Antioxidant and NMDA Receptor Blocker Wins Anoxic Brain Damage of KorEa OHCA Patients

Study Overview
=================
Brief Summary
-----------------
This study aims to investigate the efficacy and safety of Neu2000KWL, a neuroprotectant, in patients resuscitated from out-of-hospital cardiac arrest and receiving therapeutic hypothermia.

Detailed Description
-----------------
Lack of good neurological recovery is the biggest hurdle in the treatment of out-of-hospital cardia arrest. Neu2000KWL, a N-Methyl-D-aspartate (NMDA) receptor antagonist and an antioxidant, attenuated cerebral neuronal death and reduced hypoxic injury of brain in preclinical studies. Phase I clinical study has revealed that Neu2000KWL is very safe for treating human. In current study, the investigators will assess the efficacy of Neu2000KWL to compare the neurological biomarker, brain imaging, and clinical outcomes of patients successfully resuscitated from out-of-cardiac arrest treated by 3-day infusion of Neu2000KWL with patients assigned to placebo arm.

Official Title
-----------------
A Phase II, Double-blind, Randomized, Placebo-controlled, Multicenter Trial to Assess the Efficacy and Safety of Neu2000KWL in Patients Who Resuscitated After Out-of-hospital Cardiac Arrest Patient and Receiving Therapeutic Hypothermia

Conditions
-----------------
Cardiac Arrest

Intervention / Treatment
-----------------
* Drug: Neu2000KWL High-dose group
* Drug: Neu2000KWL Low-dose group
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 19 Years to 80 Years (Adult) Out-of-hospital cardiac arrest caused by non-perfusing cardiac rhythm Successful resuscitation accompanied by ROSC time of more than 20 min Therapeutic hypothermia is planned or initiated The first infusion is planned within 4 hours after ROSC Informed consent is obtained from patient or family member(s) No concern with previous cardiovascular surgery Exclusion Criteria: Hypersensitivity to aspirin or sulfasalazine Unwitnessed cardiac arrest CPR time > 60 min Therapeutic hypothermia is not planned Use of extracorporeal membrane oxygenation (ECMO) at initiation of in-hospital resuscitation (E-CPR) Very poor prognosis is expected: patients with (A) non-cardiac or respiratory arrest, (B) poor basal neurological status (C) secondary cardiac arrest caused by trauma, major bleeding, acute neurologic disease including stroke or tumor, (D) multiorgan failure or advanced malignancy Pregnant or lactating women Participated in other clinical studies within 90 days before randomization; or participating in other clinical trials at present Intracranial bleeding verified by first brain CT imaging The investigators consider the patients are not suitable for this trial

Ages Eligible for Study
-----------------
Minimum Age: 19 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neu2000KWL high dose<br> | Drug: Neu2000KWL High-dose group<br>* 1st infusion of 1500mg in patients within 4 hours following sudden cardiac arrest onset followed by 5 consecutive infusions of 750 mg at intervals of 12 hours(Total drug dosage is 5250mg.)<br>|
| Experimental: Neu2000KWL low dose<br> | Drug: Neu2000KWL Low-dose group<br>* 1st infusion of 750mg in patients within 4 hours following sudden cardiac arrest onset followed by 5 consecutive infusions of 500 mg at intervals of 12 hours (Total drug dosage is 3250mg.)<br>|
| Placebo Comparator: saline<br> | Drug: Placebo<br>* 1st infusion of the same volume of saline in patients within 4 hours following sudden cardiac arrest onset followed by 5 consecutive infusions of the same volume of saline at intervals of 12 hours<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verification of difference between of Neuron specific enolase (NSE) value at after 4th infusion of Neu2000KWL. | Blood concentration of neuron specific enolase (NSE) | The 3rd day of study (which corresponds to finished 4th infusion of Neu2000KWL). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verification of difference between the cumulative of neuron specific enolase (NSE) values at after 6th infusion of Neu2000KWL | Cumulative Blood concentration of neuron specific enolase (NSE) | The 4th day of study (which corresponds to finished 6th infusion of Neu2000KWL). | 
| Verification of the difference between groups of Change in NSE values at after the 2nd infusion of Neu2000KWL and after the 6th infusion | The difference of blood neuron specific enolase (NSE) between 24 hour (day 1) and 72 hour (day 3) after the first infusion of Neu2000KWL. | At the 24 hours and 72 hours after the first infusion of Neu2000KWL. | 
| Verification of difference between each group of NSE values at after 6th infusion after 1st infusion of Neu2000KWL and 24 hours after end of last infusion | The difference of blood neuron specific enolase (NSE) between day 4 and day 5 | The 4th and 5th day of study (which corresponds to the timepoint of finished treatment using Neu2000KWL and 24 hour after finished treatment using Neu2000KWL). | 
| Verification of difference between the cerebral infarction at analysis of brain MRI's Apparent Diffusion Coefficient(ADC) images within 48 hours of the last infusion of Neu2000KWL | Blood neuron specific enolase (NSE) at day 5 | The 5th day of study (which corresponds to 48 hours after finished treatment using Neu2000KWL). | 
| Verification of difference between groups of Neurological function evaluated by cerebral performance category (CPC) and modified Rankin Scale (mRS) at 5 day, 14 day, or discharge within 14 days, and 90 days after 1st infusion of Neu2000KWL. | Neurological function evaluated by cerebral performance category (CPC), which ranges 1 to 5 (1: best, 5: worst), and neurological function evaluated by modified Rankin Scale (mRS), which ranges 0 to 6 (0:best, 6: worst) | 5 day, 14 day, or discharge within 14 days, and 90 days after 1st infusion of Neu2000KWL | 
| Verification of difference between groups of Cumulative value of blood S100beta from 6th infusion after 1st infusion of Neu2000KWL. | Cumulative blood concentration of S100beta . | The 4th day of study (which corresponds to finished 6th infusion of Neu2000KWL). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
neuroprotection, free radical, Neu2000KWL, cerebral performance category, out-of-hospital cardiac arrest, glutamate, N-Methyl-D-aspartate (NMDA) receptor antagonist, Anti-oxidant