A Study of Intravenous (IV) Amisulpride for Prophylaxis of Post-operative Nausea and Vomiting (PONV) in Pediatric Patients

Study Overview
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Brief Summary
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Randomized, double-blind, pediatric trial of amisulpride for prophylaxis of post operative nausea and vomiting

Official Title
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Randomized, Double-blind, Phase 2/3 Study of IV Amisulpride as Prevention of Post-operative Nausea and Vomiting in Pediatric Patients

Conditions
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Nausea and Vomiting, Postoperative

Intervention / Treatment
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* Drug: Amisulpride Injection [Barhemsys]
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients aged from full-term birth to 17 years of age Signed informed consent form and/or assent and willingness of patient and parents to participate in the trial Patients undergoing non-emergency surgery, preferentially eye surgery, adenotonsillectomy or otoplasty, under general anesthesia (other than total intravenous anesthesia with propofol) expected to last at least 30 minutes from induction of anesthesia to removal of Endotracheal tube (ETT) or Laryngeal mask airway (LMA) American Society of Anesthesiologists (ASA) risk score I-III 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., true (not periodic) abstinence from sexual intercourse, surgical sterilization (of subject or partner), combined oral contraceptive pill, 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. Exclusion Criteria: Patients scheduled to undergo transplant or Central Nervous System (CNS) surgery Patients scheduled to receive only a local anesthetic and/or regional neuraxial (intrathecal or epidural) block (without general anesthesia) or to receive general anesthesia involving total intravenous anesthesia (TIVA) with propofol Patients who, in the opinion of the Investigator, are expected to remain ventilated for a significant period after surgery Patients who are expected to need a naso- or orogastric tube in situ after surgery is completed Patients who are expected to receive systemic pre/peri-operative corticosteroid therapy other than as anti-emetic prophylaxis Patients receiving amisulpride for any indication within the 2 weeks prior to randomization Patients known to be allergic to amisulpride or any of the excipients of amisulpride drug product; or to dexamethasone or ondansetron 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 less than 1 week prior to screening Patients being treated with levodopa, or any other dopamine D2-agonist Patients who are pregnant or breast feeding Patients with congenital long QT interval (QT) syndrome Patients with a tumor of the anterior pituitary Patients who have received emetogenic anti-cancer chemotherapy in the previous 4 weeks 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
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Minimum Age: 0 Years
Maximum Age: 17 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1 - Group 1: IV amisulpride 0.035 mg/kg + IV dexamethasone<br>Stage 1 - Group 1: IV amisulpride 0.035 mg/kg + IV dexamethasone | Drug: Amisulpride Injection [Barhemsys]<br>* Dose finding treatment for continuation to phase 3<br>Drug: Dexamethasone<br>* Standard of care treatment<br>|
| Experimental: Stage 1 - Group 2: IV amisulpride 0.07 mg/kg + IV dexamethasone<br>Stage 1 - Group 2: IV amisulpride 0.07 mg/kg + IV dexamethasone | Drug: Amisulpride Injection [Barhemsys]<br>* Dose finding treatment for continuation to phase 3<br>Drug: Dexamethasone<br>* Standard of care treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Complete Response | Defined as no vomiting/retching (absence of PONV) and no use of anti-emetic rescue medication, during the first 24 hours after completion of surgery. Subjects will be questioned and assessed. | 1 Day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of post-operative vomiting/retching | Subjects considered able to understand and provide a meaningful response should be asked if they have nausea (feel sick or other equivalent words) at the following times after completion of surgery (wound closure), unless an episode of PONV or discharge of the subject from the site has already occurred prior to the time point: 1 hour, 2 hours, 6 hours and 24 hours or when they first vomit, retch or receive rescue medication. In subjects aged ≥ 6 years, at the above time points and for any spontaneously reported nausea episode, nausea severity should be scored using the validated 6-point Baxter Retching Faces (BARF) scale. | 1 Day | 
| Use of rescue medication | Document use of rescue medication. | 1 Day | 
| Occurrence and severity of post-operative nausea | An episode of nausea should be recorded any time that a subject spontaneously complains of nausea (including a request for rescue medication due to nausea). Subjects considered able to understand and provide a meaningful response should be asked if they have nausea (feel sick or other equivalent words) at the following times after completion of surgery (wound closure), unless an episode of PONV or discharge of the subject from the site has already occurred prior to the time point: 1 hour, 2 hours, 6 hours and 24 hours or when they first vomit, retch or receive rescue medication. In subjects aged ≥ 6 years, at the above time points and for any spontaneously reported nausea episode, nausea severity should be scored using the validated 6-point Baxter Retching Faces (BARF) scale. | 1 Day | 
| Time to emergence of PONV | Observe for, question and document emergence of vomiting/retching and nausea. In subjects aged ≥ 6 years, at specified time points and for any spontaneously reported nausea episode, nausea severity should be scored using the validated 6-point Baxter Retching Faces (BARF) scale. | 1 Day | 
| Time to emergence of vomiting/retching, significant nausea, and rescue medication, individually | Observe for emergence of vomiting/retching, determine significance of nausea, and note rescue medication, individually. | 1 Day | 
| Different variables during different time ranges after the end of surgery (0-2 h, 2-6 h and 6-24 h) | Subjects considered able to understand and provide a meaningful response should be asked if they have nausea (feel sick or other equivalent words) at the following times after completion of surgery (wound closure), unless an episode of PONV or discharge of the subject from the site has already occurred prior to the time point: 1 hour, 2 hours, 6 hours and 24 hours or when they first vomit, retch or receive rescue medication. In subjects aged ≥ 6 years, at the above time points and for any spontaneously reported nausea episode, nausea severity should be scored using the validated 6-point Baxter Retching Faces (BARF) scale. | 1 Day | 
| The above variables in the sub-groups of patients who did and did not receive opioid analgesia | Concomitant medications will be reviewed. | 1 Day | 
| Safety: The nature and frequency of adverse events and laboratory and electrocardiography (ECG) abnormalities | Adverse events, laboratory and ECG abnormalities will be noted. Blood samples should be drawn at screening (unless recent pre-existing results are available) and again post-operatively, as soon as practically possible after the patient's entry to the post-anesthesia care unit, recovery room or equivalent, and in any event within 1 hour after the end of surgery. Twelve-lead ECGs will be collected at screening. An ECG already taken as part of medical care within the period of 2 weeks prior to screening may be used to determine eligibility and to provide baseline ECG data. In the peri-/post-operative period, continuous Holter monitoring of the ECG will be performed, from at least 10 minutes prior until at least 2 hours after the start of administration of amisulpride study medication. | 7 Days | 
| Key pharmacokinetics parameter - Peak Plasma Concentration | Plasma samples will be drawn as required at specified timepoints to determine the PK profile of peak plasma concentration of amisulpride in subjects. | 1 Day | 
| Key pharmacokinetics parameter - Total Exposure | Plasma samples will be drawn as required at specified timepoints to determine the PK profile of total exposure of amisulpride in subjects. | 1 Day |