Phase II Dose-ranging Study of APD421 in PONV

Study Overview
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Brief Summary
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To assess the efficacy and safety of different doses of APD421 in the prevention of post-operative nausea and vomiting (PONV) in adult patients at moderate to high-risk of PONV. Patients must be undergoing elective surgery under general anaesthesia (hysterectomy (any surgical technique), cholecystectomy (any surgical technique) or other elective surgery scheduled to last at least one hour from induction of anaesthesia), requiring at least one overnight stay in hospital, and have at least 2 of the following risk factors for PONV: Past history of PONV and/or motion sickness; Non-smoking status; Female gender; Planned opiate use for post-operative analgesia.

Official Title
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Randomised, Double-blind, Placebo-controlled, Dose-ranging Phase II Study of APD421 for the Prevention of Post-operative Nausea and Vomiting

Conditions
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Postoperative Nausea and Vomiting

Intervention / Treatment
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* Drug: APD421
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female patients ≥ 18 years of age Ability and willingness to give written informed consent Patients undergoing elective surgery under general anaesthesia requiring at least one overnight stay in hospital for either: Hysterectomy (any surgical technique) Cholecystectomy (any surgical technique) Other elective surgery requiring overnight admission to hospital and scheduled to last at least 1 hour from induction of anaesthesia Patients with at least 2 of the following risk factors for PONV: Past history of PONV and/or motion sickness Habitual non-smoking status Female sex Expected to receive opioid analgesia post-operatively American Society of Anesthesiologists (ASA) risk score I-III Adequate cardiac, hepatic and renal function QTc interval < 500 ms Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) < 5 x upper limit normal (ULN) Bilirubin < 3 x ULN Creatinine < 2 x ULN Adequate haematological function Haemoglobin ≥ 9 g/dL White blood count ≥ 3.0 x 109/L Platelet count ≥ 100 x 109/L For females of child-bearing potential: ability and willingness to use a highly effective form of contraception (e.g., abstinence from sexual intercourse, surgical sterilisation (of subject or partner) or 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) between the date of screening and at least 48 hours after administration of study drug. Exclusion Criteria Patients undergoing outpatient/day case surgery Patients undergoing surgery where the patient is expected to remain ventilated for a period after surgery Patients undergoing intra-thoracic, transplant or central nervous system surgery Patients receiving a local anaesthetic/regional neuraxial (intrathecal or epidural) block Patients who are expected to need a naso- or oral-gastric tube in situ after surgery is completed Patients receiving the active ingredient of APD421 for any indication within the last 2 weeks Patients who are allergic to the active ingredient or any of the excipients of APD421 Patients with a pre-existing vestibular disorder or history of dizziness Patients with pre-existing nausea or vomiting in the 24 hours before surgery Patients treated with regular anti-emetic therapy including corticosteroids Patients being treated with medications which could induce 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 Patients being treated with levodopa Patients who are pregnant or breast feeding Patients with a history of alcohol abuse Patients with pre-existing, clinically significant cardiac arrhythmia Patients diagnosed with Parkinson's disease Patients who have received 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 participated in a previous study within the last 28 days (French sites only: Patients who have participated in a previous study within the last 6 months, if required by national or local regulations)

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 |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* IV<br>|
| Experimental: Low dose APD421<br>1mg dose level | Drug: APD421<br>* IV<br>|
| Experimental: Mid Dose APD421<br>5mg dose level | Drug: APD421<br>* IV<br>|
| Experimental: High Dose APD421<br>20mg dose level | Drug: APD421<br>* IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-operative Nausea or Vomiting |  | 24 hours |