Postoperative Nausea and Vomiting (PONV)
Conditions
Keywords
Drug Therapy
Brief summary
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
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.
Interventions
DRUGTAK-951
TAK-951 SC injection
DRUGOndansetron
Ondansetron IV injection
Ondansetron placebo-matching IV injection
DRUGTAK-951 Placebo
TAK-951 placebo-matching SC injection
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants undergoing elective surgery under general anesthesia, expected to last for at least 1 hour from induction of anesthesia to wound closure. 2. Participants are expected to require or have agreed to stay, at least 1 overnight in the hospital. 3. Participants American Society of Anesthesiologists (ASA) physical status is ASA I-III. 4. Participants with 3 or more Apfel risk factors defined as: 1. Female sex. 2. Nonsmoking status (never smoked or stopped smoking ≥12 months ago). 3. History of PONV or motion sickness. 4. Planned use of postoperative opioid analgesics.
Exclusion criteria
1. Participants who are expected to remain intubated post-anesthesia. 2. 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. 3. 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. 4. 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. 5. Participants who have an allergy or contraindication to the recommended and available rescue therapy for the treatment of PONV. 6. Circumstance that, in the investigator's opinion, make participation in this clinical study inappropriate. 7. 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. 8. 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). 9. Participants who have had 3 incidents of vasovagal syncope within the last 5 years. 10. 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. 11. 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. 12. Participants with a history of acute myocardial ischemia within the last 12 months. 13. 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. 14. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response in the Immediate Postoperative Period | 6 hours post-surgery (Day 1) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Emesis in the First 6 Hours Post-Surgery | Within 6 hours post-surgery (Day 1) | 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. |
| Percentage of Participants With Emesis Within 24 Hours Post-Surgery | Within 24 hours post-surgery (up to Day 2) | 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. |
| Percentage of Participants With Absence of Nausea in the First 6 Hours Post-Surgery | Within 6 hours post-surgery (Day 1) | 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. |
| Percentage of Participants With Absence of Nausea in the First 24 Hours Post-Surgery | Within 24 hours post-surgery (up to Day 2) | 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. |
| Percentage of Participants Requiring Rescue Therapy for Breakthrough PONV Within 24 Hours Post-Surgery | Within 24 hours post-surgery (up to Day 2) | 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. |
| Time From End of Surgery to First Emetic Event | Within 24 hours post-surgery (up to Day 2) | 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. |
| Peak Nausea Verbal Rating Scale (VRS) Score | 30 minutes; 1, 2, 6, and 24 hours post-surgery (up to Day 2) | 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. |
| Percentage of Participants With Complete Response Within 24 Hours Post-Surgery | Within 24 hours post-surgery (up to Day 2) | 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. |
| 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) | From first administration of study drug up to Day 14 | 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. |
| Percentage of Participants With Markedly Abnormal Vital Signs | From first administration of study drug up to Day 14 | 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. |
| Percentage of Participants With Clinically Significant Electrocardiogram (ECG) | From first administration of study drug up to Day 14 | 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). |
| Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | From first administration of study drug up to Day 14 | 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. |
| Percentage of Participants With TAK-951 Antidrug Antibodies (ADA) | Within 6 hours post-surgery (Day 1) | 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. |
| Percentage of Participants With Total Response | Within 24 hours post-surgery (up to Day 2) | 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 7 sites in the United States from 20 October 2020 to 21 March 2022. Participants with a diagnosis of postoperative nausea and vomiting (PONV) were enrolled in 1:1 ratio.
Pre-assignment details
Participants received prophylaxis either with ondansetron before induction followed by TAK-951 placebo or prophylaxis with ondansetron placebo before induction followed by TAK-951 4 mg. Due to dosing error, of the 39 participants in the TAK-951 4 mg SC group, 18 participants received an unintended mis-dose of TAK-951 redacted mg. Data for these participants were collected and reported separately only for the outcome measures reporting data for the safety, pharmacokinetic, and immunogenicity set.
Participants by arm
| Arm | Count |
|---|---|
| Ondansetron 4 mg IV Participants received prophylaxis with ondansetron 4 mg, IV immediately before induction and TAK-951 placebo SC approximately 30 to 45 minutes before the end of surgery (wound closure). | 41 |
| TAK-951 4 mg SC 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). | 39 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Reason not Specified | 3 | 6 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Ondansetron 4 mg IV | TAK-951 4 mg SC | Total |
|---|---|---|---|
| Age, Continuous | 46.0 years STANDARD_DEVIATION 10.32 | 45.1 years STANDARD_DEVIATION 10.57 | 45.6 years STANDARD_DEVIATION 10.39 |
| Body Mass Index (BMI) | 34.41 kg/m^2 STANDARD_DEVIATION 8.909 | 32.47 kg/m^2 STANDARD_DEVIATION 7.574 | 33.47 kg/m^2 STANDARD_DEVIATION 8.29 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 9 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 29 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Height | 164.57 cm STANDARD_DEVIATION 8.448 | 164.32 cm STANDARD_DEVIATION 9.499 | 164.44 cm STANDARD_DEVIATION 8.919 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 10 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 31 Participants | 27 Participants | 58 Participants |
| Region of Enrollment United States | 41 Participants | 39 Participants | 80 Participants |
| Sex: Female, Male Female | 38 Participants | 38 Participants | 76 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants |
| Weight | 93.85 kg STANDARD_DEVIATION 27.439 | 87.61 kg STANDARD_DEVIATION 22.258 | 90.81 kg STANDARD_DEVIATION 25.087 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 41 | 0 / 21 | 0 / 18 |
| other Total, other adverse events | 36 / 41 | 15 / 21 | 16 / 18 |
| serious Total, serious adverse events | 0 / 41 | 0 / 21 | 0 / 18 |
Outcome results
Primary
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.
Time frame: 6 hours post-surgery (Day 1)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Complete Response in the Immediate Postoperative Period | 48.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Complete Response in the Immediate Postoperative Period | 71.8 percentage of participants |
95% CI: [0.031, 0.452]
Secondary
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.
Time frame: 30 minutes; 1, 2, 6, and 24 hours post-surgery (up to Day 2)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery. Overall number of participants analyzed are the participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ondansetron 4 mg IV | Peak Nausea Verbal Rating Scale (VRS) Score | 1 Hour Post Surgery | 0.099 score on a scale | Standard Error 0.254 |
| Ondansetron 4 mg IV | Peak Nausea Verbal Rating Scale (VRS) Score | 6 Hours Post Surgery | -0.020 score on a scale | Standard Error 0.073 |
| Ondansetron 4 mg IV | Peak Nausea Verbal Rating Scale (VRS) Score | 2 Hours Post Surgery | 0.043 score on a scale | Standard Error 0.201 |
| Ondansetron 4 mg IV | Peak Nausea Verbal Rating Scale (VRS) Score | 24 Hours Post Surgery | 0.203 score on a scale | Standard Error 0.142 |
| Ondansetron 4 mg IV | Peak Nausea Verbal Rating Scale (VRS) Score | 30 Minutes Post Surgery | 0.159 score on a scale | Standard Error 0.227 |
| TAK-951 4 mg SC | Peak Nausea Verbal Rating Scale (VRS) Score | 24 Hours Post Surgery | 0.000 score on a scale | Standard Error 0.117 |
| TAK-951 4 mg SC | Peak Nausea Verbal Rating Scale (VRS) Score | 30 Minutes Post Surgery | 0.347 score on a scale | Standard Error 0.184 |
| TAK-951 4 mg SC | Peak Nausea Verbal Rating Scale (VRS) Score | 1 Hour Post Surgery | 0.500 score on a scale | Standard Error 0.204 |
| TAK-951 4 mg SC | Peak Nausea Verbal Rating Scale (VRS) Score | 2 Hours Post Surgery | 0.308 score on a scale | Standard Error 0.162 |
| TAK-951 4 mg SC | Peak Nausea Verbal Rating Scale (VRS) Score | 6 Hours Post Surgery | 0.077 score on a scale | Standard Error 0.059 |
Comparison: 30 Minutes Post Surgery95% CI: [-0.402, 0.777]
Comparison: 1 Hour Post Surgery95% CI: [-0.258, 1.059]
Comparison: 2 Hours Post Surgery95% CI: [0, 0.786]
Comparison: 6 Hours Post Surgery95% CI: [-0.093, 0.286]
Comparison: 24 Hours Post Surgery95% CI: [-0.575, 0.17]
Secondary
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.
Time frame: Within 24 hours post-surgery (up to Day 2)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants Requiring Rescue Therapy for Breakthrough PONV Within 24 Hours Post-Surgery | 56.1 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants Requiring Rescue Therapy for Breakthrough PONV Within 24 Hours Post-Surgery | 33.3 percentage of participants |
95% CI: [-0.448, -0.019]
Secondary
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.
Time frame: Within 24 hours post-surgery (up to Day 2)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Absence of Nausea in the First 24 Hours Post-Surgery | 34.1 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Absence of Nausea in the First 24 Hours Post-Surgery | 48.7 percentage of participants |
95% CI: [-0.073, 0.365]
Secondary
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.
Time frame: Within 6 hours post-surgery (Day 1)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Absence of Nausea in the First 6 Hours Post-Surgery | 41.5 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Absence of Nausea in the First 6 Hours Post-Surgery | 59.0 percentage of participants |
95% CI: [-0.029, 0.41]
Secondary
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.
Time frame: From first administration of study drug up to Day 14
Population: Safety Analysis Set (SAF) included all participants who were randomized to treatment and received both doses of double-blind study drug. The data for this outcome measure was collected and reported separately for the participants who received the unintended mis-dose of TAK-951 redacted mg.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Any Treatment Emergent Adverse Event (TEAE) | 87.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Any Treatment Emergent Adverse Event (TEAE) | 71.4 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Any Treatment Emergent Adverse Event (TEAE) | 88.9 percentage of participants |
Secondary
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).
Time frame: From first administration of study drug up to Day 14
Population: SAF included all participants who were randomized to treatment and received both doses of double-blind study drug. The data for this outcome measure was collected and reported separately for the participants who received the unintended mis-dose of TAK-951 redacted mg. Overall number analyzed is the number of participants with data available for analyses. Clinical significance is based on PI determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Clinically Significant Electrocardiogram (ECG) | 2.4 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Clinically Significant Electrocardiogram (ECG) | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Clinically Significant Electrocardiogram (ECG) | 0.0 percentage of participants |
Secondary
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.
Time frame: Within 24 hours post-surgery (up to Day 2)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Complete Response Within 24 Hours Post-Surgery | 41.5 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Complete Response Within 24 Hours Post-Surgery | 59.0 percentage of participants |
95% CI: [-0.044, 0.394]
Secondary
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.
Time frame: Within 6 hours post-surgery (Day 1)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Emesis in the First 6 Hours Post-Surgery | 17.1 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Emesis in the First 6 Hours Post-Surgery | 7.7 percentage of participants |
95% CI: [-0.253, 0.059]
Secondary
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.
Time frame: Within 24 hours post-surgery (up to Day 2)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Emesis Within 24 Hours Post-Surgery | 24.4 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Emesis Within 24 Hours Post-Surgery | 10.3 percentage of participants |
95% CI: [-0.316, 0.033]
Secondary
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.
Time frame: From first administration of study drug up to Day 14
Population: SAF included all participants who were randomized to treatment and received both doses of double-blind study drug. Number analyzed is the number of participants with data available for analysis for the specified category. The data for this outcome measure was collected and reported separately for the participants who received the unintended mis-dose of TAK-951 redacted mg.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Gamma Glutamyl Transferase (U/L): High: >3*ULN | 0.0 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Alanine Aminotransferase (U/L): High: >3*ULN | 0.0 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Glucose (millimoles per liter [mmol/L]): High: >10 | 4.9 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Protein (g/L): Low: <0.8*LLN | 2.4 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Albumin (g/L): Low: <25 | 0.0 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Erythrocytes (10^12 per liter [10^12/L]): Low: <0.8*Lower Limit of Normal (LLN) | 14.6 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Hematocrit (percent [%]): Low: <0.8*LLN | 12.2 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Hemoglobin (grams per liter [g/L]): Low: <0.8*LLN | 14.6 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Glucose (millimoles per liter [mmol/L]): Low: <3 | 0.0 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Aspartate Aminotransferase (units per liter[U/L]): High: >3*Upper Limit of Normal (ULN) | 0.0 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Potassium (mmol/L): High: >5.5 | 2.4 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Albumin (g/L): Low: <25 | 4.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Erythrocytes (10^12 per liter [10^12/L]): Low: <0.8*Lower Limit of Normal (LLN) | 14.3 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Hemoglobin (grams per liter [g/L]): Low: <0.8*LLN | 23.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Hematocrit (percent [%]): Low: <0.8*LLN | 23.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Aspartate Aminotransferase (units per liter[U/L]): High: >3*Upper Limit of Normal (ULN) | 4.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Alanine Aminotransferase (U/L): High: >3*ULN | 4.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Protein (g/L): Low: <0.8*LLN | 4.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Gamma Glutamyl Transferase (U/L): High: >3*ULN | 5.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Glucose (millimoles per liter [mmol/L]): Low: <3 | 4.8 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Glucose (millimoles per liter [mmol/L]): High: >10 | 0.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Potassium (mmol/L): High: >5.5 | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Erythrocytes (10^12 per liter [10^12/L]): Low: <0.8*Lower Limit of Normal (LLN) | 27.8 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Gamma Glutamyl Transferase (U/L): High: >3*ULN | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Hematocrit (percent [%]): Low: <0.8*LLN | 11.1 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Glucose (millimoles per liter [mmol/L]): High: >10 | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Glucose (millimoles per liter [mmol/L]): Low: <3 | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Hemoglobin (grams per liter [g/L]): Low: <0.8*LLN | 11.1 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Albumin (g/L): Low: <25 | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Alanine Aminotransferase (U/L): High: >3*ULN | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Potassium (mmol/L): High: >5.5 | 0.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Protein (g/L): Low: <0.8*LLN | 16.7 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Clinical Laboratory Values | Aspartate Aminotransferase (units per liter[U/L]): High: >3*Upper Limit of Normal (ULN) | 0.0 percentage of participants |
Secondary
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.
Time frame: From first administration of study drug up to Day 14
Population: SAF included all participants who were randomized to treatment and received both doses of double-blind study drug. The data for this outcome measure was collected and reported separately for the participants who received the unintended mis-dose of TAK-951 redacted mg.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | Respiratory Rate (breaths/min): High: >16 | 100.0 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | BMI (kg/m^2): High: >25.0 | 90.2 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | SBP (mmHg): High: >140 | 70.7 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | SBP (millimeters of mercury [mmHg]): Low: <85 | 7.3 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | Heart Rate (beats per minute [beats/min]): Low: <60 | 36.6 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | DBP (mmHg): High: >90 | 43.9 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | Respiratory Rate (breaths per minute [breaths/min]): Low: <12 | 46.3 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | Heart Rate (beats/min): High: >100 | 14.6 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With Markedly Abnormal Vital Signs | DBP (mmHg): Low: <50 | 22.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | SBP (millimeters of mercury [mmHg]): Low: <85 | 9.5 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Heart Rate (beats per minute [beats/min]): Low: <60 | 19.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Heart Rate (beats/min): High: >100 | 66.7 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Respiratory Rate (breaths per minute [breaths/min]): Low: <12 | 19.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Respiratory Rate (breaths/min): High: >16 | 100.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | SBP (mmHg): High: >140 | 42.9 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | DBP (mmHg): Low: <50 | 33.3 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | DBP (mmHg): High: >90 | 14.3 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | BMI (kg/m^2): High: >25.0 | 85.7 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | SBP (mmHg): High: >140 | 77.8 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | DBP (mmHg): Low: <50 | 55.6 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Heart Rate (beats/min): High: >100 | 72.2 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | BMI (kg/m^2): High: >25.0 | 88.9 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | DBP (mmHg): High: >90 | 38.9 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | SBP (millimeters of mercury [mmHg]): Low: <85 | 16.7 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Respiratory Rate (breaths/min): High: >16 | 100.0 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Heart Rate (beats per minute [beats/min]): Low: <60 | 22.2 percentage of participants |
| TAK-951 Redacted mg SC | Percentage of Participants With Markedly Abnormal Vital Signs | Respiratory Rate (breaths per minute [breaths/min]): Low: <12 | 55.6 percentage of participants |
Secondary
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.
Time frame: Within 6 hours post-surgery (Day 1)
Population: Immunogenicity Set included all participants who received at least 1 dose of study drug, had an ADA status assessment at baseline, and at least 1 postbaseline sample. Overall number analyzed is the number of participants with non-missing data for this outcome measure i.e., responders. The data for this outcome measure was collected and reported separately for the participants who received the unintended mis-dose of TAK-951 redacted mg.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With TAK-951 Antidrug Antibodies (ADA) | Any Antidrug Antibody Positive | 0.0 percentage of participants |
| Ondansetron 4 mg IV | Percentage of Participants With TAK-951 Antidrug Antibodies (ADA) | Any Antidrug Antibody Negative | 100.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With TAK-951 Antidrug Antibodies (ADA) | Any Antidrug Antibody Positive | 0.0 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With TAK-951 Antidrug Antibodies (ADA) | Any Antidrug Antibody Negative | 100.0 percentage of participants |
Secondary
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.
Time frame: Within 24 hours post-surgery (up to Day 2)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron 4 mg IV | Percentage of Participants With Total Response | 34.1 percentage of participants |
| TAK-951 4 mg SC | Percentage of Participants With Total Response | 48.7 percentage of participants |
95% CI: [-0.073, 0.365]
Secondary
TAK-951 Plasma Concentrations
Time frame: 1-3, 4-6, 7-9, 10-18, and 22-26 hours post-dose (up to Day 2)
Population: PK Set included all participants who received study drug and had at least 1 evaluable PK sample. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified timepoint. The data for this outcome measure was collected and reported separately for the participants who received the unintended mis-dose of TAK-951 redacted mg.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ondansetron 4 mg IV | TAK-951 Plasma Concentrations | 4-6 Hours Post Dose | 18456.11 picograms per milliliter(pg/mL) | Standard Deviation 13906.45 |
| Ondansetron 4 mg IV | TAK-951 Plasma Concentrations | 10-18 Hours Post Dose | 4478.22 picograms per milliliter(pg/mL) | Standard Deviation 2433.185 |
| Ondansetron 4 mg IV | TAK-951 Plasma Concentrations | 22-26 Hours Post Dose | 672.63 picograms per milliliter(pg/mL) | Standard Deviation 699.161 |
| Ondansetron 4 mg IV | TAK-951 Plasma Concentrations | 1-3 Hours Post Dose | 24734.50 picograms per milliliter(pg/mL) | Standard Deviation 14782.359 |
| Ondansetron 4 mg IV | TAK-951 Plasma Concentrations | 7-9 Hours Post Dose | 10568.31 picograms per milliliter(pg/mL) | Standard Deviation 8140.684 |
| TAK-951 4 mg SC | TAK-951 Plasma Concentrations | 4-6 Hours Post Dose | 36950.00 picograms per milliliter(pg/mL) | Standard Deviation 26649.65 |
| TAK-951 4 mg SC | TAK-951 Plasma Concentrations | 1-3 Hours Post Dose | 58229.41 picograms per milliliter(pg/mL) | Standard Deviation 42971.281 |
| TAK-951 4 mg SC | TAK-951 Plasma Concentrations | 7-9 Hours Post Dose | 17741.76 picograms per milliliter(pg/mL) | Standard Deviation 9705.848 |
Secondary
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.
Time frame: Within 24 hours post-surgery (up to Day 2)
Population: FAS included all participants who were randomized to treatment and received both doses of double-blind study drug before and during surgery. Overall number analyzed are the number of participants with events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ondansetron 4 mg IV | Time From End of Surgery to First Emetic Event | NA hours |
| TAK-951 4 mg SC | Time From End of Surgery to First Emetic Event | NA hours |
95% CI: [0.122, 1.259]