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

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

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.

Study Overview

• Status: Unknown
• Conditions: Cardiac Arrest
• Intervention / Treatment: Drug: Neu2000KWL High-dose group; Drug: Neu2000KWL Low-dose group; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Bucheon, Korea, Republic of, 14584
    • SoonChunHyang University Bucheon Hospital
  • Busan, Korea, Republic of, 49241
    • Pusan National University Hospital
  • Gwangju, Korea, Republic of, 61469
    • Chonnam National University Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 06273
    • Gangnam Severance Hospital
  • Korea
    • Daegu, Korea, Korea, Republic of, 41944
      • Kyungpook National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 19 Years to 80 Years (Adult)
2. Out-of-hospital cardiac arrest caused by non-perfusing cardiac rhythm
3. Successful resuscitation accompanied by ROSC time of more than 20 min
4. Therapeutic hypothermia is planned or initiated
5. The first infusion is planned within 4 hours after ROSC
6. Informed consent is obtained from patient or family member(s)
7. No concern with previous cardiovascular surgery

Exclusion Criteria:

1. Hypersensitivity to aspirin or sulfasalazine
2. Unwitnessed cardiac arrest
3. CPR time > 60 min
4. Therapeutic hypothermia is not planned
5. Use of extracorporeal membrane oxygenation (ECMO) at initiation of in-hospital resuscitation (E-CPR)
6. 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
7. Pregnant or lactating women
8. Participated in other clinical studies within 90 days before randomization; or participating in other clinical trials at present
9. Intracranial bleeding verified by first brain CT imaging
10. The investigators consider the patients are not suitable for this trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: saline	Drug: Placebo; 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
Experimental: Neu2000KWL high dose	Drug: Neu2000KWL High-dose group; 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.)
Experimental: Neu2000KWL low dose	Drug: Neu2000KWL Low-dose group; 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.)

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).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious adverse event	Safety Outcome Measure Number of participants with treatment-related adverse events assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0	90 days
Mortality within 90 days	Safety Outcome Measure	90 days

Collaborators and Investigators

• Sponsor: GNT Pharma
• Collaborators: Samsung Medical Center; Pusan National University Hospital; Chonnam National University Hospital; Kyungpook National University Hospital; Gangnam Severance Hospital; Soonchunhyang University Hospital
• Investigators: Principal Investigator: Jin-Ho Choi, MD, Professor, Department of Emergency Medicine, Samsung Medical Center

Publications and helpful links

General Publications

• Choi JH, Chun BJ, Yeom SR, Chung SP, Lee YH, Kim YH, Lee JS, Lee JH, Lee HG, Jin JY, An CS, Gwag BJ. Rationale and methods of the Antioxidant and NMDA receptor blocker Weans Anoxic brain damage of KorEa OHCA patients (AWAKE) trial. Trials. 2022 Jul 23;23(1):587. doi: 10.1186/s13063-022-06452-0.

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2018
• Primary Completion (Anticipated): May 1, 2021
• Study Completion (Anticipated): May 1, 2021

Study Registration Dates

• First Submitted: July 26, 2018
• First Submitted That Met QC Criteria: August 28, 2018
• First Posted (Actual): August 29, 2018

Study Record Updates

• Last Update Posted (Actual): March 6, 2019
• Last Update Submitted That Met QC Criteria: March 5, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: neuroprotection; out-of-hospital cardiac arrest; glutamate; Anti-oxidant; Neu2000KWL; free radical; cerebral performance category; N-Methyl-D-aspartate (NMDA) receptor antagonist
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Arrest; Out-of-Hospital Cardiac Arrest; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Salicylates
• Other Study ID Numbers: Neu2000KWL-P02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No