Study to Evaluate The Safety and Efficacy of Balovaptan in Participants With Acute Ischemic Stroke at a High Risk of Developing Malignant Brain Edema

Study Overview
=================
Brief Summary
-----------------
This study is designed to evaluate the safety, efficacy, and pharmacokinetics of balovaptan compared with placebo in participants with acute ischemic stroke (AIS) at risk of developing Malignant Cerebral Edema (MCE)

Official Title
-----------------
A Phase II, Randomized, Double Blind, Placebo Controlled Multicenter Study to Evaluate The Safety and Efficacy of Balovaptan in Patients With Acute Ischemic Stroke at High Risk of Developing Malignant Cerebral Edema

Conditions
-----------------
Acute Ischemic Stroke

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of LVO in the anterior circulation such that study drug administration can be initiated within 12 hours of LKW and at risk of MCE development, as defined as follows: Documented occlusion of terminus ICA and/or MCA on CTA or magnetic resonance angiogram and ASPECTS score </=5 on NCCT and NIHSS >15 for the non-dominant hemisphere and >20 for the dominant hemisphere (or > 20 if dominant/non-dominant hemisphere unknown) Present with a WUS </=8 hours from awakening provided the above criteria are met Participants with a history of seizures on anti-epileptic medications may be included if they have been on stable doses of those medications for at least 12 weeks prior to LKW, they have not experienced seizures during that time frame, and their anti-epileptic medicines are continued during the study For women of childbearing potential: participants who agree to remain abstinent (refrain from heterosexual intercourse) or use contraception and agree to refrain from donating eggs No specific contraception methods for males are required. Exclusion Criteria: Participants who are >12 hours from LKW at the start of treatment with study drug or >8 hours from awakening with WUS Any MLS on brain imaging Evidence of intracranial hemorrhage at screening based on NCCT Contraindication to MRI examination Evidence of additional anterior cerebral artery (ACA) infarction Diagnosis of brain death Planned surgical decompression prior to randomization Participants with a known history of a hereditary bleeding disorder which increases bleeding risk Chronic kidney disease stage III or higher Hepatic injury Diagnosis of diabetes insipidus Participants who have received any prophylactic hyperosmolar therapy Participants who have received treatment with any other V1a and/or V2 receptor-blocking agent or glyburide A preexisting medical condition for which the participant is unlikely to survive the next 6 months Planned limitation or withdrawal of life-sustaining treatment during hospital admission Participants who are pregnant or breastfeeding, or intending to become pregnant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 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: Balovaptan<br>Balovaptan will be administered as IV infusion once a day over 3 days | Drug: Balovaptan<br>* Intravenous Solution<br>|
| Placebo Comparator: Placebo<br>Placebo will be administered as IV infusion once a day over 3 days | Drug: Placebo<br>* Matching Intravenous Solution<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of midline shift (MLS) at 72 hours from Last Known Well (LKW) | Midline shift will be measured in millimeter on non-contrast computer tomography (NCCT) | 72 Hours from Last Known Well | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with modified Rankin Scale-Structured Interview (mRS-SI) score </= 4 vs. >4 |  | At Day 90 | 
| Amount of MLS | MLS will be measured in millimeter on NCCT | At 48 hours and 96-120 hours from LKW | 
| Percentage of Participants with Surgical DHC Performed |  | From Baseline up to Day 90 | 
| Percentage of Participants Who Received Hyperosmolar therapy following initiation of study treatment |  | From Baseline up to Day 90 | 
| National Institute of Health Stroke Scale (NIHSS) score |  | At Day 4 and Day 90 | 
| Mortality | Mortality in the first 30 days after the enrollment | At Day 30 | 
| mRS-SI score |  | At Day 30 | 
| Functional Independence Measure (FIM) score |  | At Discharge or Day 10 and Day 90 | 
| Glasgow Outcome Scale Extended (GOSE) Score |  | at Discharge or Day 10, Day 30 and Day 90 | 
| Stroke Impact Scale-16 (SIS-16) score |  | At Day 30 and Day 90 | 
| Length (in days) of ICU and Hospital Stay |  | From Baseline to Day 90 | 
| Number of participants with adverse events and severity of adverse events | Severity will be determined according to the NCI CTCAE v5.0 | From Baseline to Day 90 | 
| Plasma concentrations of balovaptan at specified timepoints |  | From Baseline to 120 Hours After the End of the Last Infusion (or at discharge) | 
| Area under the concentration-time curve from Time 0 to 24 hours after a given dose (AUC24hr) | As calculated by NCA from measured concentration | From Baseline to 120 Hours After the End of the Last Infusion (or at discharge)] | 
| Maximum observed concentration (Cmax) | As calculated by NCA or taken directly from measured concentration | From Baseline to 120 Hours After the End of the Last Infusion (or at discharge)] | 
| Plasma drug concentration 24hours after the administration of a given dose (C24hr) | As calculated by NCA or taken directly from measured concentration | From Baseline to 120 Hours After the End of the Last Infusion (or at discharge)] | 
| Number of participants with safety findings on brain imaging |  | From Baseline to Day 90 |