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Study of NNZ-2566 in Patients With Traumatic Brain Injury (INTREPID2566)

Primary Purpose

Brain Injuries

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
NNZ-2566
Placebo
Sponsored by
Neuren Pharmaceuticals Limited
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Brain Injuries

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Non-penetrating TBI.
  • Male.
  • Age 18-70 years.
  • Admission to hospital.
  • Post resuscitation GCS 4-12.
  • Have at least one reactive pupil.
  • Randomization within 7 hours of injury with the ability to receive investigational product within 8 hours of injury.
  • Hemodynamically stable after resuscitation (systolic blood pressure (SBP) >100 mm Hg).
  • Willing to undergo all neuropsychological and activities of daily living (ADL) testing (i.e. understand English, able to read, write, have sufficient motor dexterity and, be available for follow-up visits at 4-6 weeks and 12-14 weeks post injury).

Exclusion Criteria:

  • Penetrating brain injury.
  • Spinal cord injury.
  • Presence or known history of prior cerebral injury requiring hospitalization that would, in the opinion of the Investigator, interfere with or bias the assessment of efficacy.
  • Non-traumatic brain injury.
  • Known history of any medical or psychiatric disorder, or any severe concomitant disease, that in the opinion of the Investigator would interfere with or bias the assessment of efficacy. This includes the following: schizophrenia; bipolar disorder; major depressive disorder; post traumatic stress disorder (PTSD); generalized anxiety disorder; attention deficit hyperactivity disorder; neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease, vascular dementia, Diffuse Lewy Body Disease); stroke; brain tumor; multiple sclerosis (MS); seizure disorders; chronic pain disorder; alcoholism or substance abuse.
  • Significant non-central nervous system (CNS) injuries sustained at the time of the TBI that in the opinion of the Investigator would interfere with or bias the assessment of efficacy.
  • Weight >150 kg.
  • Participation in another clinical trial within the previous 4 weeks.
  • Clinical state requiring greater than 6 L colloid or crystalloid fluid resuscitation prior to randomization.
  • Inability to obtain informed consent from legally acceptable representative.
  • Prior enrollment in this study.

  • QTc Exclusions. The study will use the exclusion criteria as defined in ICH Guideline E14 to exclude patients with a risk of QT/QTc prolongation, as follows:

    • A marked baseline prolongation of corrected QT/QTc interval >450 ms.
    • History of risk factors for torsade de pointes (e.g. heart failure, hypokalemia (serum potassium at screening (<3.0 mmol/L)or family history of long QT syndrome).

Sites / Locations

  • University of South Alabama
  • University of Arizona
  • Arrowhead Regional Medical Center
  • Ronald Reagan UCLA Medical Center
  • University of California, Davis Medical Center
  • University of Miami, Lois Pope Life Center
  • The Queen's Medical Center
  • Our Lady of the Lake Hospital
  • Detroit Receiving Hospital and University Health Center
  • Sinai Grace Hospital
  • Bronson Methodist Hospital
  • SUNY Upstate Medical University
  • University of Cincinnati, Mayfield Clinic
  • Miami Valley Hospital
  • St Luke's University Hospital
  • University of Pittsburgh Medical Center
  • Texas Health Harris Methodist Hospital Fort Worth
  • Inova Fairfax Hospital
  • Charleston Area Medical Center
  • University of Wisconsin, Froedtert Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

NNZ-2566

Sodium Chloride (0.9%) for Injection

Arm Description

20 mg/kg intravenous bolus infusion over 10 minutes followed by a continuous intravenous infusion of 1 mg/kg/h (Cohort 1, n=20), 3 mg/kg/h (Cohort 2, n=20) or 6 mg/kg/h (Cohort 3, n=133) intravenous infusion for a total of 72 consecutive hours.

Intravenous bolus infusion over 10 minutes followed by a continuous intravenous infusion (Cohort 1, n=10), (Cohort 2, n=10) or (Cohort 3, n=67) intravenous infusion for a total of 72 consecutive hours.

Outcomes

Primary Outcome Measures

Reduced incidence, compared to placebo, of adverse events (AEs) and serious adverse events (SAEs)

Secondary Outcome Measures

Evidence of efficacy in modifying global outcomes by evaluating Glasgow Outcome Scale - Extended (GOS-E) and activities of daily living (Mayo-Portland Adaptability Inventory - 4th Edition (MPAI-4))
Improvement in cognitive and neuropsychological functioning.
Modification of the acute physiological processes in TBI by evaluating electroencephalographic (EEG) determinants in patients with moderate to severe TBI (defined as GCS 4-12), and biomarker levels.
Blood pharmacokinetics (PK) of an intravenous (i.v) dose of NNZ-2566 when administered as a 10-minute infusion immediately followed by a 72-hour infusion.

Full Information

First Posted
December 8, 2008
Last Updated
February 1, 2018
Sponsor
Neuren Pharmaceuticals Limited
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1. Study Identification

Unique Protocol Identification Number
NCT00805818
Brief Title
Study of NNZ-2566 in Patients With Traumatic Brain Injury
Acronym
INTREPID2566
Official Title
A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of NNZ-2566 in Patients With Traumatic Brain Injury
Study Type
Interventional

2. Study Status

Record Verification Date
February 2018
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
January 2016 (Actual)
Study Completion Date
January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Neuren Pharmaceuticals Limited

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine whether NNZ-2566 is safe and effective in the treatment of Traumatic Brain Injury (TBI).
Detailed Description
Moderate to severe traumatic brain injury frequently results in persistent problems with memory, attention span, mood and more complex brain functioning such as planning and organizing. There are currently no drugs available to reduce the brain damage or the persisting symptoms that result from TBI. The longer term goal of this study is to provide physicians with a safe and effective treatment for TBI.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain Injuries

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
261 (Actual)

8. Arms, Groups, and Interventions

Arm Title
NNZ-2566
Arm Type
Experimental
Arm Description
20 mg/kg intravenous bolus infusion over 10 minutes followed by a continuous intravenous infusion of 1 mg/kg/h (Cohort 1, n=20), 3 mg/kg/h (Cohort 2, n=20) or 6 mg/kg/h (Cohort 3, n=133) intravenous infusion for a total of 72 consecutive hours.
Arm Title
Sodium Chloride (0.9%) for Injection
Arm Type
Placebo Comparator
Arm Description
Intravenous bolus infusion over 10 minutes followed by a continuous intravenous infusion (Cohort 1, n=10), (Cohort 2, n=10) or (Cohort 3, n=67) intravenous infusion for a total of 72 consecutive hours.
Intervention Type
Drug
Intervention Name(s)
NNZ-2566
Other Intervention Name(s)
Glycyl-L-2-Methylprolyl-L-Glutamic Acid
Intervention Description
Solution for intravenous infusion. 20 mg/kg intravenous bolus infusion over 10 minutes followed by a continuous intravenous infusion of 1, 3, or 6 mg/kg/h for a total of 72 consecutive hours.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sodium Chloride 0.9% Injection
Intervention Description
Sodium Chloride 0.9% Injection
Primary Outcome Measure Information:
Title
Reduced incidence, compared to placebo, of adverse events (AEs) and serious adverse events (SAEs)
Time Frame
AEs to discharged or Day 30 post randomization, whichever occurs first, and SAEs through to 3 months (defined as 12-14 weeks), post randomization.
Secondary Outcome Measure Information:
Title
Evidence of efficacy in modifying global outcomes by evaluating Glasgow Outcome Scale - Extended (GOS-E) and activities of daily living (Mayo-Portland Adaptability Inventory - 4th Edition (MPAI-4))
Time Frame
1 month (defined as 4-6 weeks) and 3 months (defined as 12-14 weeks), post randomization.
Title
Improvement in cognitive and neuropsychological functioning.
Time Frame
1 month (defined as 4-6 weeks) and at 3 months (defined as 12-14 weeks), post randomization.
Title
Modification of the acute physiological processes in TBI by evaluating electroencephalographic (EEG) determinants in patients with moderate to severe TBI (defined as GCS 4-12), and biomarker levels.
Time Frame
Baseline through to 72 hours post-start of infusion.
Title
Blood pharmacokinetics (PK) of an intravenous (i.v) dose of NNZ-2566 when administered as a 10-minute infusion immediately followed by a 72-hour infusion.
Time Frame
Start of infusion through to 12 hours post infusion.

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Non-penetrating TBI. Male. Age 18-70 years. Admission to hospital. Post resuscitation GCS 4-12. Have at least one reactive pupil. Randomization within 7 hours of injury with the ability to receive investigational product within 8 hours of injury. Hemodynamically stable after resuscitation (systolic blood pressure (SBP) >100 mm Hg). Willing to undergo all neuropsychological and activities of daily living (ADL) testing (i.e. understand English, able to read, write, have sufficient motor dexterity and, be available for follow-up visits at 4-6 weeks and 12-14 weeks post injury). Exclusion Criteria: Penetrating brain injury. Spinal cord injury. Presence or known history of prior cerebral injury requiring hospitalization that would, in the opinion of the Investigator, interfere with or bias the assessment of efficacy. Non-traumatic brain injury. Known history of any medical or psychiatric disorder, or any severe concomitant disease, that in the opinion of the Investigator would interfere with or bias the assessment of efficacy. This includes the following: schizophrenia; bipolar disorder; major depressive disorder; post traumatic stress disorder (PTSD); generalized anxiety disorder; attention deficit hyperactivity disorder; neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease, vascular dementia, Diffuse Lewy Body Disease); stroke; brain tumor; multiple sclerosis (MS); seizure disorders; chronic pain disorder; alcoholism or substance abuse. Significant non-central nervous system (CNS) injuries sustained at the time of the TBI that in the opinion of the Investigator would interfere with or bias the assessment of efficacy. Weight >150 kg. Participation in another clinical trial within the previous 4 weeks. Clinical state requiring greater than 6 L colloid or crystalloid fluid resuscitation prior to randomization. Inability to obtain informed consent from legally acceptable representative. Prior enrollment in this study. QTc Exclusions. The study will use the exclusion criteria as defined in ICH Guideline E14 to exclude patients with a risk of QT/QTc prolongation, as follows: A marked baseline prolongation of corrected QT/QTc interval >450 ms. History of risk factors for torsade de pointes (e.g. heart failure, hypokalemia (serum potassium at screening (<3.0 mmol/L)or family history of long QT syndrome).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ross R Bullock, M.D., PhD
Organizational Affiliation
University of Miami, Lois Pope Life Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of South Alabama
City
Mobile
State/Province
Alabama
ZIP/Postal Code
36617
Country
United States
Facility Name
University of Arizona
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
Arrowhead Regional Medical Center
City
Colton
State/Province
California
ZIP/Postal Code
92324
Country
United States
Facility Name
Ronald Reagan UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of California, Davis Medical Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
University of Miami, Lois Pope Life Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
The Queen's Medical Center
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96813
Country
United States
Facility Name
Our Lady of the Lake Hospital
City
Baton Rouge
State/Province
Louisiana
ZIP/Postal Code
70808
Country
United States
Facility Name
Detroit Receiving Hospital and University Health Center
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Sinai Grace Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48235
Country
United States
Facility Name
Bronson Methodist Hospital
City
Kalamazoo
State/Province
Michigan
ZIP/Postal Code
49007
Country
United States
Facility Name
SUNY Upstate Medical University
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
University of Cincinnati, Mayfield Clinic
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Miami Valley Hospital
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45409
Country
United States
Facility Name
St Luke's University Hospital
City
Bethlehem
State/Province
Pennsylvania
ZIP/Postal Code
18015
Country
United States
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Texas Health Harris Methodist Hospital Fort Worth
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Inova Fairfax Hospital
City
Falls Church
State/Province
Virginia
ZIP/Postal Code
22042
Country
United States
Facility Name
Charleston Area Medical Center
City
Charleston
State/Province
West Virginia
ZIP/Postal Code
25304
Country
United States
Facility Name
University of Wisconsin, Froedtert Hospital
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31198061
Citation
Lee JW. The EEG Ictal-Interictal Continuum-A Metabolic Roar But a Whimper of a Functional Outcome. Epilepsy Curr. 2019 Jul-Aug;19(4):234-236. doi: 10.1177/1535759719855968. Epub 2019 Jun 14.
Results Reference
derived
PubMed Identifier
30624278
Citation
Lee H, Mizrahi MA, Hartings JA, Sharma S, Pahren L, Ngwenya LB, Moseley BD, Privitera M, Tortella FC, Foreman B. Continuous Electroencephalography After Moderate to Severe Traumatic Brain Injury. Crit Care Med. 2019 Apr;47(4):574-582. doi: 10.1097/CCM.0000000000003639.
Results Reference
derived
Links:
URL
http://www.neurenpharma.com
Description
Click here for more information about this study

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Study of NNZ-2566 in Patients With Traumatic Brain Injury

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