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

Primary Purpose

Infarction, Middle Cerebral Artery, Middle Cerebral Artery Stroke, Stroke, Acute

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
recombinant human erythropoietin alfa
0.9% NaCl
Sponsored by
Max-Planck-Institute of Experimental Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Infarction, Middle Cerebral Artery focused on measuring stroke, EPO, erythropoietin, ischemia, hypoxia, antiapoptosis, neuroprotection, rtPA, thrombolysis, stroke, middle cerebral artery, Ischemic stroke in the middle cerebral artery territory

Eligibility Criteria

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

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

Sites / Locations

  • Neurologische Klinik des Städtischen Klinikums Braunschweig
  • Neurologische Klink, Klinikum Bremen-Mitte
  • Neurologische Klinik, Allgemeines Krankenhaus Celle
  • Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus der TU Dresden
  • Neurologische Klinik, Universität Erlangen-Nürnberg
  • Klinik für Neurologie, Universität Essen
  • Neurologische Universitätsklinik der Georg-August-Universität Goettingen
  • Neurologische Klinik, Medizinische Hochschule Hannover
  • Klinik und Poliklinik für Neurologie der Universität Leipzig

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

placebo

verum

Arm Description

50ml 0.9% NaCL

erythropoietin alfa 40,000 IU iv in 50ml 0.9% NaCl

Outcomes

Primary Outcome Measures

Neurological/functional outcome as measured by the Barthel Index (BI)

Secondary Outcome Measures

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

Full Information

First Posted
January 17, 2008
Last Updated
October 21, 2008
Sponsor
Max-Planck-Institute of Experimental Medicine
Collaborators
Johnson & Johnson, Parexel
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1. Study Identification

Unique Protocol Identification Number
NCT00604630
Brief Title
Multicenter Efficacy Study of Recombinant Human Erythropoietin in Acute Ischemic Stroke
Acronym
ESS
Official Title
German Multicenter EPO Stroke Trial (Phase II/III)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2008
Overall Recruitment Status
Completed
Study Start Date
January 2003 (undefined)
Primary Completion Date
June 2008 (Actual)
Study Completion Date
June 2008 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Max-Planck-Institute of Experimental Medicine
Collaborators
Johnson & Johnson, Parexel

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Infarction, Middle Cerebral Artery, Middle Cerebral Artery Stroke, Stroke, Acute
Keywords
stroke, EPO, erythropoietin, ischemia, hypoxia, antiapoptosis, neuroprotection, rtPA, thrombolysis, stroke, middle cerebral artery, Ischemic stroke in the middle cerebral artery territory

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
522 (Actual)

8. Arms, Groups, and Interventions

Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
50ml 0.9% NaCL
Arm Title
verum
Arm Type
Active Comparator
Arm Description
erythropoietin alfa 40,000 IU iv in 50ml 0.9% NaCl
Intervention Type
Drug
Intervention Name(s)
recombinant human erythropoietin alfa
Other Intervention Name(s)
ERYPO
Intervention Description
40,000 IU in 50ml 0.9% NaCl iv on 3 consecutive days, starting within 6 hours after onset of symptoms
Intervention Type
Drug
Intervention Name(s)
0.9% NaCl
Intervention Description
50ml 0.9% NaCl iv on 3 consecutive days, starting within 6 hours after onset of symptoms
Primary Outcome Measure Information:
Title
Neurological/functional outcome as measured by the Barthel Index (BI)
Time Frame
day 90
Secondary Outcome Measure Information:
Title
Modified Rankin Scale (mRS) responder
Time Frame
day 90
Title
Barthel Index (BI)
Time Frame
day 30
Title
mRS
Time Frame
day30, day 90
Title
NIH Stroke Scale
Time Frame
day 1, 3, 7, 30, 90
Title
Proportion of subjects with minimal disability (mRS 0-1)
Time Frame
day 30, day 90
Title
All-cause mortality
Time Frame
day 90
Title
Mortality directly related to stroke
Time Frame
day 90
Title
Proportion of subjects with BI >= 95
Time Frame
day 30, day 90
Title
Proportion of subjects with BI=100
Time Frame
day 30, day 90
Title
Proportion of subjects with neurological recovery
Time Frame
day 3, 7, 30, 90
Title
Distribution of mRS scores
Time Frame
day 30, day 90
Title
Distribution of BI scores
Time Frame
day 30, day 90
Title
Distribution of NIH Stroke Scale scores
Time Frame
day 30, day 90
Title
Serum level of glial damage markers S100B and GFAP
Time Frame
day 1, 2, 3, 4, 7
Title
Lesion size (MRI DWI, flair)
Time Frame
day 1, day 7
Title
Overall survival
Time Frame
day 90
Title
Late recovery index (BI day 90 versus BI day 30)
Time Frame
day 30 to day 90

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Neurologische Klinik des Städtischen Klinikums Braunschweig
City
Braunschweig
ZIP/Postal Code
D-38126
Country
Germany
Facility Name
Neurologische Klink, Klinikum Bremen-Mitte
City
Bremen
ZIP/Postal Code
D-28177
Country
Germany
Facility Name
Neurologische Klinik, Allgemeines Krankenhaus Celle
City
Celle
ZIP/Postal Code
D-29223
Country
Germany
Facility Name
Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus der TU Dresden
City
Dresden
ZIP/Postal Code
D-01307
Country
Germany
Facility Name
Neurologische Klinik, Universität Erlangen-Nürnberg
City
Erlangen
ZIP/Postal Code
D-91054
Country
Germany
Facility Name
Klinik für Neurologie, Universität Essen
City
Essen
ZIP/Postal Code
D-45147
Country
Germany
Facility Name
Neurologische Universitätsklinik der Georg-August-Universität Goettingen
City
Goettingen
ZIP/Postal Code
D-37075
Country
Germany
Facility Name
Neurologische Klinik, Medizinische Hochschule Hannover
City
Hannover
ZIP/Postal Code
D-30625
Country
Germany
Facility Name
Klinik und Poliklinik für Neurologie der Universität Leipzig
City
Leipzig
ZIP/Postal Code
D-04103
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
11259643
Citation
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.
Results Reference
background
PubMed Identifier
12435860
Citation
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.
Results Reference
background
PubMed Identifier
11095504
Citation
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.
Results Reference
background
PubMed Identifier
11307627
Citation
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.
Results Reference
background
PubMed Identifier
14530580
Citation
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.
Results Reference
background
PubMed Identifier
15642952
Citation
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.
Results Reference
background
PubMed Identifier
16339796
Citation
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.
Results Reference
background
PubMed Identifier
17033631
Citation
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.
Results Reference
background
PubMed Identifier
17728357
Citation
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.
Results Reference
background
PubMed Identifier
21852153
Citation
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.
Results Reference
derived
PubMed Identifier
19834012
Citation
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.
Results Reference
derived
Links:
URL
http://www.em.mpg.de
Description
homepage of the Max-Planck-Institute of Experimental Medicine
URL
http://www.epo-study.de/index.html
Description
information about the German Multicenter EPO Stroke Study and previous related trials

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Multicenter Efficacy Study of Recombinant Human Erythropoietin in Acute Ischemic Stroke

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