E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Post-operative nausea and vomiting |
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E.1.1.1 | Medical condition in easily understood language |
Feeling sick and vomiting after an operation |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066962 |
E.1.2 | Term | Procedural nausea |
E.1.2 | System Organ Class | 10022117 - Injury, poisoning and procedural complications |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of 5 mg and 10 mg APD421 to placebo as treatment of established PONV, in patients who have had prior PONV prophylaxis |
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E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of APD421 given as treatment for PONV
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients ≥ 18 years of age. 2. Provision of written informed consent. 3. 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. 4. 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. 5. 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. 6. 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. |
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E.4 | Principal exclusion criteria |
1. Patients scheduled to undergo transplant surgery or any surgery where post-operative emesis may pose a significant danger to the patient. 2. Patients planned to receive only a local anaesthetic and/or regional neuraxial (intrathecal or epidural) block. 3. Patients who have received amisulpride for any indication within the last 2 weeks. 4. Patients who are allergic to amisulpride or any of the excipients of APD421. 5. Patients with a significant, ongoing history of vestibular disease or dizziness. 6. Patients with a known prolactin-dependent tumour (e.g. pituitary gland prolactinoma or breast cancer) or phaeochromocytoma. 7. Patients with documented or suspected alcohol or substance abuse within the past 6 months. 8. Patients with direct or indirect evidence of clinically significant hypokalaemia, such as a serum potassium level < 3.0 mmol/L. 9. 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. 10. Patients who have a documented, clinically significant cardiac arrhythmia or congenital long QT syndrome. 11. Patients who are pregnant or breast feeding. 12. Patients being treated with levodopa. 13. Patients diagnosed with Parkinson’s disease. 14. Patients who have received emetogenic anti-cancer chemotherapy in the previous 4 weeks. 15. Patients with a history of epilepsy. 16. Any other concurrent disease or illness that, in the opinion of the investigator makes the patient unsuitable for the study. 17. 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). 18. Patients under legal protection. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Success in primary PONV treatment, defined as no emetic episodes from 30 minutes to 24 hours after administration of study medication and no administration of further anti-emetic medication at any time in the 24-hour period after administration of study medication. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoints will be assessed during the period beginning with the first episode of PONV, ending 24 hours after administration of study medication. Nausea assessment then completed at 5, 15, 30 and 120 minutes after administration. Vomiting, retching and requirement for rescue medication continually assessed throughout the 24 hour period following administration of study drug/placebo. If patient already discharged prior to 24 hrs: emesis, nausea and rescue medication assessments to be done via patient diary and telephone follow-up. |
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E.5.2 | Secondary end point(s) |
Efficacy: - The occurrence and severity of nausea and of significant nausea, including measures of the time course of nausea, such as area under the curve for nausea scores for time periods up to 24 hours. -The occurrence of vomiting (to include retching) after administration of study medication - Use of anti-emetic rescue medication (see Section 5.3 regarding use of rescue medication) - Time to failure of primary treatment - Sub-analyses of success and failure according to various parameters, including by time of onset of PONV relative to end of surgery and by sex - Time to discharge from PACU/recovery unit and hospital/clinic Safety: - The nature and frequency of adverse events and laboratory abnormalities |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Nausea assessment will be assessed during the period beginning with the first episode of PONV. Nausea assessment then completed at 5, 15, 30 and 120 minutes after administration. Vomiting, retching and requirement for rescue medication continually assessed throughout the 24 hour period following administration of study drug/placebo. If patient already discharged prior to 24 hrs: emesis, nausea and rescue medication assessments to be done via patient diary and telephone follow-up. Blood samples taken post operatively, 5, 30 and 120 minutes following administration and then 6, 24 hours and at discharge for pK. Samples for blood chemistry and haematology taken post operatively, and then at 1 hour prior to discharge or 24 hours post administration (whichever is earlier). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
Germany |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |