Efficacy and Safety Study of DP-b99 in Treating Acute Ischemic Stroke

Acute Ischemic Stroke Clinical Trial

— MACSI  

Official title:

A Double Blind, Randomized, Placebo-controlled, Parallel Group, Multicenter Phase 3 Pivotal Study to Assess the Safety and Efficacy of 1mg/kg/Day Intravenous DP-b99 Over 4 Consecutive Days Versus Placebo When Initiated Within Nine Hours of Acute Ischemic Stroke Onset

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00893867
• Other study ID #: Ptcl-01373
• Status: Terminated
• Phase: Phase 3
• First received: May 4, 2009
• Last updated: October 23, 2012
• Start date: December 2009
• Est. completion date: April 2012

Study information

• Verified date: October 2012
• Source: D-Pharm Ltd.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationIsrael: Ministry of HealthSouth Africa: Medicines Control CouncilCanada: Health CanadaFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesAustria: Agency for Health and Food SafetyCzech Republic: State Institute for Drug ControlNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Poland: The Central Register of Clinical TrialsSlovakia: State Institute for Drug ControlSpain: Agencia Española de Medicamentos y Productos SanitariosSwitzerland: SwissmedicHungary: National Institute of PharmacyPortugal: INFARMED - National Authority of Medicines and Health ProductsItaly: Agenzia Italiana del Farmaco (AIFA)Brazil:Agência Nacional de Vigilância Sanitária (Anvisa)
• Study type: Interventional

Clinical Trial Summary

The purpose of this trial is to determine if intravenous administration of the metal ion trapping agent DP-b99 up to 9 hours following acute ischemic stroke onset, and then for 3 additional days (4 consecutive days in total) is effective in improving long term outcome. Patients will be followed up for 3 months after the stroke.

Description:

This will be a randomized, double-blind, placebo-controlled, multicenter, multi-national, parallel-arm, pivotal study comparing a placebo group to a DP-b99 group treated with intravenous 1.0 mg/kg/d for 4 consecutive days, in acute ischemic stroke patients with an entry National Institutes of Health Stroke Scale (NIHSS) score of 10-16 and a clinical syndrome that includes at least 1 of the following: language dysfunction, visual field defect or Extinction and Inattention (formerly Neglect) (as reflected by at least 1 point on any of the corresponding items of the NIHSS: 9, 3 or 11). An interim analysis for futility will be performed after Day 90 (or last available observation) primary endpoint data have been collected on about 45% of subjects planned to be enrolled. Clinical trial material (CTM) will be administered within 9 hours after the onset of acute ischemic stroke symptoms. Subjects will be randomized at a ratio of 1:1 to receive either DP-b99 or placebo. A data and safety monitoring board (DSMB) will assess the accumulating safety data periodically and will oversee the interim futility analysis.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 446
• Est. completion date: April 2012
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

Inclusion criteria:

1. M or F age 18 - 85, inclusive

2. Suffered an acute, likely hemispheric, ischemic stroke, defined as acute, focal, neurological deficit(s), secondary to a presumed vascular event, which must include at least one of the following components (as reflected by at least 1 point on any of the corresponding items of the NIHSS: 3, 9 or 11):

• Visual

• Best Language

• Extinction and Inattention (formerly Neglect)

3. Suffered the onset of an acute ischemic stroke that can be evaluated and treatment initiated within 9 hours after the onset of acute ischemic stroke symptoms.

4. Screening NIHSS score of 10 to 16, inclusive

5. Readily accessible peripheral venous access for clinical trial material (CTM) administration and blood sampling

6. Ability to understand the requirements of the study and be willing to provide written informed consent as evidenced by signature on an informed consent document approved by an institutional review board or independent ethics committee, and agree to abide by the study restrictions and return for the required assessments.

7. Provided written authorization for use and disclosure of protected health information in accordance with the Health Insurance Portability and Accountability Act in the United States and the Personal Information Protection and Electronic Documents Act in Canada

Exclusion Criteria:

1. An intracerebral or subarachnoid hemorrhage per screening/baseline computerized tomography scan or susceptibility-weighted magnetic resonance imaging

2. A candidate for either:

1. thrombolytic therapy, or have been treated with thrombolytic therapy for the current stroke

2. mechanical thromboembolectomy, or have been treated with mechanical thromboembolectomy for the current stroke

3. Delirious, comatose or stuporous or demented, or having a mental impairment that in the investigator's opinion renders the subject incapable to participate in the study

4. Have seizure(s) anytime from stroke onset to screening/baseline NIHSS evaluation

5. Neurological or non-neurological comorbidities that in the investigator's opinion may lead, independent of the current stroke, to further deterioration in the subject's neurological status during the trial period, or may render the study's neurological assessments inconclusive for the purpose of evaluating solely the stroke's effects

6. Likely to undergo a procedure involving cardiopulmonary bypass during the study period

7. Suffered a myocardial infarction in the last 90 days

8. Any medical condition that in the investigator's opinion may threaten the subject's ability to complete the study (e.g., concurrent significant or life-threatening diseases, such as malignancies or end stage organ failure)

9. Rapid spontaneous improvement of neurological signs during screening/baseline assessments

10. Premorbid neurological deficits and functional limitations assessed by a pre-stroke Modified Rankin Scale score of > 1

11. Suffered a stroke within 90 days of the screening/baseline assessments that is either diagnostically confirmed or assumed to be in the same cerebral territory as is the current acute stroke

12. Either severe hypertension or hypotension, as measured by at least 2 consecutive supine measurements taken 10 minutes apart prior to randomization.

13. Significant current renal or hepatic disease(s): a serum creatinine concentration of >2.5 mg/dL; alanine aminotransferase, aspartate aminotransferase, or gamma-glutamyl transferase values that are three times greater than the upper limit of normal.

14. Have a platelet count of <100,000/mm3 or, for patients on oral anticoagulants at study entry, INR of >4

15. Female of childbearing potential who is not willing to use adequate and effective birth control measures for the duration of the trial. Effective birth control measures include hormonal contraception, a barrier method such as a diaphragm, intrauterine device and/or condom with spermicide

16. Positive urine pregnancy test at screening/baseline or be a lactating female

17. Currently dependent on, or abusing, alcohol or one or more of the following:

sympathomimetic amines, cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives and hypnotics

18. Received an investigational drug or product or participated in an investigational drug study within a period of 30 days prior to receiving study medication or have previously participated in a clinical trial involving DP-b99

19. Severe anemia as measured by a hemoglobin value of < 7 g/dl.

20. In a dependent relationship with the physician or the study sponsor.

21. Known hypersensitivity to any component of the investigational product.

Study Design

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

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Ischemia
• Stroke

Intervention

Drug:
• DP-b99
1mg/kg/day over 4 consecutive days given intravenously and initiated up to 9 hours following acute stroke onset.
• Placebo
1mg/kg/day over 4 consecutive days given intravenously and initiated up to 9 hours following acute stroke onset.

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	Landeskrankenhaus Klagenfurt	Klagenfurt
Austria	Abt. Neurologie und Psychiatrie	Linz
Austria	LKH St. Pölten Department of Neurology	St. Pölten
Brazil	Santa Casa de Misericordia de Belo Horizonte Departamento de Neurologia	Belo Horizonte
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre
Brazil	Hospital Mãe de Deus	Porto Alegre
Brazil	Hospital Moinhos de Vento	Porto Alegre
Brazil	Santa Casa de Misericórdia de Porto Alegre Policlinica Santa Clara Sala de Neurologia	Porto Alegre
Brazil	Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto Unidade de Emergência Centro de Estudos	Ribeirão Preto
Brazil	UNIFESP	San Paulo
Brazil	Hospital São José de Joinville	Santa Catarina
Brazil	Hospital Santa Marcelina	Sao Paulo
Canada	Grey Nun's Community Hospital	Edmonton
Canada	University of Alberta Hospital	Edmonton
Canada	Hamilton Health Sciences Centre	Hamilton
Canada	Hamilton Health Sciences Centre	Hamilton	Ontario
Canada	Kingston General Hospital	Kingston
Canada	Chinook Regional Hospital	Lethbridge
Canada	CHA- Hôpital de l'Enfant-Jésus	Quebec
Czech Republic	University Hospital Brno	Brno
Czech Republic	University Hospital Hradec Kralove, Clinic of Neurology	Hradec Kralove
Czech Republic	Hospital Jihlava Clinic of Neurology	Jihlava
Czech Republic	Hospital Vítkovice Clinic of Neurology	Ostrava
Czech Republic	County Hospital Pardubice Clinic of Neurology	Pardubice
Czech Republic	Clinic of Neurology, Stroke Center, Charles University	Prague
Czech Republic	University Hospital Kralovske Vinohrady	Prague
Czech Republic	University Hospital Motol Clinic of Neurology	Prague
France	CHU Jean Minjoz Besançon	Besancon
France	Hopital Pellegrin-Tripode	Bordeaux
France	CHU Henri Mondor	Créteil
France	Hopital Gui de Chauliac	Montpellier
France	Hôpital Bichat	Paris
France	Hôpital Lariboisière - Service Neurologie	Paris
France	Hôpital Saint Jean	Perpignan
Germany	Ärztlicher Direktor Neurologische Klinik, Neurologische Klink GmbH der Rhoen-Klinikum AG	Bad Neustadt / Saale
Germany	Marien-Krankenhaus gGmbH, Abteilung für Neurologie	Bergisch Gladbach
Germany	DRK Kliniken Berlin, Klinik fuer Neurologie	Berlin
Germany	Vivantes Klinikum Neukölln, Klinik für Neurologie, Stroke Unit	Berlin
Germany	Klinikum Bremen-Mitte	Bremen
Germany	Klinikum Bremerhaven-Reinkenheide gGmbH, Neurologische Klinik	Bremerhaven
Germany	Klinikum Chemnitz GmbH Chefarzt Klinik für Neurologie	Chemnitz
Germany	Helios Klinikum Erfurt GmbH	Erfurt
Germany	Universitätsklinikum Erlangen, Neurologische klinik	Erlangen
Germany	Universitätsklinikum Essen, Klinik und Poliklinik für Neurologie	Essen
Germany	Neurologische Universitätsklinik Freiburg, Neurozentrum	Freiburg
Germany	Klinikum Fulda, Neurologische Klinik	Fulda
Germany	Evangelische Kliniken Gelsenkirchen GmbH Klinik für Neurologie und Klinische Neurophysiologie	Gelsenkirchen
Germany	Georg-August-Universitat Gottingen Neurologische Klinik	Gottingen
Germany	Ernst Moritz Arndt University	Grifswald
Germany	Askepios Klinik Altona	Hamburg
Germany	Askepios Klinik Heidberg	Hamburg
Germany	Klinikum Köln Merheim, Department of Neurology	Koln
Germany	Universitätsklinikum Leipzig AöR, Klinik und Poliklinik für Neurologie	Leipzig
Germany	Klinikum der Otto-von-Guericke-Universität Magdeburg, Neurologische Universitätsklinik	Magdeburg
Germany	Johannes Gutenberg Universitat, Klinik und Poliklinik fur Neurologie	Mainz
Germany	Klinikum 1 Minden, Neurologische Klinik	Minden
Germany	Universität Rostock Chefarzt Abteilung Neurologie	Rostock
Germany	ASKLEPIOS Fachklinikum Teupitz	Teupitz
Germany	Krankenhaus der Bramherzigen Brüder	Trier
Germany	Universitätsklinikum Ulm, Abteilung für Neurologie im RKU	Ulm
Germany	Heinrich Braun Klinikum Zwickau	Zwickau
Hungary	Állami Egészségügyi Központ	Budapest
Hungary	Fovárosi Önkormányzat Péterfy Sándor utcai Kórház- Rendelointézet és Baleseti Központ	Budapest
Hungary	Kenezy Korhaz Rendelointezet Egezsegugyi Szolgaltato Nonprofit Kft.	Debrecen
Hungary	University of Debrecen, Medical and Health Science Center	Debrecen
Hungary	Aladár Petz County Teaching Hospital	Gyor
Hungary	PM Flór Ferenc County Hospital	Kistarcsa
Hungary	Borsod-Abaúj-Zemplén County Hospital Miskolc	Miskolc
Hungary	Pécsi Tudományegyetem Klinikai Központ	Pecs
Hungary	Zala Megyei Kórház	Zalaegerszeg
Israel	Bnai Zion Medical Center	Haifa
Israel	Neurological Dept. Edith Wolfson Medical Center	Holon
Israel	Meir Medical Center	Kfar Saba
Israel	Sourasky Medical Center	Tel Aviv
Israel	Chaim Sheba Medical Center	Tel Hashomer
Italy	Ospedale Regionale Valle d'Aosta	Aosta
Italy	Dipartimento di Neuroscienze, Ospedale di Brotzu	Cagliari
Italy	Ospedale di Circolo di Varese	Lombardia
Italy	Istituto Scientifico San Raffaele - Stroke Unit	Milano
Italy	Istituto Neurologico C. Mondino	Pavia
Italy	Università di Perugia, Division of Internal and Cardiovascular Medicine - Stroke Unit	Perugia
Italy	Presidio Ospedaliero di Piacenza	Piacenza
Italy	Azienda Ospedaliera Sant'Andrea, Stroke Unit	Rome
Italy	Istituto Patologia Generale U.C.S.C	Rome
Italy	U.O.C. Stroke Unit	Rome
Italy	Università di Roma "La Sapienza" - Stroke Unit	Rome
Italy	Azienda Ospedaliera Universitaria "Santa Maria della Misericordia" Stroke Unit	Udine
Korea, Republic of	Dong-A Medical Center	Busan
Korea, Republic of	Inje University BUSAN Paik Hospital	Busan
Korea, Republic of	Inje University ILSAN Paik Hospital	Goyang
Korea, Republic of	Chonnam National University Hospital	Gwangju
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	ASAN Medical Center	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's hospital	Seoul
Netherlands	Catharina Ziekenhuis Neurologie	Eindhoven
Netherlands	Medisch Spectrum Twente Hoofd Afdeling Vasculaire Neurologie	Enschede
Netherlands	Atrium MC Parkstad	Heerlen
Netherlands	Isala Klinieken Ploikliniek Neurologie	Zwolle
Poland	Pomerania Traumatology Center, Regional Specialist Hospital im. Nicolaus Copernicus	Gdansk
Poland	Medical University of Lublin, Department of Neurology, Stroke Unit	Lublin
Poland	Samodzielny Publiczny Zespol Zakladow Opieki Zdrowotnej w Sandomierzu	Sandomierz
Poland	Szpital Powiatowy im. Marii Curie - Sklodowskiej w Skarzysku-Kamiennej	Skarzysko-Kamienna
Poland	Wojewodzki Szpital Specjalistyczny Nr 1 im. Prof. Jozefa Gasinskiego	Tychy
Poland	Instytut Psychiatrii i Neurologii Oddzial Neurologiczny z Pododdzialem Udarowym	Warsaw
Poland	Medical University of Warsaw, Department of Neurology	Warsaw
Poland	Szpital Wolski im. dr Anny Gostynskiej Samodzielny Publiczny Zaklad Opieki Zdrowotnej, Oddzial Neurologii	Warsaw
Poland	Wojskowy Instytut Medyczny, Oddzial Neurologii	Warsaw
Portugal	Hospital Professor Doutor Fernando Fonseca, EPE	Amadora
Portugal	Centro Hospitalar de Coimbra EPE	Coimbra
Portugal	Hospitais da Universidadde de Coimbra, EPE	Coimbra
Portugal	Centro de Estudos Egas Moniz - Hospital de Santa Maria	Lisboa
Portugal	Hospital de São Sebastião, EPE	Santa Maria da Feira
Slovakia	Neurology Clinic, Faculty Hospital in Martin	Martin
Slovakia	University Hospital Nitra	Nitra
Slovakia	Hospital un Poliklinic	Spisska Nova Ves
Slovakia	Faculty Hospital Trnava	Trnava
Slovakia	Neurology dept.,Hospital Zilina	Zilina
South Africa	Fichmed	Bloemfontein
South Africa	Constantiaberg Medi-clinic	Cape Town
South Africa	Union Hospital	Gauteng
South Africa	Helderberg Research Institute	Western Cape
South Africa	Triervlei Trial Centre	Western Cape
South Africa	Clinical Projects Research	Worcester
Spain	Hospital Universitario de Albacete	Albacete
Spain	Hospital De La Santa Ta Creu i Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Germans Triasy Pujol	Barcelona
Spain	Hospital Vall D'hebron	Barcelona
Spain	Hospital Gregorio Maranon	Madrid
Spain	Hospital La Princesa	Madrid
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitario Clinico San Carlos	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Clinico Universitario de Santiago	Santiago de Compostela
Spain	Consorcio Hospital General Universitario Valencia	Valencia
Spain	Hospital Clinico Universitario De Valladolid	Valladolid
Switzerland	Universitätsspital Basel, Neurologie	Basel
Switzerland	Universitätsspital Zürich, Klinik für Neurologie	Zurich
United States	Tufts Medical Center	Boston	Massachusetts
United States	Presbitarian Hospital	Charlotte	North Carolina
United States	Associated Neurologists, P.C.	Danbury	Connecticut
United States	The Methodist Hospital	Houston	Texas
United States	The University of Kentucky The Methodist Hospital	Lexington	Kentucky
United States	University of Louisville, Kentucky Neuroscience Research	Louisville	Kentucky
United States	Research Center of Southern California	Oceanside	California
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Carilion Clinic	Roanoke	Virginia
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Capital Health Regional Medical Center Neuroscience Institute	Trenton	New Jersey
United States	Legacy Meridian Park Medical Center	Tualatin	Oregon
United States	St. Elizabeth's Medical Center	Youngstown	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
D-Pharm Ltd.

Countries where clinical trial is conducted

United States,  Austria,  Brazil,  Canada,  Czech Republic,  France,  Germany,  Hungary,  Israel,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Slovakia,  South Africa,  Spain,  Switzerland, 

References & Publications (5)

Barkalifa R, Hershfinkel M, Friedman JE, Kozak A, Sekler I. The lipophilic zinc chelator DP-b99 prevents zinc induced neuronal death. Eur J Pharmacol. 2009 Sep 15;618(1-3):15-21. doi: 10.1016/j.ejphar.2009.07.019. Epub 2009 Jul 19. — View Citation

Diener HC, Schneider D, Lampl Y, Bornstein NM, Kozak A, Rosenberg G. DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke. Stroke. 2008 Jun;39(6):1774-8. doi: 10.1161/STROKEAHA.107.506378. Epub 2008 Apr 10. — View Citation

Rosenberg G, Angel I, Kozak A. Clinical pharmacology of DP-b99 in healthy volunteers: first administration to humans. Br J Clin Pharmacol. 2005 Jul;60(1):7-16. — View Citation

Rosenberg G, Bornstein N, Diener HC, Gorelick PB, Shuaib A, Lees K; MACSI investigators. The Membrane-Activated Chelator Stroke Intervention (MACSI) Trial of DP-b99 in acute ischemic stroke: a randomized, double-blind, placebo-controlled, multinational pivotal phase III study. Int J Stroke. 2011 Aug;6(4):362-7. doi: 10.1111/j.1747-4949.2011.00608.x. Epub 2011 Jun 6. — View Citation

Rosenberg G, Marshall LS, Caraco Y. The neuroprotective agent DP-b99 does not interact with s-warfarin in vivo despite significant CYP2C9 inhibition in vitro. Basic Clin Pharmacol Toxicol. 2011 Apr;108(4):289-92. doi: 10.1111/j.1742-7843.2010.00654.x. Epub 2010 Dec 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Modified Rankin Scale (mRS) categorical analysis ("shift")		90 days	No
Secondary	Recovery, defined as a score of = 1 on modified Rankin Score		90 days	No
Secondary	Safety and tolerability	the numbers of patients with treatment-emergent adverse events, results of physical examination, 12-lead electrocardiogram, vital signs and laboratory tests (complete blood count, chemistry and urinalysis)	throughout study - baseline until day 90	Yes
Secondary	recovery as assessed by an NIHSS of not more than 1		90 days	No
Secondary	'home time'	exploratory endpoint of 'home time', which measures the length of time (as number of nights)spent at home/relatives' home between hospital discharge and day 90	90 days	No