A Study of TAK-951 to Stop Adults Getting Nausea and Vomiting After Planned Surgery

Study Overview
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Brief Summary
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Some adults are at a higher risk of feeling sick (nausea) or being sick (vomiting) after they have surgery. In this study, these adults will have planned surgery. The main aim of this study is to learn if TAK-951 stops these adults from getting nausea or vomiting after surgery. This will be compared with another medicine called ondansetron. Another aim is to check for side effects from the study medicines. Before surgery, the study doctor will check who can take part in this study. Those who can take part will be picked for either Treatment Group A or Treatment Group B by chance. Treatment Group A: Just before surgery, participants will receive a placebo slowly through a vein (infusion). Just before the end of the surgery, they will receive TAK-951 as an injection under the skin. Treatment Group B: Just before surgery, participants will receive ondansetron slowly through a vein (infusion). Just before the end of the surgery, they will receive a placebo as an injection under the skin. In this study, a placebo will look like TAK-951 but will not have any medicine in it. Participants will not know which study medicines they received, or in which order, nor will their study doctors or surgeons. This is to help make sure the results are more reliable. Participants will stay in the hospital for 24 hours after their surgery so that the study doctors can check for nausea and vomiting. The study doctors will also check for side effects from the study medicines. Participants will visit the hospital for a check-up 14 days later.

Detailed Description
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The drug being tested in this study is called TAK-951. TAK-951 is being tested for prophylaxis for postoperative nausea and vomiting in high-risk participants. The study will enroll a maximum of 160 patients, to allow a sample size of up to approximately 100 participants who have received both doses of Double-blind study drug/matching placebo. Participants will be randomly assigned in a 1:1 ratio to either Treatment Group A or Treatment Group B which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): Treatment Group A: Just before surgery, participants will receive a placebo slowly through a vein (infusion). Just before the end of the surgery, they will receive TAK-951 as an injection under the skin. Treatment Group B: Just before surgery, participants will receive ondansetron slowly through a vein (infusion). Just before the end of the surgery, they will receive a placebo as an injection under the skin. In this study, a placebo will look like TAK-951 but will not have any medicine in it. This trial will be conducted in the United States. The overall time to participate in the study from the time of surgery to completion is approximately 14 days. Participants will make multiple visits to the clinic and will be contacted by telephone after receiving their last dose of the drug for a follow-up assessment.

Official Title
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A Randomized Double-Blind, Sponsor-Open, Double-Dummy, Proof of Concept Phase 2 Study to Evaluate the Efficacy and Safety of TAK-951 Versus Ondansetron in the Prophylaxis of Postoperative Nausea and Vomiting in High-Risk Subjects

Conditions
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Postoperative Nausea and Vomiting (PONV)

Intervention / Treatment
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* Drug: TAK-951
* Drug: Ondansetron
* Drug: Ondansetron Placebo
* Drug: TAK-951 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants undergoing elective surgery under general anesthesia, expected to last for at least 1 hour from induction of anesthesia to wound closure. Participants are expected to require or have agreed to stay, at least 1 overnight in the hospital. Participants American Society of Anesthesiologists (ASA) physical status is ASA I-III. Participants with 3 or more Apfel risk factors defined as: Female sex. Nonsmoking status (never smoked or stopped smoking ≥12 months ago). History of PONV or motion sickness. Planned use of postoperative opioid analgesics. Exclusion Criteria: Participants who are expected to remain intubated post-anesthesia. Participants who experience nausea or vomiting within 24 hours before surgery or are diagnosed with gastroparesis, cyclic vomiting syndrome, or other condition associated with acute or chronic nausea and vomiting. Participants who have received, or are expected to receive, any excluded drug preoperatively within 24 hours before induction, during surgery, or within 24 hours after surgery. Participants scheduled to receive neuraxial anesthesia (e.g., epidural, spinal, or caudal anesthesia), regional blocks, or total IV anesthesia, and/or planned to receive different drugs for premedication, induction, maintenance, or reversal of anesthesia than those specified in the protocol. Participants who have an allergy or contraindication to the recommended and available rescue therapy for the treatment of PONV. Circumstance that, in the investigator's opinion, make participation in this clinical study inappropriate. Participants found at the screening to have a QT interval with Fridericia correction method (QTcF) ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events. Assessments showing bundle branch block and a prolonged QTcF should be discussed with the study monitor and the sponsor for potential inclusion. Participants who have a direct family history of premature sudden death or channelopathy, personal history of Brugada syndrome (right bundle branch block pattern with ST elevation in leads V1-V3), long QT, short QT, arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy or catecholaminergic polymorphic ventricular tachycardia (VT). Participants who have had 3 incidents of vasovagal syncope within the last 5 years. Participants with an average heart rate (HR) <55 or >100 bpm or systolic blood pressure (SBP) <90 mm Hg or Diastolic blood pressure (DBP) <60 mm Hg during screening or prior to randomization on the day of surgery. Participants with a clinically significant ECG abnormality indicative of acute cardiac instability as determined by the investigator at screening, including more than first-degree atrioventricular block, nonsustained or sustained VT, or ECG changes consistent with acute myocardial ischemia or infarction. Participants with a history of acute myocardial ischemia within the last 12 months. Participants receiving beta-blockers chronically or between screening and surgery that cannot be safely withheld on the day of surgery in the investigator's judgment. Participants receiving certain other cardiovascular medications, such as vasodilators for hypertension, chronically or between screening and surgery that in the investigator's judgment cannot be adequately managed in the perioperative setting considering the potential vasodilatory effects of TAK-951 and anesthesia standard of care. The investigators must consult with the medical monitor regarding the eligibility of participants who are receiving beta-blockers, vasodilators, and other classes of medications that act on HR or BP. Participants with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN) or total bilirubin >1.5 times the ULN.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ondansetron 4 mg IV<br>Participants received prophylaxis with ondansetron 4 mg, intravenously (IV) immediately before induction and TAK-951 placebo subcutaneously (SC) approximately 30 to 45 minutes before the end of surgery (wound closure). | Drug: Ondansetron<br>* Ondansetron IV injection<br>Drug: TAK-951 Placebo<br>* TAK-951 placebo-matching SC injection<br>|
| Experimental: TAK-951 4 mg SC<br>Participants received prophylaxis with ondansetron placebo IV immediately before induction and TAK 951 4 mg, SC, approximately 30 to 45 minutes before the end of surgery (wound closure). | Drug: TAK-951<br>* TAK-951 SC injection<br>Drug: Ondansetron Placebo<br>* Ondansetron placebo-matching IV injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response in the Immediate Postoperative Period | Percentage of participants with complete response, defined as no emesis (vomiting or retching) and no need for rescue therapy (indicated if vomiting/retching and/or nausea score ≥4 or upon participant's request) were reported. The severity of nausea was scored using a self-reported, 11-point numerical Verbal Rating Scale (VRS), where 0 represents no nausea and 10 represents the worst nausea possible. Significant nausea was defined as a VRS score ≥4. Percentages are rounded off to whole number at the nearest single decimal. | 6 hours post-surgery (Day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response Within 24 Hours Post-Surgery | Percentage of participants with complete response, defined as no emesis (vomiting or retching) and no need for rescue therapy (indicated if vomiting/retching and/or nausea score ≥4 or upon participant's request) were reported. The severity of nausea was scored using a self-reported, 11-point numerical Verbal Rating Scale (VRS), where 0 represents no nausea and 10 represents the worst nausea possible. Significant nausea was defined as a VRS score ≥4. Percentages are rounded off to whole number at the nearest single decimal. | Within 24 hours post-surgery (up to Day 2) | 
| Percentage of Participants With Emesis in the First 6 Hours Post-Surgery | Percentage of participants with emesis, defined as vomiting (the forceful discharge of even the smallest amount of stomach contents) or retching (the same muscular movements as vomiting but without expulsion of stomach contents) were reported. Percentages are rounded off to whole number at the nearest single decimal. | Within 6 hours post-surgery (Day 1) | 
| Percentage of Participants With Emesis Within 24 Hours Post-Surgery | Percentage of participants with emesis, defined as vomiting (the forceful discharge of even the smallest amount of stomach contents) or retching (the same muscular movements as vomiting but without expulsion of stomach contents) were reported. Percentages are rounded off to whole number at the nearest single decimal. | Within 24 hours post-surgery (up to Day 2) | 
| Percentage of Participants With Absence of Nausea in the First 6 Hours Post-Surgery | Percentage of participants without nausea, defined as urge to vomit without the presence of expulsive muscular movements were reported. Percentages are rounded off to whole number at the nearest single decimal. | Within 6 hours post-surgery (Day 1) | 
| Percentage of Participants With Absence of Nausea in the First 24 Hours Post-Surgery | Percentage of participants without nausea, defined as urge to vomit without the presence of expulsive muscular movements were reported. CMH method was used for analysis. Percentages are rounded off to whole number at the nearest single decimal. | Within 24 hours post-surgery (up to Day 2) | 
| Percentage of Participants Requiring Rescue Therapy for Breakthrough PONV Within 24 Hours Post-Surgery | Percentage of participants to whom rescue therapy was given as per local standard of care guidelines were reported. Percentages are rounded off to whole number at the nearest single decimal. | Within 24 hours post-surgery (up to Day 2) | 
| Time From End of Surgery to First Emetic Event | Duration between end of wound closure to first emetic event i.e., vomiting or retching was reported. If a participant did not have an emetic event within 24 hours post-surgery, they were censored at 24 hours post-surgery. Cox proportional hazard model was used for analysis. | Within 24 hours post-surgery (up to Day 2) | 
| Peak Nausea Verbal Rating Scale (VRS) Score | VRS was used to score postoperative nausea on 11-point numerical scale. The score ranges from 0-10, where 0 represents 'no nausea' and 10 represents 'worst nausea possible'. Higher score represents worsening of disease. Mixed-effects model for repeated measures (MMRM) was used for analysis. Least square mean (LSM) estimates extracted from MMRM are presented in the data table for each time point. | 30 minutes; 1, 2, 6, and 24 hours post-surgery (up to Day 2) | 
| Percentage of Participants With Total Response | Percentage of participants with total response, defined as no emesis, no nausea (VRS score <1), and no need for rescue therapy were reported. VRS was used to score postoperative nausea on 11-point numerical scale, where 0 represents 'no nausea' and 10 represents 'worst nausea possible'. Percentages are rounded off to whole number at the nearest single decimal. | Within 24 hours post-surgery (up to Day 2) | 
| TAK-951 Plasma Concentrations |  | 1-3, 4-6, 7-9, 10-18, and 22-26 hours post-dose (up to Day 2) | 
| Percentage of Participants With Any Treatment Emergent Adverse Event (TEAE) | An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an AE with an onset that occurs after receiving study drug. Percentages are rounded off to whole number at the nearest single decimal. | From first administration of study drug up to Day 14 | 
| Percentage of Participants With Markedly Abnormal Vital Signs | Vital signs included heart rate, respiratory rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP), body temperature and BMI. Percentage of participants with markedly abnormal vital sign values were reported. Percentages are rounded off to whole number at the nearest single decimal. Only categories with at least 1 participant with data are reported. | From first administration of study drug up to Day 14 | 
| Percentage of Participants With Clinically Significant Electrocardiogram (ECG) | Percentage of participants with clinically significant ECG interpretation were reported. Percentages are rounded off to whole number at the nearest single decimal. A combined ECG interpretation was derived using ECG heart rate, PR interval, RR interval, QRS duration, QT interval, and QT interval with Fridericia correction method (QTcF). | From first administration of study drug up to Day 14 | 
| Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Laboratory parameters included hematology and serum chemistry. Percentage of participants with markedly abnormal clinical laboratory values were reported. Percentages are rounded off to whole number at the nearest single decimal. Only categories with at least 1 participant with data are reported. | From first administration of study drug up to Day 14 | 
| Percentage of Participants With TAK-951 Antidrug Antibodies (ADA) | Percentage of participants with ADA results as: ADA negative, ADA positive were reported. Participants with ADA positive status are defined as those who had confirmed positive ADA status in baseline or at least 1 postbaseline assessments. Participants with ADA negative status are defined as those who did not have positive ADA response at baseline and in all postbaseline assessments. | Within 6 hours post-surgery (Day 1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy