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Progesterone for the Treatment of Traumatic Brain Injury III (ProTECT)

Primary Purpose

Traumatic Brain Injury

Status
Terminated
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Progesterone
Placebo
Sponsored by
David Wright
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring Trauma, Brain Injury

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Moderate to severe brain injury (GCS 12-4)
  • Age 18 years or older
  • Blunt, closed head injury
  • Study drug initiated within 4 hours of injury

Exclusion Criteria:

  • Non-Survivable injury
  • Bilateral dilated unresponsive pupils
  • Severe intoxication (ETOH > 250 mg %)
  • Spinal cord injury with neurological deficits
  • Inability to perform activities of daily living prior to injury
  • Cardiopulmonary arrest
  • Status epilepticus on arrival
  • Systolic blood pressure (SBP) < 90 on arrival or for at least 5 minutes prior to enrollment
  • O2 Sat < 90 on arrival or for at least 5 minutes prior to enrollment
  • Prisoner or ward of state
  • Pregnant
  • Active breast or reproductive organ cancers
  • Known allergy to progesterone or intralipid components (egg yolk)
  • Known history of clotting disorder
  • Active thromboembolic event
  • Concern for inability to follow up at 6 months
  • Anyone listed in the Opt out registry

Sites / Locations

  • Maricopa Integrated Health System
  • Banner Good Samaritan
  • Scottsdale Healthcare
  • University of Arizona Medical Center
  • Santa Clara Valley Hospital
  • Stanford Medical Center
  • San Francisco General Hospital
  • Regional Medical Center-San Jose
  • Grady Memorial Hospital
  • University of Kentucky Medical Center
  • University of Maryland Shock Trauma
  • Detroit Receiving Hospital
  • Henry Ford Hospital
  • Sinai Grace Hospital
  • Hurley Medical Center
  • Beaumont Royal Oak Hospital
  • Hennepin County Medical Center
  • North Memorial Hospital
  • Regions Hospital
  • St. Johns Mercy Medical Center
  • Columbia New York Presbyterian Hospital
  • University Hospital
  • Oregon Health Sciences University
  • St. Luke's Hospital
  • Geisinger Medical Center
  • Penn State Milton S. Hershey Medical Center
  • Hahnemann University Hospital
  • University of Pennsylvania Hospital
  • Thomas Jefferson UniversityHospital
  • Temple University Hospital
  • Regional Medical Center/Elvis Presley Memorial Trauma Center (The MED)
  • Austin/Brackenridge
  • Memorial Hermann
  • Brooke Army Medical Center
  • Virginia Commonwealth
  • Froedtert East Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Progesterone

Placebo

Arm Description

Following a one hour loading dose of 0.714 mg/kg per infusion pump through a dedicated IV line, the study drug (progesterone) will be administered as a continuous intravenous infusion at 0.5 mg/kg/hr for 71 hours, then tapered over an additional 24 hours. To simplify the infusion protocol, a weight based dosing table will be used by the on-sight pharmacy to mix the correct dose for a 10 cc/hour continuous infusion over the 72 hour steady state period followed by three additional 8-hour decrements (7.5 cc/hr-5.0 cc/hr-2.5 cc/hr) to zero, for a total treatment duration of 96 hour. The progesterone will be combined with a 20% Intralipid mixture for infusion.

Placebo stock solution was the ethanol diluent required for dissolving progesterone. The volume of placebo to be mixed with intralipid was based on the same mg/kg/hr volume that would be required if PROG had been in the vial. Using an infusion pump through a dedicated IV line - a one hour "loading dose" of placebo plus intralipid was administered as a continuous intravenous infusion for 71 hours, then tapered over an additional 24 hours. To simplify the infusion protocol, a weight based dosing table was used by the on-sight pharmacy to mix the correct "dose" for a 10 cc/hour continuous infusion over the 72 hour steady state period followed by three additional 8-hour decrements (7.5 cc/hr-5.0 cc/hr-2.5 cc/hr) to zero, for a total treatment duration of 96 hour. The placebo will be combined with a 20% Intralipid mixture for infusion.

Outcomes

Primary Outcome Measures

Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE)
A measure of functional recovery: A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery. Favorable outcome was defined via stratified dichotomy based on the severity of the initial injury. For subjects with a severe injury, a GOS-E of 3 or higher were considered to be a favorable outcome; for subjects with moderate-to-severe injury, a GOS-E of 5 or higher was considered to be a favorable outcome; for subjects with a moderate injury, a GOS-E of 7 or higher was considered to be a favorable outcome.

Secondary Outcome Measures

Mortality
Disability Rating Scale
A measure of functional impairment, with complete recovery scored a 0 and vegetative state scored a 29.
Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis
Phlebitis/Thrombophlebitis (not due to infiltration or misplacement of the IV)
Potentially Associated Adverse Events: Pulmonary Embolism
Pulmonary embolism - Events were defined based on either positive chest computed tomography (CT) scanning or ventilation/perfusion lung scan (V/Q).
Potentially Associated Adverse Events: Acute Ischemic Stroke
Acute ischemic stroke - Events were defined based on either positive computed tomography (CT) scanning, magnetic resonance imaging (MRI), or neurologist diagnosis of cerebrovascular accident (CVA)
Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT)
DVT - Events were defined based on a positive Doppler ultrasound exam
Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level
Unexplained increased liver enzymes (e.g. not due to liver injury ) - Events were defined based on aspartate transaminase (AST) and alanine transaminase (ALT) levels > 500 U/L and/or total bilirubin levels > 2.0 mg/dL.
Potentially Associated Adverse Events: Sepsis
Sepsis - Events must have met Centers for Disease Control and Prevention (CDC) definition of sepsis. The definition includes that a patient ≤1 year of age has at least 1 of the following clinical signs or symptoms with no other recognized cause: fever (>38°C rectal), hypothermia (<37°C rectal), apnea, or bradycardia, and blood culture not done or no organisms detected in blood and no apparent infection at another site and physician institutes treatment for sepsis.
Potentially Associated Adverse Events: Pneumonia
Events must have met Centers for Disease Control and Prevention (CDC) definition of pneumonia. There are three specific types of pneumonia: clinically defined pneumonia, pneumonia with specific laboratory findings, and pneumonia in immunocompromised patients. There are specific algorithms to identify each pneumonia, which include x-ray findings, fever with no other cause, leukopenia or leukocytosis, altered mental status with no other cause (adults >70 years old), new onset of purulent sputum, change in character of sputum, increase respiratory secretions, increase suctioning requirements, new onset or worsening cough, dyspnea, tachypnea, rales, bronchial breath sounds, or worsening gas exchange, increased oxygen requirements, or increased ventilator demand). Also, labs can identify pneumonia such as positive growth in blood culture, positive Gram stain, and histopathologic exam evidence.
Potentially Associated Adverse Events: Central Nervous System (CNS) Infection
CNS infection - Events must have met Centers for Disease Control and Prevention (CDC) definition of CNS infection. The definition includes intracranial infection, Meningitis, ventriculitis, and spinal abscess without meningitis.
Potentially Associated Adverse Events: Myocardial Infarction (MI)
Myocardial infarction - Events were defined based on serial cardiac enzyme elevation consistent with MI and/or new ST elevation on electrocardiogram (ECG) consistent with MI. Potentially associated adverse events (those events which are included as outcome measures) were specifically defined per the protocol, and the classification of an event as a PAAE was determined by the site. The reported name of the associated event, however, was subject to clinical judgement and case details; these were then further coded by the Principal Investigator. Since these data points do not share the same definition, there is no reason to expect perfect concordance. (For example, the potentially associated adverse event of myocardial infarction may include MedDRA codes other than myocardial infarction.)

Full Information

First Posted
January 14, 2009
Last Updated
December 16, 2015
Sponsor
David Wright
Collaborators
Medical University of South Carolina, Neurological Emergencies Treatment Trials Network (NETT)
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1. Study Identification

Unique Protocol Identification Number
NCT00822900
Brief Title
Progesterone for the Treatment of Traumatic Brain Injury III
Acronym
ProTECT
Official Title
Phase 3 Clinical Trial to Determine if Progesterone Along With Standard Medical Care for Brain Injury is More Effective at Limiting the Amount of Damage Cause by a Traumatic Brain Injury Than Standard Medical Care Alone.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Terminated
Why Stopped
futility: low conditional power to demonstrate benefit of progesterone
Study Start Date
March 2010 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
July 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David Wright
Collaborators
Medical University of South Carolina, Neurological Emergencies Treatment Trials Network (NETT)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The ProTECT study will determine if intravenous (IV) progesterone (started within 4 hours of injury and given for a total of 96 hours), is more effective than placebo for treating victims of moderate to severe acute traumatic brain injury.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Traumatic Brain Injury
Keywords
Trauma, Brain Injury

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
882 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Progesterone
Arm Type
Experimental
Arm Description
Following a one hour loading dose of 0.714 mg/kg per infusion pump through a dedicated IV line, the study drug (progesterone) will be administered as a continuous intravenous infusion at 0.5 mg/kg/hr for 71 hours, then tapered over an additional 24 hours. To simplify the infusion protocol, a weight based dosing table will be used by the on-sight pharmacy to mix the correct dose for a 10 cc/hour continuous infusion over the 72 hour steady state period followed by three additional 8-hour decrements (7.5 cc/hr-5.0 cc/hr-2.5 cc/hr) to zero, for a total treatment duration of 96 hour. The progesterone will be combined with a 20% Intralipid mixture for infusion.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo stock solution was the ethanol diluent required for dissolving progesterone. The volume of placebo to be mixed with intralipid was based on the same mg/kg/hr volume that would be required if PROG had been in the vial. Using an infusion pump through a dedicated IV line - a one hour "loading dose" of placebo plus intralipid was administered as a continuous intravenous infusion for 71 hours, then tapered over an additional 24 hours. To simplify the infusion protocol, a weight based dosing table was used by the on-sight pharmacy to mix the correct "dose" for a 10 cc/hour continuous infusion over the 72 hour steady state period followed by three additional 8-hour decrements (7.5 cc/hr-5.0 cc/hr-2.5 cc/hr) to zero, for a total treatment duration of 96 hour. The placebo will be combined with a 20% Intralipid mixture for infusion.
Intervention Type
Drug
Intervention Name(s)
Progesterone
Intervention Description
Following a one hour loading dose of 0.714 mg/kg per infusion pump through a dedicated IV line, the study drug (progesterone or placebo) will be administered as a continuous intravenous infusion at 0.5 mg/kg/hr for 71 hours, then tapered over an additional 24 hours. To simplify the infusion protocol, a weight based dosing table will be used by the on-sight pharmacy to mix the correct dose for a 10 cc/hour continuous infusion over the 71 hour steady state period followed by three additional 8-hour decrements (7.5 cc/hr-5.0 cc/hr-2.5 cc/hr) to zero, for a total treatment duration of 96 hour. The progesterone/placebo will be combined with a 20% Intralipid mixture for infusion.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo stock solution is the ethanol diluent required for dissolving progesterone. The volume of placebo to be mixed with intralipid is based on the mg/kg/hr volume. Using an infusion pump through a dedicated IV line - a one hour "loading dose" of placebo plus intralipid is administered as a continuous intravenous infusion for 71 hours, then tapered over an additional 24 hours.
Primary Outcome Measure Information:
Title
Favorable Outcome as Determined by the Glasgow Outcome Scale-Extended (GOSE)
Description
A measure of functional recovery: A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery. Favorable outcome was defined via stratified dichotomy based on the severity of the initial injury. For subjects with a severe injury, a GOS-E of 3 or higher were considered to be a favorable outcome; for subjects with moderate-to-severe injury, a GOS-E of 5 or higher was considered to be a favorable outcome; for subjects with a moderate injury, a GOS-E of 7 or higher was considered to be a favorable outcome.
Time Frame
6 months post randomization
Secondary Outcome Measure Information:
Title
Mortality
Time Frame
6 months
Title
Disability Rating Scale
Description
A measure of functional impairment, with complete recovery scored a 0 and vegetative state scored a 29.
Time Frame
6 months
Title
Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis
Description
Phlebitis/Thrombophlebitis (not due to infiltration or misplacement of the IV)
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Pulmonary Embolism
Description
Pulmonary embolism - Events were defined based on either positive chest computed tomography (CT) scanning or ventilation/perfusion lung scan (V/Q).
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Acute Ischemic Stroke
Description
Acute ischemic stroke - Events were defined based on either positive computed tomography (CT) scanning, magnetic resonance imaging (MRI), or neurologist diagnosis of cerebrovascular accident (CVA)
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT)
Description
DVT - Events were defined based on a positive Doppler ultrasound exam
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Unexplained Increased Liver-enzyme Level
Description
Unexplained increased liver enzymes (e.g. not due to liver injury ) - Events were defined based on aspartate transaminase (AST) and alanine transaminase (ALT) levels > 500 U/L and/or total bilirubin levels > 2.0 mg/dL.
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Sepsis
Description
Sepsis - Events must have met Centers for Disease Control and Prevention (CDC) definition of sepsis. The definition includes that a patient ≤1 year of age has at least 1 of the following clinical signs or symptoms with no other recognized cause: fever (>38°C rectal), hypothermia (<37°C rectal), apnea, or bradycardia, and blood culture not done or no organisms detected in blood and no apparent infection at another site and physician institutes treatment for sepsis.
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Pneumonia
Description
Events must have met Centers for Disease Control and Prevention (CDC) definition of pneumonia. There are three specific types of pneumonia: clinically defined pneumonia, pneumonia with specific laboratory findings, and pneumonia in immunocompromised patients. There are specific algorithms to identify each pneumonia, which include x-ray findings, fever with no other cause, leukopenia or leukocytosis, altered mental status with no other cause (adults >70 years old), new onset of purulent sputum, change in character of sputum, increase respiratory secretions, increase suctioning requirements, new onset or worsening cough, dyspnea, tachypnea, rales, bronchial breath sounds, or worsening gas exchange, increased oxygen requirements, or increased ventilator demand). Also, labs can identify pneumonia such as positive growth in blood culture, positive Gram stain, and histopathologic exam evidence.
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Central Nervous System (CNS) Infection
Description
CNS infection - Events must have met Centers for Disease Control and Prevention (CDC) definition of CNS infection. The definition includes intracranial infection, Meningitis, ventriculitis, and spinal abscess without meningitis.
Time Frame
within 6 months
Title
Potentially Associated Adverse Events: Myocardial Infarction (MI)
Description
Myocardial infarction - Events were defined based on serial cardiac enzyme elevation consistent with MI and/or new ST elevation on electrocardiogram (ECG) consistent with MI. Potentially associated adverse events (those events which are included as outcome measures) were specifically defined per the protocol, and the classification of an event as a PAAE was determined by the site. The reported name of the associated event, however, was subject to clinical judgement and case details; these were then further coded by the Principal Investigator. Since these data points do not share the same definition, there is no reason to expect perfect concordance. (For example, the potentially associated adverse event of myocardial infarction may include MedDRA codes other than myocardial infarction.)
Time Frame
within 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Moderate to severe brain injury (GCS 12-4) Age 18 years or older Blunt, closed head injury Study drug initiated within 4 hours of injury Exclusion Criteria: Non-Survivable injury Bilateral dilated unresponsive pupils Severe intoxication (ETOH > 250 mg %) Spinal cord injury with neurological deficits Inability to perform activities of daily living prior to injury Cardiopulmonary arrest Status epilepticus on arrival Systolic blood pressure (SBP) < 90 on arrival or for at least 5 minutes prior to enrollment O2 Sat < 90 on arrival or for at least 5 minutes prior to enrollment Prisoner or ward of state Pregnant Active breast or reproductive organ cancers Known allergy to progesterone or intralipid components (egg yolk) Known history of clotting disorder Active thromboembolic event Concern for inability to follow up at 6 months Anyone listed in the Opt out registry
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David W Wright, MD
Organizational Affiliation
Emory University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Maricopa Integrated Health System
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85008
Country
United States
Facility Name
Banner Good Samaritan
City
Phoenix
State/Province
Arizona
Country
United States
Facility Name
Scottsdale Healthcare
City
Scottsdale
State/Province
Arizona
Country
United States
Facility Name
University of Arizona Medical Center
City
Tuscon
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
Santa Clara Valley Hospital
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Stanford Medical Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
San Francisco General Hospital
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
Regional Medical Center-San Jose
City
San Jose
State/Province
California
Country
United States
Facility Name
Grady Memorial Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30303
Country
United States
Facility Name
University of Kentucky Medical Center
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
University of Maryland Shock Trauma
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Detroit Receiving Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Sinai Grace Hospital
City
Detroit
State/Province
Michigan
Country
United States
Facility Name
Hurley Medical Center
City
Flint
State/Province
Michigan
ZIP/Postal Code
48503
Country
United States
Facility Name
Beaumont Royal Oak Hospital
City
Royal Oak
State/Province
Michigan
ZIP/Postal Code
48073
Country
United States
Facility Name
Hennepin County Medical Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55414
Country
United States
Facility Name
North Memorial Hospital
City
Robbinsdale
State/Province
Minnesota
Country
United States
Facility Name
Regions Hospital
City
St. Paul
State/Province
Minnesota
ZIP/Postal Code
55101
Country
United States
Facility Name
St. Johns Mercy Medical Center
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63141
Country
United States
Facility Name
Columbia New York Presbyterian Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University Hospital
City
Cincinnatti
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
Oregon Health Sciences University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
St. Luke's Hospital
City
Bethlehem
State/Province
Pennsylvania
ZIP/Postal Code
18017
Country
United States
Facility Name
Geisinger Medical Center
City
Danville
State/Province
Pennsylvania
Country
United States
Facility Name
Penn State Milton S. Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
Hahnemann University Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19102
Country
United States
Facility Name
University of Pennsylvania Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Thomas Jefferson UniversityHospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Temple University Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
Regional Medical Center/Elvis Presley Memorial Trauma Center (The MED)
City
Memphis
State/Province
Tennessee
Country
United States
Facility Name
Austin/Brackenridge
City
Austin
State/Province
Texas
ZIP/Postal Code
78752
Country
United States
Facility Name
Memorial Hermann
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Brooke Army Medical Center
City
San Antonio
State/Province
Texas
Country
United States
Facility Name
Virginia Commonwealth
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
Froedtert East Hospital
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26464429
Citation
Zhao W, Pauls K. Architecture design of a generic centralized adjudication module integrated in a web-based clinical trial management system. Clin Trials. 2016 Apr;13(2):223-33. doi: 10.1177/1740774515611889. Epub 2015 Oct 13.
Results Reference
derived
PubMed Identifier
25493974
Citation
Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, Manley GT, Merck LH, Janis LS, Barsan WG; NETT Investigators. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014 Dec 25;371(26):2457-66. doi: 10.1056/NEJMoa1404304. Epub 2014 Dec 10.
Results Reference
derived
Links:
URL
http://sitemaker.umich.edu/protect/home
Description
Related Info

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Progesterone for the Treatment of Traumatic Brain Injury III

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