriately recording any nausea and vomiting episodes, use of rescue medication, and daily nausea ratings in the NV Subject Diary. Assessment in Subsequent Cycles (up to Five Additional Cycles for up to Six Cycles Total) Assessment questions on Days 6,
7, or 8 in each subsequent cycle (Cycles 2 to 6) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Belarus |
Belgium |
Brazil |
Bulgaria |
Chile |
Czech Republic |
Ecuador |
France |
Georgia |
Hong Kong |
Hungary |
Italy |
Korea, Republic of |
Latvia |
Mexico |
Peru |
Poland |
Portugal |
Puerto Rico |
Romania |
Russian Federation |
Slovakia |
South Africa |
Spain |
Taiwan |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The overall study ends when the last remaining subject has completed or has been discontinued from the study. The last protocol-specified contact (visits or telephone contacts) at Cycle 6, or at final chemotherapy cycle in which the patient elects to participate. For those subjects who do not complete the study or who are lost to follow up, subject participation will be considered terminated upon the completion of the last visits or phone contact. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |