Antiemetic Fosaprepitant To Remedy Nausea and Vomiting

Nausea and vomiting (NV) are common and interrelated conditions. Approximately 50% of adults experience nausea in a given year while 30% of adults experience vomiting over the same period. Of this population of symptomatic individuals with NV, 25% of patients seek care in any healthcare delivery setting. Health Care Utilization Project (HCUP) data indicates that nearly 9.0 million patients seek care for NV in emergency departments (EDs) each year in the United States.

Antiemetics are used to treat NV. Antiemetics currently utilized in the emergency department setting for NV do not always work on the first dose and have a plethora of side effects because of their peripheral mechanism of action outside of the vomiting reflex pathway in the central nervous system. These medications include ondansetron, promethazine, metoclopramide, olanzapine, haloperidol. Chief among these side effects is alteration of an aspect cardiac electrical signaling called the QT segment which represents the duration of ventricular contraction and relaxation. The QT segment is prolonged with commonly used antiemetics which can often be a prelude to cardiac dysrhythmias that are associated with mortality. As a result, patients with NV often have long length-of-stay (LOS) involving supportive care with intravenous fluids or empiric treatment with medications that can potentiate development of cardiac dysrhythmias. This is a problem in busy emergency departments (EDs) struggling to accelerate patient throughput in order to appropriately keep up with patient volume in an under-supplied hospital bed environment nationally.

Fosaprepitant and its active metabolite aprepitant are a relatively new class of antiemetic that exclusively acts in the central nervous system by blocking neurokinin (NK-1) which is a key signaling molecule in the centrally mediated aspects of the vomiting reflex. Currently, fosaprepitant and aprepitant both have only two United Stated Food and Drug Administration (USFDA) approved indications for nausea and vomiting: chemotherapy-induced and postoperative. Neurokinin inhibitors are highly effective and generally well-tolerated. Therefore, this class of medication may be a more appropriate medication for the millions of patients with nausea and vomiting that seek care in EDs. Intravenous fosaprepitant is converted to the active metabolite aprepitant on the order of minutes and is significantly cheaper to procure at this time.

• Fosaprepitant 150 mg (Drug): Fosaprepitant 150mg IV administered over 15 minutes
• Ondansetron 4 mg (Drug): Ondansetron 4mg IV administered over 15 minutes

Primary outcomes

• Relief from NV [Within 2 hours of medication administration]: Relief from nausea and vomiting will be determined by the intensity of nausea reported by participants following administration of antiemetic. Intensity of nausea will be reported as either "None," "Mild," "Moderate," or "Severe." Relief of nausea and vomiting requires a patient to present with a nausea intensity of either "Severe" or "Moderate," which is then reduced by treatment to at least "Mild" or "None," within two hours of medication administration, without the use or rescue medication. The number/percentage of participants who achieve relief from NV will be summarized by study arm.
• Occurrence of any treatment-related adverse event [2 hours following medication administration]: The primary safety/tolerability outcome for this study is the occurrence of any treatment related adverse event (TRAE) at 2 hours of medication administration. TRAEs - not including underlying pathology causing NV - and including, but not limited to: appendicitis, small bowel obstruction, constipation, gastroparesis, gastroenteritis, gastritis, will be summarized by study arm
• Requirement for additional medication [2 hours following medication administration]: Requirement of any additional medication specifically for treatment of NV at 2 hours of medication administration; the use of rescue medications to treat persistent NV, or other medications such as additional doses or use of adjunct medications will be recorded. The number/percentage of patients who require additional medication will be summarized by study arm.

Secondary outcomes

• Freedom from nausea and vomiting (NV) [2 hours following medication administration]: Freedom from nausea and vomiting (NV) will be determined by the intensity of nausea reported by participants following administration of antiemetic. Intensity of nausea will be reported as either "None," "Mild," "Moderate," or "Severe." Sustained freedom from nausea and vomiting requires a patient to present with a nausea intensity of either "Severe" or "Moderate," which is then reduced by treatment to "None" within two hours of medication administration. The number/percentage of patients with freedom from nausea/vomiting (NV) will be measured every 15 minutes for the first 2 hours. The number/percentage of patients with freedom from NV at 2 hours will be summarized by study arm.
• Sustained Relief from nausea and vomiting (NV) (at 24 hours) [At 24-hours following medication administration]: The number/percentage of patients demonstrating relief from nausea/vomiting (NV) will be measured every 15 minutes for the first 2 hours (for assessment of the primary outcome), then during every hour up to the end of the follow up period at 24 hours. Relief from NV is defined as achieving a level of relief of either "Mild" or None" at 2 hours and maintaining that level of "Mild" or "None" for the entire 24-hour period following medication administration, without use of rescue medication. The number/percentage of participants who achieve relief from NV will be summarized by study arm.
• Sustained NV Freedom (at 24 hours) [At 24- hours following medication administration]: Sustained freedom from nausea and vomiting (NV) will be determined by the intensity of nausea reported by participants following administration of antiemetic. Intensity of nausea will be reported as either "None," "Mild," "Moderate," or "Severe." Sustained freedom from nausea and vomiting requires a patient to present with a nausea intensity of either "Severe" or "Moderate," which is then reduced by treatment to "None" within two hours of medication administration (corresponding secondary outcome), and maintained at this level (i.e., "None") for the entire 24-hour follow-up period, without the use or rescue medication. The number/percentage of participants who achieve sustained freedom from NV will be summarized by study arm.
• Disposition Plan [4 hours following medication administration]: A disposition determination plan will be documented at 4 hours. Patients will be categorized as either having been either "admitted," "discharged," or status "yet to be determined." Categorical data will be summarized by study arm.
• Patient Medication Preference for subsequent episode of NV [24 hours following medication administration]: Medication preference will be assessed based on patient's preference for receiving the same antiemetic medication as administered for a subsequent episode of nausea and vomiting. Binary ("Yes" for having the same medication administered, "No" for request of a different medication) responses of patient preference will be summarized by study arm.
• Emergency Department (ED) Length of Stay (LOS) [From initial presentation to disposition in ED, approximately 4 hours]: ED LOS will be defined as the interval of time from initial presentation to final disposition in the ED, will be determined. Mean LOS results will be summarized by study arm.

Other outcomes

• Severity of Nausea [24 hours (measured every 15 minutes for the first 2 hours, then hourly after that until disposition; reassessed at 24 hours)]: Mean severity of nausea scores will be evaluated and summarized based on a visual analogue scale from 0 to 100 (0 = no nausea, 100 = worst nausea possible) such that higher scores are associated with more severe nausea. Results will be summarized by study arm.
• Functional disability [24 hours (assessed prior to receiving intervention, at 2 hour point after receiving intervention, and 24 hours after intervention)]: Patient reported functional disability will be assessed. Functional disability will be categorized as either "Severe," "Moderate," "Mild," or "Not impaired." Categorical variables will be summarized by study arm using descriptive statistics.
• Number of Vomiting Episodes [24 hours following medication administration]: The mean number of vomiting episodes per patient will be determined and summarized by study arm.
• Need for rescue antiemetic medication [2 hours (assessed at the 2 hour mark after administration of the intervention)]: Binary outcome for needing or not needing additional dosing of antiemetic medication to treat nausea will be determined. Results will be summarized by study arm.
• Number of Patients Requiring Hospitalization [24 hours]: The number/percentage of patients who require hospitalization within 24 hours due to NV symptoms will be determined. Results will be summarized by study arm.
• Fluid Treatment [4 hours]: The percentage of patients treated with IV fluids will be determined. Results will be summarized by study arm.
• Mean Fluid Volume [4 hours]: The mean per patient volume of IV fluids administered will be summarized by study arm.
• QTc Interval (QT interval corrected for heart rate) [Prior to Intervention and at disposition, approximately 2 hours]: Mean QTc durations, as calculated from ECG readings administered prior to receiving intervention and at disposition, will be determined. Prolonged QT interval is commonly associated with antiemetics and can often be a prelude to cardiac dysrhythmias associated with mortality. Mean QTc durations will be summarized by study arm.
• Revisit Rate [24 hours]: Revisit rate will be assessed as the number/percentage of participants requiring a revisit to the Emergency department for NV. Results will be summarized by study arm.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adults at least 18 years old
* Present to an emergency department (ED) for nausea and/or vomiting as defined by the International Classification of Diseases (ICD-10), or identified by treating clinician
* Following the approval of a protocol amendment, study patients who have received an antiemetic and remain persistently nauseated after 2 hours will be eligible to participate in the study

Exclusion Criteria:

* Pregnancy, desiring pregnancy, or lactating
* Antiemetic medication use less than 2 hours prior to screening
* Bradycardia (heart rate less than 60 bpm heart rate)
* Prolonged QTc (>480ms)
* Not conversant in English or Spanish
* Altered mental status
* Dementia
* Lack of phone for follow-up communication

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• Benjamin W Friedman, MD MS, Principal investigator, Montefiore Medical Center