Multicenter Efficacy Study of Recombinant Human Erythropoietin in Acute Ischemic Stroke (ESS)

German Multicenter EPO Stroke Trial (Phase II/III)

The purpose of this randomized, double-blind, placebo-controlled multicenter study is to determine in a cohort of 506 patients with acute ischemic stroke in the middle cerebral artery territory, the effect of a three-day high-dose, intravenous erythropoietin treatment on functional outcome up to a follow-up of 90 days.

Study Overview

• Status: Completed
• Conditions: Infarction, Middle Cerebral Artery; Stroke, Acute; Middle Cerebral Artery Stroke
• Intervention / Treatment: Drug: 0.9% NaCl; Drug: recombinant human erythropoietin alfa

• Study Type: Interventional
• Enrollment (Actual): 522
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Braunschweig, Germany, D-38126
    • Neurologische Klinik des Städtischen Klinikums Braunschweig
  • Bremen, Germany, D-28177
    • Neurologische Klink, Klinikum Bremen-Mitte
  • Celle, Germany, D-29223
    • Neurologische Klinik, Allgemeines Krankenhaus Celle
  • Dresden, Germany, D-01307
    • Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus der TU Dresden
  • Erlangen, Germany, D-91054
    • Neurologische Klinik, Universität Erlangen-Nürnberg
  • Essen, Germany, D-45147
    • Klinik für Neurologie, Universität Essen
  • Goettingen, Germany, D-37075
    • Neurologische Universitätsklinik der Georg-August-Universität Goettingen
  • Hannover, Germany, D-30625
    • Neurologische Klinik, Medizinische Hochschule Hannover
  • Leipzig, Germany, D-04103
    • Klinik und Poliklinik für Neurologie der Universität Leipzig

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:

• Ischemic stroke in the middle cerebral artery territory
• Clearly defined time of onset
• Confirmed by MRI (DWI, Flair)
• NIH Stroke Scale ≥ 5
• Age > 18 years
• Treatment within 6h after onset of symptoms
• Informed consent by patient, relatives or independent physician
• Life expectancy > 90 days

Exclusion Criteria:

• Coma or precoma (level of consciousness ≥ 2 in NIH Stroke Scale)
• Previous stroke within the same territory
• Intracranial or subarachnoidal hemorrhage
• Traumatic brain injury or brain operation within the last 4 weeks
• Neoplasia, septic embolism, infectious endocarditis
• MRI contraindications
• Renal failure (i.e. dependent on dialysis)
• Known malignant/life-threatening disease
• Known myeloproliferative disorder, polycythemia
• Known allergy or antibodies against erythropoietin
• Participation in other intervention trials
• Pregnancy

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
Placebo Comparator: placebo; 50ml 0.9% NaCL	Drug: 0.9% NaCl; 50ml 0.9% NaCl iv on 3 consecutive days, starting within 6 hours after onset of symptoms
Active Comparator: verum; erythropoietin alfa 40,000 IU iv in 50ml 0.9% NaCl	Drug: recombinant human erythropoietin alfa; 40,000 IU in 50ml 0.9% NaCl iv on 3 consecutive days, starting within 6 hours after onset of symptoms; Other Names: ERYPO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Neurological/functional outcome as measured by the Barthel Index (BI)	day 90

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	day 90
Modified Rankin Scale (mRS) responder	day 90
Barthel Index (BI)	day 30
mRS	day30, day 90
NIH Stroke Scale	day 1, 3, 7, 30, 90
Proportion of subjects with minimal disability (mRS 0-1)	day 30, day 90
All-cause mortality	day 90
Mortality directly related to stroke	day 90
Proportion of subjects with BI >= 95	day 30, day 90
Proportion of subjects with BI=100	day 30, day 90
Proportion of subjects with neurological recovery	day 3, 7, 30, 90
Distribution of mRS scores	day 30, day 90
Distribution of BI scores	day 30, day 90
Distribution of NIH Stroke Scale scores	day 30, day 90
Serum level of glial damage markers S100B and GFAP	day 1, 2, 3, 4, 7
Lesion size (MRI DWI, flair)	day 1, day 7
Late recovery index (BI day 90 versus BI day 30)	day 30 to day 90

Collaborators and Investigators

• Sponsor: Max-Planck-Institute of Experimental Medicine
• Collaborators: Johnson & Johnson; Parexel

Publications and helpful links

General Publications

• Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002 Aug;8(8):495-505.
• Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):4044-9. doi: 10.1073/pnas.051606598. Epub 2001 Mar 20.
• Lewczuk P, Hasselblatt M, Kamrowski-Kruck H, Heyer A, Unzicker C, Siren AL, Ehrenreich H. Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroreport. 2000 Nov 9;11(16):3485-8. doi: 10.1097/00001756-200011090-00017.
• Siren AL, Knerlich F, Poser W, Gleiter CH, Bruck W, Ehrenreich H. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol. 2001 Mar;101(3):271-6. doi: 10.1007/s004010000297.
• Herrmann M, Ehrenreich H. Brain derived proteins as markers of acute stroke: their relation to pathophysiology, outcome prediction and neuroprotective drug monitoring. Restor Neurol Neurosci. 2003;21(3-4):177-90.
• Ehrenreich H, Hasselblatt M, Knerlich F, von Ahsen N, Jacob S, Sperling S, Woldt H, Vehmeyer K, Nave KA, Siren AL. A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):862-7. doi: 10.1073/pnas.0406008102. Epub 2005 Jan 10.
• Siren AL, Radyushkin K, Boretius S, Kammer D, Riechers CC, Natt O, Sargin D, Watanabe T, Sperling S, Michaelis T, Price J, Meyer B, Frahm J, Ehrenreich H. Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain. 2006 Feb;129(Pt 2):480-9. doi: 10.1093/brain/awh703. Epub 2005 Dec 9.
• Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S, Heinz G, Erdag S, Jahn H, Degner D, Ritzen M, Mohr A, Wagner M, Schneider U, Bohn M, Huber M, Czernik A, Pollmacher T, Maier W, Siren AL, Klosterkotter J, Falkai P, Ruther E, Aldenhoff JB, Krampe H. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry. 2007 Feb;12(2):206-20. doi: 10.1038/sj.mp.4001907. Epub 2006 Oct 10.
• Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M, Siren AL, Paulus W, Nave KA, Gold R, Bartels C. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain. 2007 Oct;130(Pt 10):2577-88. doi: 10.1093/brain/awm203. Epub 2007 Aug 29.
• Woywodt A, Gerdes S, Ahl B, Erdbruegger U, Haubitz M, Weissenborn K. Circulating endothelial cells and stroke: influence of stroke subtypes and changes during the course of disease. J Stroke Cerebrovasc Dis. 2012 Aug;21(6):452-8. doi: 10.1016/j.jstrokecerebrovasdis.2010.11.003.
• Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jahnig P, Herrmann M, Knauth M, Bahr M, Heide W, Wagner A, Schwab S, Reichmann H, Schwendemann G, Dengler R, Kastrup A, Bartels C; EPO Stroke Trial Group. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009 Dec;40(12):e647-56. doi: 10.1161/STROKEAHA.109.564872. Epub 2009 Oct 15.

Helpful Links

• homepage of the Max-Planck-Institute of Experimental Medicine
• information about the German Multicenter EPO Stroke Study and previous related trials

Study record dates

Study Major Dates

• Study Start: January 1, 2003
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: January 17, 2008
• First Submitted That Met QC Criteria: January 29, 2008
• First Posted (Estimate): January 30, 2008

Study Record Updates

• Last Update Posted (Estimate): October 22, 2008
• Last Update Submitted That Met QC Criteria: October 21, 2008
• Last Verified: September 1, 2008

More Information

Terms related to this study

• Keywords: thrombolysis; stroke; erythropoietin; ischemia; hypoxia; neuroprotection; EPO; rtPA; antiapoptosis; stroke, middle cerebral artery; Ischemic stroke in the middle cerebral artery territory
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Brain Infarction; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebral Infarction; Infarction; Stroke; Infarction, Middle Cerebral Artery; Hematinics; Epoetin Alfa
• Other Study ID Numbers: BfArM-4019639/2002; "EPO Stroke Study"; "Ehrenreich EPO Stroke Study"; "Ehrenreich Study"