Study of APD421 as PONV Treatment (no Prior Prophylaxis)

Study Overview
=================
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 not had prior PONV prophylaxis.

Official Title
-----------------
Randomised, Double-blind, Placebo-controlled Study of APD421 (Amisulpride for IV Injection) as Treatment of Established Post-operative Nausea and Vomiting, in Patients Who Have Had no Prior Prophylaxis

Conditions
-----------------
Postoperative Nausea and Vomiting

Intervention / Treatment
-----------------
* Drug: APD421
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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 low to moderate 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 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 agent likely to prevent or treat nausea or vomiting (given as prophylaxis or otherwise) in the period from 12 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 being treated with regular anti-emetic therapy (dosed at least three times per week), which is still ongoing within one week prior to surgery Patients with a known prolactin-dependent tumour (e.g. pituitary gland prolactinoma or breast cancer) or phaeochromocytoma Patients being treated with levodopa Patients who are pregnant or breast feeding Patients with documented or suspected alcohol or substance abuse within the past 6 months Patients with a documented, clinically significant cardiac arrhythmia 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: APD421 standard<br>Single (standard) dose IV APD421 | Drug: APD421<br> <br> |
| Experimental: APD421 high<br>Single (high) dose IV APD421 | Drug: APD421<br> <br> |
| Placebo Comparator: Placebo<br>Single IV placebo | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 0-24 hours after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 0-2 hours after administration of study medication | 
| Number of Participants With Complete Response 2-24 Hrs | Success of initial PONV treatment, where success is defined as no emetic episodes (vomiting or retching) and no administration of anti-emetic rescue medication from 2 to 24 hours after administration of study medication. | 2-24 hours after administration of study medication | 
| Time to Treatment Failure | Time to first violation of the criteria for complete response | 0-24 hours after study drug administration | 
| Number of Patients Experiencing 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 | 30 mins to 24 hours after study drug administration | 
| Number of Participants Using Rescue Medication | Proportion of patients receiving pre-specified anti-emetic rescue medication at any time in the 24 hours post-treatment period | 0-24 hours after study drug administration | 
| Incidence of Significant Nausea | Proportion 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. | 30 mins to 24 hours after study drug administration | 
| Incidence of Nausea | Proportion 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. | 30 mins to 24 hours after study drug administration | 
| 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. | 30 mins to 24 hours after study drug administration | 
| Evolution Score of Nausea (0-30 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 four pre-planned time points: pre-dose (0-min), and 5, 15 and 30 minutes 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. | 0-30 minutes after study drug administration |