Postoperative Nausea and Vomiting
Conditions
Brief summary
Double-blind, randomised, parallel-group, placebo-controlled, adaptive, seamless, dose-selecting study to compare the efficacy of APD421 to placebo as treatment of established PONV, in patients who have had prior PONV prophylaxis.
Interventions
DRUGAPD421
DRUGPlacebo
Sponsors
Acacia Pharma Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients ≥ 18 years of age * Provision of written informed consent * Patients scheduled to undergo elective surgery (open or laparoscopic technique) under general anaesthesia (other than total intravenous anaesthesia with propofol) expected to last at least one hour from induction of anaesthesia to extubation * Patients judged by the investigator to have a moderate or high risk of experiencing PONV. In forming this judgment, investigators should pay particular attention to risk factors such as a past history of PONV and/or motion sickness; habitual non-smoking status; female sex; and likely use of opioid analgesia post-operatively. * For females of child-bearing potential: ability and willingness to use a highly effective form of contraception (as defined in ICH M3 guidance, e.g., abstinence from sexual intercourse, surgical sterilisation (of subject or partner), combined oral contraceptive pill, a double-barrier method of contraception such as either an intra-uterine device (IUD) or an occlusive cap with spermicide, in conjunction with partner's use of a condom, or any other method or combination of methods with a failure rate generally considered to be \<1% per year) between the date of screening and at least 48 hours after administration of study drug * In order to be eligible for randomisation, subjects must also: (i) have experienced a first episode of PONV not more than 24 hours after the end of their operation (wound closure) and prior to discharge from hospital (qualifying PONV episode), for which they have not already received any anti-emetic treatment; and (ii) not have received any dopamine-antagonist agent likely to prevent or treat nausea or vomiting (given as prophylaxis or otherwise) in the period from 24 hours prior to the start of their operation up to the time of the qualifying PONV episode.
Exclusion criteria
* Patients scheduled to undergo transplant surgery or any surgery where post-operative emesis may pose a significant danger to the patient * Patients planned to receive only a local anaesthetic and/or regional neuraxial (intrathecal or epidural) block * Patients who have received APD421 active ingredient for any indication within the last 2 weeks * Patients who are allergic to APD421 active ingredient or any of the excipients of APD421 * Patients with a significant, ongoing history of vestibular disease or dizziness * Patients with a known prolactin-dependent tumour (e.g. pituitary gland prolactinoma or breast cancer) or phaeochromocytoma. * Patients with documented or suspected alcohol or substance abuse within the past 6 months. * Patients with direct or indirect evidence of clinically significant hypokalaemia, such as a serum potassium level \< 3.0 mmol/L. * Patients who have received in the post-operative period, and prior to receiving study drug, any medication with a substantial risk of inducing torsades de pointes, including Class Ia antiarrhythmic agents such as quinidine, disopyramide, procainamide; Class III antiarrhythmic agents such as amiodarone and sotalol; and other medications such as bepridil, cisapride, thioridazine, methadone, IV erythromycin, IV vincamine, halofantrine, pentamidine, sparfloxacin, etc. * Patients who have a documented, clinically significant cardiac arrhythmia or congenital long QT syndrome. * Patients who are pregnant or breast feeding. * Patients being treated with levodopa. * Patients diagnosed with Parkinson's disease. * Patients who have received emetogenic anti-cancer chemotherapy in the previous 4 weeks. * Patients with a history of epilepsy. * Any other concurrent disease or illness that, in the opinion of the investigator makes the patient unsuitable for the study. * Patients who have previously participated in this study or who have participated in another interventional clinical study involving pharmacological therapy within the previous 28 days (or longer exclusion period, if required by national or local regulations). * Where local laws/regulations require: patients under legal protection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Response (Success of Initial PONV Treatment) | 0-24 hours after administration of study medication | The primary efficacy variable was the dichotomous variable: success or failure of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes\* to 24 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 24-hour period after administration of study medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Response 0-4 Hrs | 0-4 hours after administration of study medication | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes\* to 4 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 4-hour period after administration of study medication. |
| Number of Participants With Complete Response 0-6 Hrs | 0-6 hours after administration of study medication | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes to 6 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 6-hour period after administration of study medication. |
| Time to Treatment Failure | 0-24 hours after study drug administration | Time to first violation of the criteria for complete response |
| Number of Patients With Incidence of Emesis | 30 mins to 24 hours after study drug administration | Number of patients experiencing vomiting or retching during the time period from 30 minutes to 24 hours after administration of study medication |
| Number of Participants With Complete Response 0-2 Hrs | 0-2 hours after administration of study medication | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes\* to 2 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 2-hour period after administration of study medication. |
| Number of Patients With an Incidence of Significant Nausea | 30 mins to 24 hours after study drug administration | Number of patients with nausea score ≥4 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. |
| Number of Patients With an Incidence of Nausea | 30 mins to 24 hours after drug administration | Number of patients with nausea score ≥1 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. |
| Maximum Severity of Nausea | 30 mins to 24 hours after study drug administration | Highest recorded nausea score on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication. |
| Evolution Score of Nausea (0-180 Mins) | 0-180 minutes after study drug administration | The evolution score of nausea was calculated as the area under the curve (AUC) of the nausea scores on a scale 0-10 (where 0 is no nausea and 10 is the worst nausea imaginable) obtained at five pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes and 2 hours after administration of study medication, as well as any spontaneously reported episodes of nausea during the time period, plotted against time. A higher score represents a worse outcome. |
| Number of Patients Receiving Rescue Medication | 0-24 hours after study drug administration | Number of patients receiving pre-specified anti-emetic rescue medication at any time in the 24 hours post-treatment period |
Countries
France, Germany, United States
Participant flow
Recruitment details
Estimated recruitment was 700, to deliver 690 evaluable, randomised patients, providing an average of 230 evaluable patients in each of the three groups. The number of randomised patients planned per country was as follows: Germany, 190; France, 15; Canada, 100; and USA, 395
Pre-assignment details
Three patients were randomised but not dosed: 2 due to withdrawal of consent, 1 for other reasons.
Participants by arm
| Arm | Count |
|---|---|
| APD421 5mg APD421 5mg administered as a single, slow intravenous (IV) push over about two minutes | 237 |
| APD421 10mg APD421 10mg administered as a single, slow intravenous (IV) push over about two minutes | 230 |
| Placebo Matching placebo administered as a single, slow, IV push over about two minutes | 235 |
| Total | 702 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 4 | 5 |
| Overall Study | Treatment failure | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | APD421 5mg | APD421 10mg | Placebo |
|---|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical >=65 years | 64 Participants | 22 Participants | 24 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 634 Participants | 214 Participants | 204 Participants | 216 Participants |
| Age, Continuous | 46.3 Years STANDARD_DEVIATION 13.17 | 45.8 Years STANDARD_DEVIATION 13.12 | 46.9 Years STANDARD_DEVIATION 13.03 | 46.0 Years STANDARD_DEVIATION 13.38 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 5 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 62 Participants | 19 Participants | 21 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 41 Participants | 15 Participants | 14 Participants | 12 Participants |
| Race (NIH/OMB) White | 578 Participants | 196 Participants | 189 Participants | 193 Participants |
| Sex: Female, Male Female | 633 Participants | 213 Participants | 208 Participants | 212 Participants |
| Sex: Female, Male Male | 69 Participants | 24 Participants | 22 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 237 | 0 / 230 | 0 / 235 |
| other Total, other adverse events | 64 / 237 | 66 / 230 | 78 / 235 |
| serious Total, serious adverse events | 6 / 237 | 3 / 230 | 5 / 235 |
Outcome results
Primary
Number of Participants With Complete Response (Success of Initial PONV Treatment)
The primary efficacy variable was the dichotomous variable: success or failure of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes\* to 24 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 24-hour period after administration of study medication.
Time frame: 0-24 hours after administration of study medication
Population: Modified ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Participants With Complete Response (Success of Initial PONV Treatment) | 80 Participants |
| APD421 10mg | Number of Participants With Complete Response (Success of Initial PONV Treatment) | 96 Participants |
| Placebo | Number of Participants With Complete Response (Success of Initial PONV Treatment) | 67 Participants |
Comparison: The primary efficacy analysis was a comparison of the incidence of the primary efficacy variable between the two groups that received APD421 and the group that received placebo, using Pearson's χ2 test. The threshold for determining statistical significance in the comparison of incidence of success between the active and placebo groups (the primary efficacy analysis) was a p-value of 2.5% one-sided.p-value: 0.003Chi-squared
Comparison: The primary efficacy analysis was a comparison of the incidence of the primary efficacy variable between the two groups that received APD421 and the group that received placebo, using Pearson's χ2 test. The threshold for determining statistical significance in the comparison of incidence of success between the active and placebo groups (the primary efficacy analysis) was a p-value of 2.5% one-sided.p-value: 0.109Chi-squared
Secondary
Evolution Score of Nausea (0-180 Mins)
The evolution score of nausea was calculated as the area under the curve (AUC) of the nausea scores on a scale 0-10 (where 0 is no nausea and 10 is the worst nausea imaginable) obtained at five pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes and 2 hours after administration of study medication, as well as any spontaneously reported episodes of nausea during the time period, plotted against time. A higher score represents a worse outcome.
Time frame: 0-180 minutes after study drug administration
Population: Modified ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APD421 5mg | Evolution Score of Nausea (0-180 Mins) | 6994.7 Score on a scale*min | Standard Deviation 5659.6 |
| APD421 10mg | Evolution Score of Nausea (0-180 Mins) | 5637.9 Score on a scale*min | Standard Deviation 6046.6 |
| Placebo | Evolution Score of Nausea (0-180 Mins) | 7629.2 Score on a scale*min | Standard Deviation 6640.2 |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.258Wilcoxon (Mann-Whitney)
Secondary
Maximum Severity of Nausea
Highest recorded nausea score on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.
Time frame: 30 mins to 24 hours after study drug administration
Population: Modified ITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| APD421 5mg | Maximum Severity of Nausea | 4.1 Score on a scale | Standard Deviation 3.08 |
| APD421 10mg | Maximum Severity of Nausea | 3.6 Score on a scale | Standard Deviation 3.03 |
| Placebo | Maximum Severity of Nausea | 4.2 Score on a scale | Standard Deviation 3.04 |
p-value: 0.008Wilcoxon (Mann-Whitney)
p-value: 0.42Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With Complete Response 0-2 Hrs
Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes\* to 2 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 2-hour period after administration of study medication.
Time frame: 0-2 hours after administration of study medication
Population: Modified ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Participants With Complete Response 0-2 Hrs | 134 Participants |
| APD421 10mg | Number of Participants With Complete Response 0-2 Hrs | 160 Participants |
| Placebo | Number of Participants With Complete Response 0-2 Hrs | 116 Participants |
p-value: <0.001Chi-squared
p-value: 0.059Chi-squared
Secondary
Number of Participants With Complete Response 0-4 Hrs
Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes\* to 4 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 4-hour period after administration of study medication.
Time frame: 0-4 hours after administration of study medication
Population: Modified ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Participants With Complete Response 0-4 Hrs | 105 Participants |
| APD421 10mg | Number of Participants With Complete Response 0-4 Hrs | 136 Participants |
| Placebo | Number of Participants With Complete Response 0-4 Hrs | 87 Participants |
p-value: <0.001Chi-squared
p-value: 0.053Chi-squared
Secondary
Number of Participants With Complete Response 0-6 Hrs
Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) from 30 minutes to 6 hours after administration of study medication and no administration of anti-emetic rescue medication at any time in the 6-hour period after administration of study medication.
Time frame: 0-6 hours after administration of study medication
Population: Modified ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Participants With Complete Response 0-6 Hrs | 99 Participants |
| APD421 10mg | Number of Participants With Complete Response 0-6 Hrs | 121 Participants |
| Placebo | Number of Participants With Complete Response 0-6 Hrs | 77 Participants |
p-value: <0.001Chi-squared
p-value: 0.021Chi-squared
Secondary
Number of Patients Receiving Rescue Medication
Number of patients receiving pre-specified anti-emetic rescue medication at any time in the 24 hours post-treatment period
Time frame: 0-24 hours after study drug administration
Population: Modified ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Patients Receiving Rescue Medication | 155 Participants |
| APD421 10mg | Number of Patients Receiving Rescue Medication | 127 Participants |
| Placebo | Number of Patients Receiving Rescue Medication | 163 Participants |
p-value: <0.001Chi-squared
p-value: 0.179Chi-squared
Secondary
Number of Patients With an Incidence of Nausea
Number of patients with nausea score ≥1 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.
Time frame: 30 mins to 24 hours after drug administration
Population: Modified ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Patients With an Incidence of Nausea | 183 Participants |
| APD421 10mg | Number of Patients With an Incidence of Nausea | 163 Participants |
| Placebo | Number of Patients With an Incidence of Nausea | 181 Participants |
p-value: 0.065Chi-squared
p-value: 0.52Chi-squared
Secondary
Number of Patients With an Incidence of Significant Nausea
Number of patients with nausea score ≥4 on an 11-point verbal rating scale (0=no nausea, 10=worst possible nausea, therefore higher value is worse outcome) during the time period from 30 minutes to 24 hours after administration of study medication.
Time frame: 30 mins to 24 hours after study drug administration
Population: Modified ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Patients With an Incidence of Significant Nausea | 135 Participants |
| APD421 10mg | Number of Patients With an Incidence of Significant Nausea | 111 Participants |
| Placebo | Number of Patients With an Incidence of Significant Nausea | 139 Participants |
p-value: 0.009Chi-squared
p-value: 0.315Chi-squared
Secondary
Number of Patients With Incidence of Emesis
Number of patients experiencing vomiting or retching during the time period from 30 minutes to 24 hours after administration of study medication
Time frame: 30 mins to 24 hours after study drug administration
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| APD421 5mg | Number of Patients With Incidence of Emesis | 43 Participants |
| APD421 10mg | Number of Patients With Incidence of Emesis | 36 Participants |
| Placebo | Number of Patients With Incidence of Emesis | 67 Participants |
p-value: <0.001Chi-squared
p-value: 0.004Chi-squared
Secondary
Time to Treatment Failure
Time to first violation of the criteria for complete response
Time frame: 0-24 hours after study drug administration
Population: Modified ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| APD421 5mg | Time to Treatment Failure | 188 minutes |
| APD421 10mg | Time to Treatment Failure | 443 minutes |
| Placebo | Time to Treatment Failure | 120 minutes |
p-value: <0.001Regression, Cox
p-value: 0.084Regression, Cox