E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nausea and vomiting in cancer patients receiving highly emetogenic cisplatin-based chemotherapy |
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E.1.1.1 | Medical condition in easily understood language |
Nausea and vomiting in cancer patients receiving chemotheraphy |
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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 | 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 demonstrate the non-inferiority of single dose oral palonosetron 0.50 mg versus single dose I.V. palonosetron 0.25 mg in terms of percentage of patients with complete response during the acute phase (0-24 hours). |
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E.2.2 | Secondary objectives of the trial |
1) To assess the efficacy of single dose oral palonosetron 0.50 mg versus single dose I.V. palonosetron 0.25 mg by the evaluation of further secondary efficacy variables during the acute phase (0-24 hours) and to describe the efficacy during the delayed (25-120 hours) and overall (0-120 hours) phases. 2) To evaluate the safety and tolerability of oral palonosetron 0.50 mg versus I.V. palonosetron 0.25 mg for the prevention of HEC induced nausea and vomiting. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Signed written informed consent; 2.Male or female patient greater or equal than 18 years of age; 3. Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy is permitted; 4.Diagnosed with a malignant solid tumor and scheduled to receive first course of cytotoxic chemotherapy with cisplatin administered as a single I.V. dose of greater or equal than 70 mg/m2 over 1-4 hours on study Day 1, either alone or in combination with other chemotherapeutic agents; 5.If scheduled to receive combination regimens, non-cisplatin agents of moderate to high emetogenic potential (see Appendix 3, Emetogenic Levels of Intravenous Antineoplastic Agents according to MASCC/ESMO guidelines) are allowed and they must be administered following the cisplatin infusion and completed no more than 6 hours after the initiation of cisplatin infusion; 6.If scheduled to receive chemotherapy agents of minimal to low emetogenic potential (Appendix 3), they are to be given on Day 1 following cisplatin or on any subsequent study day; 7.ECOG Performance Status of 0, 1, or 2 (Appendix 4); 8.Female patients of either: a.non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is postmenopausal. For purposes of this study, postmenopausal is defined as 12 consecutive months of amenorrhea). In addition, postmenopausal definition has to be confirmed by consistent age and/or Follicle-Stimulating Hormone (FSH) levels), b.child-bearing potential with a negative urine dipstick pregnancy test within 24 hours prior to the first dose of investigational product at Day 1 and with a commitment to consistent and correct use throughout the clinical trial of one of the following contraceptive methods: - whose male partner is sterile prior to the female patient’s entry into the study and is the sole sexual partner, - using double-barrier method of contraception consisting of spermicide with either condom or diaphragm, also if taking any oral contraceptive, for a period after the trial to account for a potential drug interaction (minimum four weeks), - with intrauterine device (IUD), - with complete abstinence from intercourse for two weeks before exposure to the investigational product and throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of fourteen days); should patients become sexually active during the period described above, they must agree to follow an acceptable method of birth control, as described above; 9.Hematologic and metabolic status adequate for receiving a highly emetogenic cisplatin-based regimen and fulfillment of the following criteria: a)Total Neutrophils greater or equal than 1500/mm3 (Standard units: greater or equal than 1.5 x 10^9/L) - b)Platelets greater or equal than 100,000/mm3 (Standard units: greater or equal than 100.0 x 10^9/L) - c)Bilirubin less or equal than 1.5 x Upper Limit of Normal (ULN) - d)Liver enzymes: Without known liver metastases, Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) less or equal than 2.5 x Upper Limit of Normal (ULN) - With known liver metastases, AST and/or ALT less or equal than 5.0 x Upper Limit of Normal (ULN) - e)Serum Creatinine less or equal than 1.5 mg/dL (Standard units: less or equal than 132.6 microMOL/L) or Creatinine Clearance greater or equal than 60 mL/min; 10.If a patient has a known hepatic or renal impairment, he/she may be enrolled in this study at the discretion of the Investigator; 11.If a patient has a known history or predisposition to cardiac conduction interval abnormalities, including QTc, he/she may be enrolled in this study at the discretion of the Investigator; 12.Able to read, understand, follow the study procedure and complete patient diary. |
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E.4 | Principal exclusion criteria |
1.If female, pregnant or lactating; 2.Current use of illicit drugs or current evidence of alcohol abuse; 3.Scheduled to receive moderately emetogenic chemotherapy (MEC) or HEC (Appendix 3) from Day 2 to Day 5 following cisplatin administration; 4.Received or is scheduled to receive radiation therapy to the abdomen, or the pelvis within 1 week prior to Day 1 or between Days 1 to 5; 5.Any vomiting, retching, or mild nausea (grade greater or equal than I as defined by National Cancer Institute) within 24 hours prior to Day 1; 6. Symptomatic primary or metastatic CNS malignancy; 7.Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcemia, an active infection or any uncontrolled medical conditions (other than malignancy) that, in the opinion of the investigator, may confound the results of the study, represent another potential etiology for emesis and nausea (other than chemotherapy-induced nausea and vomiting, CINV) or pose unwarranted risks in administering the study drugs to the patient; 8.Known hypersensitivity or contraindication to 5-HT3 receptor antagonists (e.g., palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron) or dexamethasone; 9.Participation in a clinical trial involving palonosetron; 10.Any investigational drugs (other than those given in this study) taken within 4 weeks prior to Day 1, and/or is scheduled to receive any investigational drug during the study. 11.Systemic corticosteroid therapy at any dose within 72 hours prior to Day 1. However topical and inhaled corticosteroids with a steroid dose of less or equal than 10 mg of prednisone daily or its equivalent are permitted; 12.Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy; 13.Any medication with known or potential antiemetic activity within 24 hours prior to Day 1, including: - 5‑HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron, palonosetron), - NK-1 receptor antagonists (e.g., aprepitant or any other new drug of this class), - benzamides (e.g., metoclopramide, alizapride), - phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine), - benzodiazepines (except if the subject is receiving such medication for sleep or anxiety and has been on a stable dose for at least seven days prior to Day 1), - butyrophenones (e.g., haloperidol, droperidol), - anticholinergics (e.g., scopolamine, with the exception of inhaled anticholinergics for respiratory disorders e.g., ipratropium bromide), - antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine, chlorphenhyramine), except for prophylactic use for taxane therapy domperidone, - mirtazapine, - olanzapine, - prescribed cannabinoides (e.g., tetrahydrocannabinol or nabilone); 14.Any illness or condition that, in the opinion of the investigator, may confound the results of the study or pose unwarranted risks in administering the investigational product to the patient; 15.Concurrent medical condition that would preclude administration of dexamethasone for 4 days such as systemic fungal infection or uncontrolled diabetes. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of patients with Complete Response (CR) defined as no emesis, no rescue medication within 24 hours after the start of the HEC administration on Day 1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Within 24 hours after the start of the HEC administration on Day 1. |
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E.5.2 | Secondary end point(s) |
- the proportion of patients with complete response during the delayed and overall phase; - the proportion of patients with no emesis during the acute, delayed and overall phase; - the proportion of patients with no rescue medication during the acute, delayed and overall phase;
the proportion of patients with no significant nausea (maximum Visual Analogue Scale, VAS <25 mm) during the acute, delayed and overall phase; - the proportion of patients with no nausea (maximum VAS <5 mm) during the acute, delayed and overall phase; - the proportion of patients with complete protection (no emetic episode, no rescue medication and no significant nausea) during the acute, delayed and overall phase; - the proportion of patients with total control (no emetic episode, no rescue medication and no nausea) during the acute, delayed and overall phase; - severity of nausea, defined as the maximum nausea on the VAS in the acute, delayed and overall phase;
time to first emetic episode, time to first rescue medication intake, time to treatment failure (based on time to the first emetic episode or time to the first rescue medication intake, whichever occurs first); - impact on subjects’ daily life activities in the acute and delayed phase following the administration of cisplatin as assessed by the FLIE questionnaire. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
To better characterize the nausea control, severity of nausea (maximum nausea score as assessed by a Visual Analogue Scale (VAS)) will be recorded daily and descriptively summarized for the acute, delayed and overall phases by treatment. Time to first emetic episode, time to first rescue administration and time to treatment failure will be analyzed by means of a life table analysis using Kaplan-Meier estimates. To assess the impact of nausea and vomiting on patients’ quality of life, the FLIE questionnaire with a 24-hour recall period followed by a 4-day recall will be used. Number and percentage of patients (including 95% CI) with NIDL (overall, by domain and by individual item), will be presented for the 24-hour and 4-day periods by treatment using summary statistics. |
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Brazil |
Bulgaria |
Croatia |
Germany |
Hungary |
India |
Italy |
Poland |
Romania |
Russian Federation |
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
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Study completion date is defined as the date of last visit of last subject or telephone 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 | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |