| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Post-Operative Nausea and Vomiting (PONV)
Post-Discharge Nausea and Vomiting (PDNV) |
|
| MedDRA Classification |
| 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 |
• Whether a single oral dose of GW597599, when administered in combination with IV ondansetron hydrochloride, improves the prophylaxis against emesis (defined as vomiting or retching) during the first 24 hours following emergence from anesthesia in female subjects with known risk factors for PONV who are undergoing surgical procedures associated with increased emetogenic risk.
• Whether a single IV dose of GW597599, when administered in combination with IV ondansetron hydrochloride, improves the prophylaxis against emesis (defined as vomiting or retching) during the first 24 hours following emergence from anesthesia in female subjects with known risk factors for PONV who are undergoing surgical procedures associated with increased emetogenic risk. |
|
| E.2.2 | Secondary objectives of the trial |
•Determine whether a single dose of oral GW597599, when administered in combination with intravenous ondansetron hydrochloride, improves the prophylaxis against emesis.
•Determine whether a single oral or IV dose of GW597599, when administered in combination with intravenous ondansetron hydrochloride, improves the prevention of nausea during the first 24 hours.
•Determine whether a single oral or IV dose of GW597599, when administered in combination with intravenous ondansetron hydrochloride.
•Determine the safety of oral and IV GW597599, when administered in combination with intravenous ondansetron hydrochloride.
•Quantify the impact on daily life activities, as assessed by a Functional Living Index Emesis (FLIE) questionnaire.
•Evaluate population pharmacokinetics and pharmacodynamics of a single dose of oral and intravenous GW597599, when administered in combination with ondansetron hydrochloride. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Female with the following three risk factors:
• Pre-menopausal or peri-menopausal between the ages of 18 – 55 years, who is not of childbearing potential (i.e., physically incapable of becoming pregnant) or who demonstrates a negative serum or a negative urine pregnancy test within 24 hours prior to the first administration of study medication and agrees to:
abstain from sexual intercourse for two weeks prior to administration of the first dose of study medication until 30 days after the final dose of study medication, or
use hormonal methods of birth control (e.g., oral, injectable, or implantable) or other highly effective method of contraception [e.g., an intrauterine device (IUD)] in conjunction with a barrier method of contraception (condom, spermicidal foam, sponge, gel, diaphragm) if engaging in sexual intercourse for at least seven days prior to the first dose of study medication and continuing until 30 days after the final dose of study medication.
• Has never smoked or used (e.g., chewing) tobacco (including nicotine patches) for the previous 12 months.
• Known to have a history of post-operative nausea and vomiting and/or motion sickness.
2. Is undergoing a laparoscopic/laparotomic gynecological surgical procedure or laparoscopic cholecystectomy that is scheduled for no less than one hour and no longer than three hours in duration. For the purposes of this study, “scheduled” is considered the duration of time that the surgical suite is blocked for the procedure (i.e., the operating room block time) or the duration of time in which it is anticipated that the subject will be in the operative preparation/operating room.
3. Is scheduled to receive general anesthesia with an anesthetic regimen as described in the Anesthetic Regimen (see Section 4.2., “Anesthetic and Analgesic Regimens”).
4. Meets the American Society of Anesthesiologists (ASA) Physical Status Classification of I or II preoperatively on the day of surgery.
5. Has hematology and blood chemistry values within acceptable limits (i.e., within 10% outside (either above or below) normal reference values, unless otherwise specified) for surgery, including, but not limited to:
• Hemoglobin, hematocrit, total white blood cell count, platelet counts.
• Alkaline phosphatase, blood urea nitrogen or serum urea, electrolytes (sodium, potassium, chloride, bicarbonate).
• Liver function tests (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <1.5 times the upper limit of normal), serum creatinine (<1.5 times the upper limit of normal), total bilirubin (<1.5 times the upper limit of normal).
6. Is able and willing to complete daily components of the subject diary preoperatively on the day of surgery and until the end of the 120-hour assessment period, and will be available to respond to follow-up by study personnel at the 120-hour study period post-emergence from anesthesia.
7. Understands the nature and purpose of this study and the study procedures and has signed an informed consent form for this study to indicate this understanding. |
|
| E.4 | Principal exclusion criteria |
1. Meets ASA Physical Status Classification of III, IV, or V preoperatively on the day of surgery.
2. Is pregnant or lactating.
3. Is post-menopausal. If the last menstrual period was within the previous 18 months, a follicle stimulating hormone (FSH) evaluation in the postmenopausal range will satisfy that the subject is post-menopausal.
4. Is scheduled to undergo only a laparoscopic biopsy.
5. Is scheduled to receive neuroaxial anesthesia (e.g., epidural, spinal, or caudal anesthesia) or total IV anesthesia.
6. Is scheduled to receive propofol for maintenance of anesthesia.
7. Is scheduled to have gastric contents suctioned continuously during the surgical procedure via a nasogastric tube, or a nasogastric or oral gastric tube during the post-operative period. A single pass at the beginning or at the end of the surgical procedure, and intraoperative gastric suctioning of air, are permitted.
8. Has been taking more than 10 – 15 mg of oxycodone, or an equivalent opioid dose, on a regular, daily basis, for more than three consecutive days in the week prior to surgery.
9. Has received an investigational drug in the previous 30 days or who is scheduled to receive any investigational drug in addition to GW597599 during the study period.
10. Has persistent or recurrent nausea and/or vomiting due to other etiologies, including, but not limited to, gastric outlet obstruction, hypercalcemia, active peptic ulcer, increased intracranial pressure, or brain metastases.
11. Has experienced retching or vomiting or uncontrolled nausea within 48 hours prior to administration of the GW597599 study medications.
12. Has experienced significant nausea (e.g., 25 on a visual analogue scale (VAS)) in the 24-hour period prior to receiving the GW597599 study medications.
13. Has received radiation therapy to the abdomen or the pelvis in the seven days prior to receiving study medications and/or will receive radiation therapy to the abdomen or the pelvis in the evaluation period.
14. Has a history of wound dehiscence.
15. Has a history of any other illness, which, in the opinion of the Investigator, may pose an unacceptable risk by administering study medication.
16. Has any current or past medical condition (e.g., vagotomy) and/or require medication to treat a condition that could confound the evaluation of the data collected in this clinical trial.
17. Has a known hypersensitivity or contraindication to ondansetron hydrochloride or ondansetron, another 5-HT3 receptor antagonist, any scheduled anesthetic or analgesic agents, or any component of GW597599.
18. Has a known hypersensitivity to fentanyl and/or ketorolac tromethamine.
19. Has a known allergy to eggs or egg products (component of propofol).
20. Is scheduled to receive antiemetics not outlined in the study dosing scheme.
21. Has received medication with known or potential antiemetic activity within the 24 hour period prior to receiving study medications. This includes, but is not limited to:
• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron). Palonosetron is not permitted for 7 days prior to study.
• Benzamide/benzamide derivatives (e.g., metoclopramide, alizapride).
• Benzodiazepines (except if the subject is receiving such medication for sleep and has been on a stable dose for at least seven days prior to the first dose of study medication; however, lorazepam is prohibited).
• Phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine).
• Butyrophenone (e.g., haloperidol, droperidol).
• Corticosteroids (e.g., dexamethasone, methylprednisolone; with the exception of topical steroids for skin disorders and inhaled steroids for respiratory disorders).
• Anticholinergics (e.g., scopolamine).
• Antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine).
• Domperidone.
• Cannabinoids.
Note that subjects requiring one or more of these medications in the 24 hours prior to receiving study drug or during the 120-hour evaluation period, other than as described in this protocol, are also excluded.
22. Has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 within the following duration prior to administration of the study medication:
• Two days: Clarithromycin, diltiazem, erythromycin, grapefruit juice, ketoconazole, verapamil.
• Fourteen days: Fluconazole, itraconazole.
23. Has taken/received inducers of CYP3A4 and CYP3A5 within fourteen days prior to the administration of the study medication, including: carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, or troglitazone.
24. Has previously received an NK-1 receptor antagonist. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The number of subjects who achieve a complete antiemetic response (defined as no vomiting, no retching, no rescue therapy, and no premature discontinuation from the study) during the first 24 hour evaluation period following the emergence from anesthesia. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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