Efficacy and Safety Study of Intravenous Progesterone in Patients With Severe Traumatic Brain Injury

Brain Injuries Clinical Trial

— SyNAPSe  

Official title:

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study to Investigate the Efficacy and Safety of Progesterone in Patients With Severe Traumatic Brain Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01143064
• Other study ID #: BHR-100-301
• Secondary ID: 2010-018283-16
• Status: Completed
• Phase: Phase 3
• First received: June 10, 2010
• Last updated: June 11, 2014
• Start date: June 2010
• Est. completion date: March 2014

Study information

• Verified date: June 2014
• Source: BHR Pharma, LLC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustria: Agency for Health and Food SafetyBelgium: Federal Agency for Medicinal Products and Health ProductsChina: Food and Drug AdministrationCzech Republic: State Institute for Drug ControlFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of PharmacyIsrael: Ministry of HealthItaly: Ministry of HealthMalaysia: Ministry of HealthNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Romania: National Medicines AgencyRussia: Ministry of Health of the Russian FederationSingapore: Health Sciences AuthoritySpain: Agencia Española de Medicamentos y Productos SanitariosTaiwan: Center for Drug EvaluationThailand: Food and Drug AdministrationUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

The SyNAPSe trial will study if giving intravenous (i.v.) progesterone within 8 hours of the injury for a total of 120 hours to severe traumatic brain injury patients improves their recovery.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1195
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Male or female patients between the age of 16 and 70 years, inclusive

2. Weight from 45 to 135 kg, inclusive

3. Sustained a closed head trauma no more than 8 hours before start of study drug infusion

4. TBI diagnosed by history and clinical examination

5. Post-resuscitation Glasgow Coma Scale (GCS) score between 3 to 8, inclusive

6. At least one reactive pupil (pinpoint pupils due to opioid pain treatment are considered reactive)

7. Evidence of TBI confirmed by abnormalities consistent with trauma on CT scan upon admission (diffuse injury II-IV, evacuated and non-evacuated mass lesion, Marshall's CT Classification)

8. Indication for ICP monitoring

Exclusion Criteria:

1. Life expectancy of less than 24 hours as determined by the Investigator

2. Prolonged and/or uncorrectable hypoxia (Pa02< 60 mmHg) or hypotension (systolic blood pressure < 90 mmHg) at the time of randomization

3. Any spinal cord injury

4. Pregnancy

5. Penetrating head injury

6. Bilaterally fixed dilated pupils at the time of randomization

7. Coma suspected to be primarily due to other causes (e.g. alcohol)

8. Pure epidural hematoma

9. Preexisting clinically significant disease or chronic condition that can be ascertained at the time of admission and could affect functional outcome

10. Severe cardiac or hemodynamic instability prior to randomization

11. Known treatment with another investigational drug therapy or procedure within 30 days of injury

12. A history of allergic reaction to progesterone and related drugs or any of the components of the infusion

13. Any disease, in the opinion of the Investigator, that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study.

14. Patients who, in the opinion of the Investigator, would not be able or willing to comply with the protocol through the final visit (6 months post-injury)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Injuries

Intervention

Drug:
• Progesterone
Intravenous administration of 0.71mg/kg/hr for 1hr followed by 0.5mg/kg/hr administered intravenously for an additional 119 hrs.
• Lipid emulsion without progesterone
Intravenous administration equal to 0.71mg/kg/hr for 1hr followed by 0.5mg/kg/hr administered intravenously for an additional 119 hrs.

Locations

Country	Name	City	State
Argentina	Hospital Francisco Lopez Lima	General Roca	Rio Negro
Argentina	Hospital Central de Mendoza	Mendoza
Argentina	Hospital San Martin	Paraná
Argentina	Hospital Nacional "Profesor Alejandro Posadas"	Provincia de Buenos Aires
Argentina	Hospital Regional De Comodoro Rivadavia (HRCR)	Provincia de Chubut
Argentina	Hospital de Emergencias Clemente Alvarez (HECA)	Rosario	Santa Fe
Argentina	Hospital Dr. José Maria Cullen	Santa Fé
Austria	Medizinische Universität Graz	Graz
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Unfallkrankenhaus Salzburg	Salzburg
Austria	Landesklinikum Wiener Neustadt	Vienna
Belgium	ULB Erasme	Brussels
Belgium	Ziekenhuis Oost-Limburg, Location Sint Jan	Genk
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	University Hospital of the Free University Brussels (UZ Brussel)	Jette
Belgium	University Hospital Gasthuisberg	Leuven
China	Chengdu Military General Hospital	Chengdu
China	The First Affiliated Hospital of Fujian Medical University	Fuzhou
China	The 2nd Affiliated Hospital of Zhejiang University	Hangzhou
China	The Second Hospital of Shandong University	Jinan
China	Huashan Hospital of Fudan University	Shanghai
China	Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai
China	General Hospital of Tianjin Medical University	Tianjin
China	The Affiliated Hospital of Xuzhou Medical College	Xuzhou
Czech Republic	Fakultní nemocnice Brno Neurochirurgická klinika	Brno
Czech Republic	Fakultní nemocnice u sv. Anny v Brne, Neurochirurgická klinika	Brno
Czech Republic	Fakultní Nemocnice Plzen, Neurochirurgicé Oddelení	Plzen
Czech Republic	Fakultní nemocnice Kralovske Vinohrady	Praha
Finland	Tampere University Hospital	Tampere
France	Groupe Hospitalier Pellegrin	Bordeaux
France	Hôpital Pierre Wertheimer	Bron
France	Centre Hospitalier Universitaire de Grenoble- Hópital Michallon	La Tronche
France	CHRU de Lille- Hópital Roger Salengro	Lille
France	Centre Hospitalier Universitaire de Limoges	Limoges
France	Centre Hospitalier Universitaire Hôpital Nord	Marseille
France	Hópital Central - CHU de Nancy	Nancy
France	Groupe Hospitalier La Salpêtrière	Paris
Germany	Charité - Universitätsmedizin Berlin	Berlin
Germany	Klinikum der J.W. Goethe-Universität	Frankfurt
Germany	Universitätsmedizin Göttingen	Göttingen
Germany	Berufsgenossenschaftliche Kliniken	Halle
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Krankenhaus Merheim	Köln
Germany	Universitätsklinikum Gießen und Marburg gGmbH	Marburg
Germany	Klinikum Nürnberg	Nürnberg
Germany	Niels-Stensen-Kliniken	Osnabrück
Germany	Universitätsklinikum Ulm	Ulm
Hungary	Honvédelmi Minisztérium Állami Egészségügyi Központ	Budapest
Hungary	Pécsi Tudományegyetem Általános Orvostudományi Kar	Pécs
Hungary	Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ	Szeged
Israel	Rambam Medical Center	Haifa
Israel	Hadassah Medical Organization	Jerusalem
Israel	Rabin Medical Center	Petach-Tikva
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Israel	Chaim Sheba Medical Center	Tel-Hashomer
Italy	Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena	Milano
Italy	Fondazione San Raffaele del Monte Tabor	Milano
Italy	Azienda Ospedaliera San Gerardo	Monza
Italy	Azienda Ospedaliero Universitaria Maggiore della Caritá	Novara
Italy	Azienda Ospedaliera San Camillo Forlanini	Rome
Italy	Azienda Ospedaliero Universitaria Integrata di Verona	Verona
Malaysia	Hospital Raja Permaisuri Bainun	Ipoh, Perak
Malaysia	Hospital Kuala Lumpur	Kuala Lumpur
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Malaysia	Hospital Tengku Ampuan Afzan	Kuantan, Pahang
Malaysia	Sarawak General Hospital	Kuching, Sarawak
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Romania	Spitalul Clinic Judetean de Urgenta Timisoara	Timisoara
Russian Federation	State Budget Educational Institution of Higher Professional Education "Kemerovskaya State Medical Academy of Federal Agency of Healthcare and Social Development"	Kemerovo
Russian Federation	State Professional Institution of High Professional Education "Krasnoyarsk State Medical University named after Prof. V.F. Voyno-Yasenetsky of Ministry of Health and Social Development"	Krasnoyarsk
Russian Federation	State Institution "Burdenko Neurosurgical Institute of RAMS"	Moscow
Russian Federation	State Healthcare Facility "Murmansk Regional Clinical Hospital n.a. Bayandin"	Murmansk
Russian Federation	Saint Petersburg Healthcare Institution "City Mariinsky Hospital"	St. Petersburg
Russian Federation	State Institution of Health Care "Sverdlovsk Regional Clinical Hospital #1"	Yekaterinburg
Singapore	National Neuroscience Institute	Singapore
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Universitario de Bellvitge	Barcelona
Spain	Hospital Universitario Vall Hebrón	Barcelona
Spain	Hospital Universitario de Girona Dr. Josep Trueta	Girona
Spain	Hospital Universitario de Gran Canaria Dr. Negrín	Las Palmas de Gran Canaria
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitari Son Espases	Palma de Mallorca
Spain	Hospital Parc Taulí	Sabadell	Barcelona
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Clínico Universitario De Valencia	Valencia
Spain	Hospital Universitari i Politecnic La Fé de Valencia	Valencia
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
Thailand	Chiang Mai University	Chiang Mai
Thailand	Faculty of Medicine, Prince of Songkla University	Hat yai
Thailand	Khon Kaen Hospital	Khon Kaen
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	University Hospital Coventry	Coventry
United Kingdom	Royal Preston Hospital	Fulwood	Preston
United Kingdom	Leeds Teaching Hospitals NHS, Leeds General Infirmary	Leeds
United Kingdom	The Royal London Hospital	London
United Kingdom	The James Cook University Hospital	Middlesbrough
United Kingdom	Southampton University Hospital	Southampton
United States	Summa Health System	Akron	Ohio
United States	Albany Medical Center Hospital	Albany	New York
United States	Mission Hospital	Asheville	North Carolina
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Saint Alphonsus Regional Medical Center	Boise	Idaho
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	John H. Stroger Jr. Hospital of Cook County	Chicago	Illinois
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	University of Missouri Health Care	Columbia	Missouri
United States	University of South Carolina School of Medicine	Columbia	South Carolina
United States	Miami Valley Hospital	Dayton	Ohio
United States	Delray Medical Center	Delray Beach	Florida
United States	Denver Health Medical Center	Denver	Colorado
United States	Mercy Medical Center	Des Moines	Iowa
United States	Duke University Medical Center	Durham	North Carolina
United States	Texas Tech University Health Sciences Center	El Paso	Texas
United States	Marshall University Joan C. Edwards School of Medicine	Huntington	West Virginia
United States	Methodist Hospital	Indianapolis	Indiana
United States	Wishard Health Services	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Johnson City Medical Center	Johnson City	Tennessee
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Truman Medical Center Hospital Hill	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	LAC+USC Medical Center	Los Angeles	California
United States	University of Louisville Hospital	Louisville	Kentucky
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	University of South Alabama Medical Center	Mobile	Alabama
United States	West Virginia University Hospital	Morgantown	West Virginia
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Christiana Care Health System Hospital	Newark	Delaware
United States	OU Medical Center	Oklahoma City	Oklahoma
United States	The Nebraska Medical Center	Omaha	Nebraska
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Hospital & Health Center	Portland	Oregon
United States	Maine Medical Center	Portland	Maine
United States	St. Mary's of Michigan	Saginaw	Michigan
United States	University of California San Diego Medical Center	San Diego	California
United States	LSU Health - Shreveport	Shreveport	Louisiana
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Lester E. Cox Memorial Hospital	Springfield	Missouri
United States	Saint John's Hospital	Springfield	Illinois
United States	Tallahassee Memorial Healthcare	Tallahassee	Florida
United States	Tampa General Hospital	Tampa	Florida
United States	Westchester Medical Center	Valhalla	New York
United States	Wake Forest University-Baptist Medical Center	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts
United States	St. Elizabeth Health Center	Youngstown	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
BHR Pharma, LLC	INC Research, PRA Health Sciences

Countries where clinical trial is conducted

United States,  Argentina,  Austria,  Belgium,  China,  Czech Republic,  Finland,  France,  Germany,  Hungary,  Israel,  Italy,  Malaysia,  Netherlands,  Romania,  Russian Federation,  Singapore,  Spain,  Taiwan,  Thailand,  United Kingdom, 

References & Publications (2)

Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007 Apr;49(4):391-402, 402.e1-2. Epub 2006 Sep 29. — View Citation

Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12(2):R61. doi: 10.1186/cc6887. Epub 2008 Apr 30. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Glasgow Outcome Scale (GOS)	The GOS (Jennett and Bond, 1975) assesses mortality and disability in traumatic brain injury (TBI) patients according to the designation: Good Recovery, Moderate Disability, Severe Disability, Vegetative State or Dead.	6 months	No
Secondary	Mortality	The mortality rate at one and six months will be compared between the two treatment groups.	1 month and 6 months post injury	Yes
Secondary	Glasgow Outcome Scale		Month 3	No
Secondary	Glasgow Outcome Scale - Extended (GOS-E)	The GOS-E assessment of mortality and disability in TBI patients extends the original five GOS categories of functional outcome to eight categories: Dead; Vegetative State; Lower Severe Disability; Upper Severe Disability; Lower Moderate Disability; Upper Moderate Disability; Lower Good Recovery; Upper Good Recovery	3 months and 6 months post injury	No
Secondary	Short Form (36) Health Survey (SF-36)	The SF-36 is a validated survey of patient health consisting of eight scaled scores. The eight sections are: vitality; physical functioning; bodily pain; general health perceptions; role physical; role emotional; role mental; mental health; The 8 scales can also be further summarized to provide a summary score for physical health and a summary score for mental health.	3 months and 6 months post injury	No
Secondary	Effect of progesterone on Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP), and Therapeutic Intensity Level (TIL)		Admission through post-infusion Day 6	No
Secondary	Effect of progesterone on the progression of intracranial pathology		Admission and Day 6 computed tomography (CT) scans	No

External Links

•   Sponsor website
•   Trial website