Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Intravenous N-Acetylcysteine for the Treatment of Acute Ischemic Stroke

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04918719
Recruitment Status : Not yet recruiting
First Posted : June 9, 2021
Last Update Posted : June 11, 2021
Sponsor:
Information provided by (Responsible Party):
David Tanen, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Brief Summary:

Stroke is a major cause of death and long-term disability in the developed world. While t-PA and mechanical thrombectomy have been shown to decrease disability in properly selected patients, many patients are left with lifelong symptoms. There are currently limited options available for patients who are not candidates for treatment with t-PA and/or mechanical thrombectomy.

N-Acetylcysteine (NAC) is an FDA approved antioxidant and anti-inflammatory agent that has been used safely for many years in the treatment of acetaminophen overdose. In studies, the oral form has been shown to improve outcomes in acute ischemic stroke and has been shown to decrease the effects of ischemic brain injury in animal models. In a small human trial, it improved outcomes in patients suffering from mild traumatic brain injury (TBI). The intravenous formulation has a long safety record. It is not FDA approved for treating stroke but was reviewed by the FDA and was given an FDA IND for this study.

The investigators propose a prospective randomized, double-blind, placebo-controlled study to evaluate the efficacy of administering intravenous N-acetylcysteine to patients with acute ischemic stroke. Eligible subjects will receive a commercially available form of intravenous NAC (Acetadote®) through for the first 21 hours following their enrollment. Patients enrolled who receive t-PA for thrombolysis will have their intravenous NAC infusion delayed for 24 hours after the completion of their t-PA infusion. Patients undergoing thrombectomy will be excluded from enrollment. Subjects will be evaluated by emergency department and/or division of neurology physicians at the time of enrollment, during their hospitalization, as well as 30 days and 90 days after enrollment. At each visit, subjects will be assessed for functional status and quality of life.

This study is designed to compare the efficacy of intravenous N-acetylcysteine compared to normal treatment in patients with acute ischemic stroke.


Condition or disease Intervention/treatment Phase
Acute Ischemic Stroke Drug: Acetylcysteine Drug: Dextrose in Water Phase 2

Detailed Description:

Stroke is a leading cause of death and long-term disability in the United States, affecting more than 795,000 individuals annually. Of these, about 87% are ischemic strokes. In properly selected patients, intravenous recombinant tissue plasminogen activator (t-PA) has been shown to improve functional outcomes if given within 4.5 hours of the onset of stroke symptoms. Endovascular treatment both via clot retrieval devices and catheter directed t-PA has demonstrated benefit in well-selected patients with a large vessel occlusion and significant salvable tissue, also known as the penumbra. For patients who are not candidates for treatment with t-PA or mechanical thrombectomy, current treatment is centered on supportive care.

N-Acetylcysteine (NAC) is an FDA approved medication that has been used successfully for many years in the treatment of acute acetaminophen overdose. It is generally well tolerated with the exception of rare anaphylactoid type reactions to the intravenous formulation. In mouse studies, N-acetylcysteine (NAC) has led to an increase in glutathione levels in the neurons along with a reduced number of microbleeds in ischemic models. NAC treated rats have been demonstrated to have increased level of glutathione in the astrocytes which provides a neuroprotective effect. This reduced the number of microbleeds and prevented further thrombosis or infarct . The efficacy of NAC by scavenging of ROS and increasing mitochondrial activities has been shown to reduce noise-induced hearing loss in chinchilla models. Another study on transient cerebral ischemia rat models defined a new pharmacokinetic in which the neuroprotective effects of NAC are mediated by the increased protein levels of hypoxia-induced factor 1 (HIF-1), its target erythropoietin (EPO) and glucose transporter (GLUT-3).

Studies have shown consistent, similar results for ischemic brain injury in rat. Consistent human studies showing neuroprotective effects which lead to reduced symptoms after traumatic brain injury, reduced noise-induced hearing loss and as a treatment for Parkinson's disease. NAC has been shown to stimulate mitochondrial Complex 1 and 4 activities in vivo and in vitro in pre-synaptic terminals. The antioxidant effect of NAC by scavenging of ROS may prevent intracellular damage by inhibiting NF-kappaB, TNFalpha and Na+, K+ -ATPase inhibition of the neurons. In a human study of NAC for Parkinson's disease, NAC was found to mitigate the effects of ischemic brain injury in animal models. The antioxidant effect from repletion of intracellular glutathione is thought to preserve mitochondrial function and decrease cellular apoptosis. A placebo-controlled human trial demonstrated that NAC is able to decrease the effects of mild traumatic brain injury 7 days after blast injury. A recent study has shown that sufficient plasma and CSF levels can be achieved at well tolerated doses: 7 mg/kg, 35 mg/kg and 50 mg/kg.

A recent randomized placebo-controlled trial demonstrated improvement in patients given oral N-acetylcysteine every four hours for a total of 72 hours after enrollment in their NIH stroke scale and modified Rankin Score at 90 days. Intravenous N-Acetylcysteine given over 21 hours has proven to be equally efficacious in the treatment of acetaminophen toxicity and is currently the standard of care for that indication. The investigators aim to determine if intravenous NAC completed over a 21-hour course will improve NIH Stroke Scale and modified Rankin scores at 90 days. of NAC following an acute ischemic stroke.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 118 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized double blinded clinical trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Sylvia Youn, Pharm.D., the ED Pharmacist will maintain drug accountability logs in compliance with FDA regulations. She will instruct other ED pharmacists about the study and the randomization log which will be kept in the pharmacy room in the ED. She will also create study drug labels to keep the nurses, physicians and patients blinded to the study medication.
Primary Purpose: Treatment
Official Title: Randomized Placebo Controlled Trial of Intravenous N-Acetylcysteine for the Treatment of Acute Ischemic Stroke
Estimated Study Start Date : June 1, 2021
Estimated Primary Completion Date : January 25, 2023
Estimated Study Completion Date : March 25, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: NAC arm

Both arms are subjects who present with neurological deficits consistent with stroke without hemorrhage less than 24 hours since symptom onset. Both arms will receive standard of care with the study intervention being considered an "add-on" therapy. Thirty minutes after enrollment, eligible subjects will be randomized into one of two arms: placebo or N-Acetylcysteine (NAC). Any patient receiving t-PA who enrolls in the study will have their study drug infusion delayed by 24 hours after the completion of the t-PA infusion.

The dosing of NAC will be similar to the standard intravenous acetaminophen toxicity dosing: 150mg/kg in 200 milliliters of 5% Dextrose (D5W) infused over 1 hour, immediately followed by 50mg/kg in 500mL D5W infused over 4 hours, then 100mg/kg in 1000 milliliters D5W infused over 16 hours.

Drug: Acetylcysteine
The dosing of Acetylcysteine will be similar to the standard intravenous acetaminophen toxicity dosing: 150mg/kg in 200 milliliters of 5% Dextrose (D5W) infused over 1 hour, immediately followed by 50mg/kg in 500mL D5W infused over 4 hours, then 100mg/kg in 1000 milliliters D5W infused over 16 hours. (Any patient receiving t-PA who enrolls in the study will have their study drug infusion delayed by 24 hours after the completion of the t-PA infusion. )
Other Name: N-acetylcysteine

Placebo Comparator: Placebo arm

Both arms are subjects who present with neurological deficits consistent with stroke without hemorrhage less than 24 hours since symptom onset. Both arms will receive standard of care with the study intervention being considered an "add-on" therapy. Thirty minutes after enrollment, eligible subjects will be randomized into one of two arms: placebo or N-Acetylcysteine(NAC). Any patient receiving t-PA who enrolls in the study will have their study drug infusion delayed by 24 hours after the completion of the t-PA infusion.

The placebo will consist of a 5% Dextrose in Water (D5W) instead of NAC (dosage and timings are the same as the NAC arm).

Drug: Dextrose in Water
The placebo will consist of a 5% Dextrose in Water instead of NAC (dosage and timigs are the same as the NAC arm). (Any patient receiving t-PA who enrolls in the study will have their study drug infusion delayed by 24 hours after the completion of the t-PA infusion. )
Other Names:
  • D5W
  • 5% Dextrose in Water




Primary Outcome Measures :
  1. National Institutes of Health Stroke Scale (NIHSS) [ Time Frame: From the time of enrollment until 90 days (looking at change in NIHSS) ]
    The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. The single patient assessment requires less than 10 minutes to complete. The evaluation of stroke severity depends upon the ability of the observer to accurately and consistently assess the patient.


Secondary Outcome Measures :
  1. Modified Rankin Scale for Neurologic Disability(MRS) [ Time Frame: Obtained at 90 days ]
    The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is usually added for patients who expire. The Modified Rankin Score (mRS) is the most widely used outcome measure in stroke clinical trials. Standardized interviews to obtain a mRS score are recommended at 3 months (90 days) following hospital discharge.

  2. Glascow Outcome Scale (GOS) [ Time Frame: Obtained at 90 days ]

    The Glasgow Outcome Score applies to patients with brain damage allowing the objective assessment of their recovery in five categories. This allows a prediction of the long-term course of rehabilitation to return to work and everyday life.

    1. Death Severe injury or death without recovery of consciousness
    2. Persistent vegetative state Severe damage with prolonged state of unresponsiveness and a lack of higher mental functions
    3. Severe disability Severe injury with permanent need for help with daily living
    4. Moderate disability No need for assistance in everyday life, employment is possible but may require special equipment.
    5. Low disability Light damage with minor neurological and psychological deficits.

  3. Barthel Index (BI) [ Time Frame: Obtained at 90 days ]
    The Barthel index is an ordinal scale that measures functional independence in the domains of personal care and mobility in patients with chronic, disabling conditions, especially in the rehabilitation settings.

  4. Neuronal specific enolase blood level [ Time Frame: From the time of enrollment and at 90 days ]
    Neuronal specific enolase levels obtained at enrollment at at 90 days

  5. s100b blood level [ Time Frame: From the time of enrollment and at 90 days ]
    s100b levels obtained at enrollment at at 90 days

  6. MRI [ Time Frame: Comparison of the volume of stroke noted on initial MRI will be compared to MRI at 90 days ]
    Volumetric measure the extent of stroke will be quantitated



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Consecutive subjects between ages 18 years or older evaluated in the emergency department at Harbor-UCLA Medical Center with signs and symptoms of acute ischemic stroke presenting within 24 hours of symptom onset. All individuals regardless of gender or race will be included. For adults who cannot consent for themselves because of the severity of their stroke, one of the investigators will offer participation in the study to the family member who possesses the authority for medical decision making for the patient. There is no financial incentive for either the patient or the investigator. It will also be explained that the potential benefit of giving N-acetylcysteine is unknown and that the patient will receive excellent care (standard for their presentation) whether they participate or not and outside of not receiving the study drug.

Our patients tend to be economically disadvantaged but since there are no financial incentives either for the patient or for the investigators, this bias has been minimized. Patients will receive the same care whether they participate in the study or decline.

Exclusion Criteria:

  • Evidence of hemorrhagic stroke on initial CT scan
  • Need for thrombectomy as determined by the treating neurologist -Known allergy to NAC
  • Protected populations, including age < 18, known pregnancy, and prisoners
  • Patients who are DNR/DNI at the time of presentation with a short life expectancy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04918719


Contacts
Layout table for location contacts
Contact: David Tanen, MD 424-306-5412 dtanen@emedharbor.edu
Contact: Elizabeth Burrola 310-222-3624 lburrola@lundquist.org

Sponsors and Collaborators
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Investigators
Layout table for investigator information
Principal Investigator: David Tanen, MD Lundquist LABiomed
  Study Documents (Full-Text)

Documents provided by David Tanen, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center:
Additional Information:
Publications:

Layout table for additonal information
Responsible Party: David Tanen, Associate Residency Director & Senior Physician, Department of Emergency Medicine, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
ClinicalTrials.gov Identifier: NCT04918719    
Other Study ID Numbers: 32358-01
First Posted: June 9, 2021    Key Record Dates
Last Update Posted: June 11, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David Tanen, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center:
non-hemorrhagic
Additional relevant MeSH terms:
Layout table for MeSH terms
Stroke
Cerebral Infarction
Ischemia
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Brain Infarction
Brain Ischemia
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes