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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Progesterone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 882
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Maricopa Integrated Health System
    • Phoenix, Arizona, United States
      • Banner Good Samaritan
    • Scottsdale, Arizona, United States
      • Scottsdale Healthcare
    • Tuscon, Arizona, United States, 85724
      • University of Arizona Medical Center
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Medical Center
    • Palo Alto, California, United States, 94304
      • Santa Clara Valley Hospital
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital
    • San Jose, California, United States
      • Regional Medical Center-San Jose
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Shock Trauma
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48202
      • Detroit Receiving Hospital
    • Detroit, Michigan, United States
      • Sinai Grace Hospital
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Royal Oak Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • Hennepin County Medical Center
    • Robbinsdale, Minnesota, United States
      • North Memorial Hospital
    • St. Paul, Minnesota, United States, 55101
      • Regions Hospital
  • Missouri
    • St. Louis, Missouri, United States, 63141
      • St. Johns Mercy Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia New York Presbyterian Hospital
  • Ohio
    • Cincinnatti, Ohio, United States, 45267
      • University Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • St. Luke's Hospital
    • Danville, Pennsylvania, United States
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19102
      • Hahnemann University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Hospital
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson UniversityHospital
  • Tennessee
    • Memphis, Tennessee, United States
      • Regional Medical Center/Elvis Presley Memorial Trauma Center (The MED)
  • Texas
    • Austin, Texas, United States, 78752
      • Austin/Brackenridge
    • Houston, Texas, United States, 77030
      • Memorial Hermann
    • San Antonio, Texas, United States
      • Brooke Army Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert East Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Progesterone; 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.	Drug: Progesterone; 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.
Placebo Comparator: Placebo; 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.	Drug: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 months post randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		6 months
Disability Rating Scale	A measure of functional impairment, with complete recovery scored a 0 and vegetative state scored a 29.	6 months
Potentially Associated Adverse Events: Phlebitis/Thrombophlebitis	Phlebitis/Thrombophlebitis (not due to infiltration or misplacement of the IV)	within 6 months
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).	within 6 months
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)	within 6 months
Potentially Associated Adverse Events: Deep Venous Thrombosis (DVT)	DVT - Events were defined based on a positive Doppler ultrasound exam	within 6 months
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.	within 6 months
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.	within 6 months
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.	within 6 months
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.	within 6 months
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.)	within 6 months

Collaborators and Investigators

• Sponsor: David Wright
• Collaborators: Medical University of South Carolina; Neurological Emergencies Treatment Trials Network (NETT)

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: January 14, 2009
• First Submitted That Met QC Criteria: January 14, 2009
• First Posted (Estimate): January 15, 2009

Study Record Updates

• Last Update Posted (Estimate): January 20, 2016
• Last Update Submitted That Met QC Criteria: December 16, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Brain Injury; Trauma
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: IRB00014409; 1RO1 NS062778-01