E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Post-operative nausea and vomiting (PONV) |
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E.1.1.1 | Medical condition in easily understood language |
Nausea and sickness after an operation |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
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 | 10036285 |
E.1.2 | Term | Postoperative nausea |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
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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 evaluate the efficacy, safety, and tolerability of 6 mg, 12 mg, 18 mg, 24 mg, or 36 mg IV doses of vestipitant versus a standard dose of 4 mg ondansetron to treat breakthrough PONV after a failed prophylaxis regimen that includes 4 mg IV ondansetron prior to surgery. To examine the benefit of IV doses of vestipitant on post-operative symptoms of nausea compared to ondansetron.
• To evaluate the impact of IV doses of vestipitant on discharge readiness and time to discharge compared to ondansetron.
• To evaluate the PK and exposure-response relationship of IV vestipitant in subjects with PONV.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Male or Female post-operative surgical subjects between the ages of 18-75 years of age, inclusive, at the time of signing the informed consent.
2. A female subject is eligible to participate if she is
• of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea
or
• of child-bearing potential and agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or Investigator) prior to Study Treatment dosing, to sufficiently minimize the risk of pregnancy at that point.
3. Has 3 or more of the following independent risk factors for PONV:
a. female gender
b. non-smoker (defined for this study as one who has not smoked or used tobacco [including chewing tobacco, a nicotine patch, or other nicotine-withdrawal formulation] for at least the previous 6 months. Rare/infrequent [2 or less cigarettes a week] smoking is allowed, at the Investigator’s discretion)
c. history of PONV or motion sickness
d. planned post-operative opioids.
4. Has received one dose of ondansetron as part of a PONV prophylaxis regimen for the surgical procedure.
5. Has received general anesthesia with an anesthetic regimen as described in the Anesthetic Regimen Guidelines.
6. Meets American Society of Anesthesiologists (ASA) Physical Status Classification of 1 or 2 without an “E” modifier preoperatively on the day of surgery and has hematology and blood chemistry values within acceptable limits for surgery.
7. Is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form.
8. Experiences breakthrough PONV defined as:
a. post-operative nausea of ≥ 7 on the Nausea Numeric Rating Scale with 0 being no nausea and 10 being the worst nausea possible
-OR-
b. nausea resulting in a subject request for an anti-emetic
-OR-
c. an episode of emesis or retching
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. A history of HIV.
2. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of Screening.
3. An ALT or AST >2.5 x ULN at Screening.
4. Pregnant females as determined by positive [serum or urine] hCG test at Screening or prior to dosing.
5. Lactating females.
6. The subject is scheduled to undergo a laparoscopic biopsy only
7. The subject has a history of or is scheduled to undergo cardiac/cardiothoracic surgery
8. The subject is scheduled to receive neuroaxial anesthesia (e.g., epidural, spinal, or caudal anesthesia) or total IV anesthesia.
9. The subject is scheduled to receive propofol for maintenance of anesthesia (propofol as an induction agent is allowed).
10. The subject is scheduled to receive an NK1 inhibitor (aprepitant/fosaprepitant) as part of a PONV prophylaxis regimen for the surgical procedure.
11. The subject 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, will be permitted.
12. The subject received an investigational drug within 30 days or was scheduled to receive any investigational drug in addition to vestipitant during the study period.
13. The subject 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, chemotherapy, or brain metastases.
14. The subject received radiation therapy to the abdomen or the pelvis within 7 days prior to receiving study medications and/or received radiation therapy to the abdomen or the pelvis in the evaluation period.
15. The subject has a history of wound dehiscence.
16. The subject has a history of any other illness, which, in the opinion of the Investigator, might pose an unacceptable risk by administering study medication.
17. QTc prior to Study Treatment as follows:
Pre-Operative or Post Operative, Pre-Dose QTc > 450 msec ( >480 msec for subject with Bundle Branch Block).
18. The subject has any current or past medical condition (e.g., vagotomy) and/or required medication to treat a condition that could affect the evaluation of the study.
19. The subject has a known contraindication or hypersensitivity to ondansetron or ondansetron injection, any scheduled anaesthetic or analgesic agents, vestipitant or any component of the vestipitant formulation including Captisol™.
20. The subject received medication with known or potential antiemetic activity after the induction of anaesthesia (during the intraoperative or post-operative period) other than the planned Study Treatment, ondansetron or vestipitant.
21. Current or planned use of strong or moderate inhibitors of CYP3A within 7 days or inducers of CYP3A within 14 days prior to study medication administration.
22. The subject is unwilling or unable to follow the procedures outlined in the protocol.
23. The subject is mentally or legally incapacitated.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is number of patients achieving Complete Response after receiving study drug to treat breakthrough PONV.
The primary safety and tolerability endpoints will be adverse and serious adverse event observation and safety laboratory evaluations.
Additional efficacy evaluation will include a numeric Nausea Numeric Rating Scale (NNRS) for assessment of subject nausea.
Time to PONV Discharge-Ready. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy endpoint is number of subjects achieving Complete Response after receiving Study Treatment to treat breakthrough PONV. The period for the primary efficacy endpoint begins 10 minutes after infusion end. Complete Response is defined as no emesis and no further rescue medication from 10 minutes after infusion end through 24 hours or discharge from the hospital/clinic, whichever is sooner. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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) | 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 | Yes |
E.8.1.4 | Double blind | No |
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.8.2.4 | Number of treatment arms in the trial | 6 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Germany |
Poland |
Russian Federation |
Ukraine |
United Kingdom |
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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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |