Clinical trial NCT00893867: Efficacy and Safety Study of DP-b99 in Treating Acute Ischemic Stroke
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Ischemic Stroke
Keywords: acute ischemic stroke
neuroprotective agent
Lead sponsor: D-Pharm Ltd.
Sponsor class: INDUSTRY
First posted: 2009-05-06
Enrollment: 446
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Modified Rankin Scale (mRS) categorical analysis ("shift")
timeFrame: 90 days
Secondary outcomes:
measure: Recovery, defined as a score of ≤ 1 on modified Rankin Score
timeFrame: 90 days
measure: Safety and tolerability
timeFrame: throughout study - baseline until day 90
measure: recovery as assessed by an NIHSS of not more than 1
timeFrame: 90 days
measure: 'home time'
timeFrame: 90 days
Other outcomes:
Locations:
city: Oceanside
country: United States
facility: Research Center of Southern California
state: California
city: Danbury
country: United States
facility: Associated Neurologists, P.C.
state: Connecticut
city: Savannah
country: United States
facility: Memorial Health University Medical Center
state: Georgia
city: Lexington
country: United States
facility: The University of Kentucky The Methodist Hospital
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville, Kentucky Neuroscience Research
state: Kentucky
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Trenton
country: United States
facility: Capital Health Regional Medical Center Neuroscience Institute
state: New Jersey
city: Charlotte
country: United States
facility: Presbitarian Hospital
state: North Carolina
city: Youngstown
country: United States
facility: St. Elizabeth's Medical Center
state: Ohio
city: Tualatin
country: United States
facility: Legacy Meridian Park Medical Center
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Roanoke
country: United States
facility: Carilion Clinic
state: Virginia
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Klagenfurt
country: Austria
facility: Landeskrankenhaus Klagenfurt
city: Linz
country: Austria
facility: Abt. Neurologie und Psychiatrie
city: St. Pölten
country: Austria
facility: LKH St. Pölten Department of Neurology
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia de Belo Horizonte Departamento de Neurologia
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
city: Porto Alegre
country: Brazil
facility: Hospital Mãe de Deus
city: Porto Alegre
country: Brazil
facility: Santa Casa de Misericórdia de Porto Alegre Policlinica Santa Clara Sala de Neurologia
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto Unidade de Emergência Centro de Estudos
city: San Paulo
country: Brazil
facility: UNIFESP
city: Santa Catarina
country: Brazil
facility: Hospital São José de Joinville
city: Sao Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Centre
state: Ontario
city: Edmonton
country: Canada
facility: Grey Nun's Community Hospital
city: Edmonton
country: Canada
facility: University of Alberta Hospital
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Centre
city: Kingston
country: Canada
facility: Kingston General Hospital
city: Lethbridge
country: Canada
facility: Chinook Regional Hospital
city: Quebec
country: Canada
facility: CHA- Hôpital de l'Enfant-Jésus
city: Brno
country: Czech Republic
facility: University Hospital Brno
city: Hradec Kralove
country: Czech Republic
facility: University Hospital Hradec Kralove, Clinic of Neurology
city: Jihlava
country: Czech Republic
facility: Hospital Jihlava Clinic of Neurology
city: Ostrava
country: Czech Republic
facility: Hospital Vítkovice Clinic of Neurology
city: Pardubice
country: Czech Republic
facility: County Hospital Pardubice Clinic of Neurology
city: Prague
country: Czech Republic
facility: Clinic of Neurology, Stroke Center, Charles University
city: Prague
country: Czech Republic
facility: University Hospital Kralovske Vinohrady
city: Prague
country: Czech Republic
facility: University Hospital Motol Clinic of Neurology
city: Besancon
country: France
facility: CHU Jean Minjoz Besançon
city: Bordeaux
country: France
facility: Hopital Pellegrin-Tripode
city: Créteil
country: France
facility: CHU Henri Mondor
city: Montpellier
country: France
facility: Hopital Gui de Chauliac
city: Paris
country: France
facility: Hôpital Bichat
city: Paris
country: France
facility: Hôpital Lariboisière - Service Neurologie
city: Perpignan
country: France
facility: Hôpital Saint Jean
city: Bad Neustadt / Saale
country: Germany
facility: Ärztlicher Direktor Neurologische Klinik, Neurologische Klink GmbH der Rhoen-Klinikum AG
city: Bergisch Gladbach
country: Germany
facility: Marien-Krankenhaus gGmbH, Abteilung für Neurologie
city: Berlin
country: Germany
facility: DRK Kliniken Berlin, Klinik fuer Neurologie
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln, Klinik für Neurologie, Stroke Unit
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Bremerhaven
country: Germany
facility: Klinikum Bremerhaven-Reinkenheide gGmbH, Neurologische Klinik
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz GmbH Chefarzt Klinik für Neurologie
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt GmbH
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Neurologische klinik
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik und Poliklinik für Neurologie
city: Freiburg
country: Germany
facility: Neurologische Universitätsklinik Freiburg, Neurozentrum
city: Fulda
country: Germany
facility: Klinikum Fulda, Neurologische Klinik
city: Gelsenkirchen
country: Germany
facility: Evangelische Kliniken Gelsenkirchen GmbH Klinik für Neurologie und Klinische Neurophysiologie
city: Gottingen
country: Germany
facility: Georg-August-Universitat Gottingen Neurologische Klinik
city: Grifswald
country: Germany
facility: Ernst Moritz Arndt University
city: Hamburg
country: Germany
facility: Askepios Klinik Altona
city: Hamburg
country: Germany
facility: Askepios Klinik Heidberg
city: Koln
country: Germany
facility: Klinikum Köln Merheim, Department of Neurology
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR, Klinik und Poliklinik für Neurologie
city: Magdeburg
country: Germany
facility: Klinikum der Otto-von-Guericke-Universität Magdeburg, Neurologische Universitätsklinik
city: Mainz
country: Germany
facility: Johannes Gutenberg Universitat, Klinik und Poliklinik fur Neurologie
city: Minden
country: Germany
facility: Klinikum 1 Minden, Neurologische Klinik
city: Rostock
country: Germany
facility: Universität Rostock Chefarzt Abteilung Neurologie
city: Teupitz
country: Germany
facility: ASKLEPIOS Fachklinikum Teupitz
city: Trier
country: Germany
facility: Krankenhaus der Bramherzigen Brüder
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Abteilung für Neurologie im RKU
city: Zwickau
country: Germany
facility: Heinrich Braun Klinikum Zwickau
city: Budapest
country: Hungary
facility: Fővárosi Önkormányzat Péterfy Sándor utcai Kórház- Rendelőintézet és Baleseti Központ
city: Budapest
country: Hungary
facility: Állami Egészségügyi Központ
city: Debrecen
country: Hungary
facility: Kenezy Korhaz Rendelointezet Egezsegugyi Szolgaltato Nonprofit Kft.
city: Debrecen
country: Hungary
facility: University of Debrecen, Medical and Health Science Center
city: Gyor
country: Hungary
facility: Aladár Petz County Teaching Hospital
city: Kistarcsa
country: Hungary
facility: PM Flór Ferenc County Hospital
city: Miskolc
country: Hungary
facility: Borsod-Abaúj-Zemplén County Hospital Miskolc
city: Pecs
country: Hungary
facility: Pécsi Tudományegyetem Klinikai Központ
city: Zalaegerszeg
country: Hungary
facility: Zala Megyei Kórház
city: Haifa
country: Israel
facility: Bnai Zion Medical Center
city: Holon
country: Israel
facility: Neurological Dept. Edith Wolfson Medical Center
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Tel Hashomer
country: Israel
facility: Chaim Sheba Medical Center
city: Aosta
country: Italy
facility: Ospedale Regionale Valle d'Aosta
city: Cagliari
country: Italy
facility: Dipartimento di Neuroscienze, Ospedale di Brotzu
city: Lombardia
country: Italy
facility: Ospedale di Circolo di Varese
city: Milano
country: Italy
facility: Istituto Scientifico San Raffaele - Stroke Unit
city: Pavia
country: Italy
facility: Istituto Neurologico C. Mondino
city: Perugia
country: Italy
facility: Università di Perugia, Division of Internal and Cardiovascular Medicine - Stroke Unit
city: Piacenza
country: Italy
facility: Presidio Ospedaliero di Piacenza
city: Rome
country: Italy
facility: Azienda Ospedaliera Sant'Andrea, Stroke Unit
city: Rome
country: Italy
facility: Istituto Patologia Generale U.C.S.C
city: Rome
country: Italy
facility: U.O.C. Stroke Unit
city: Rome
country: Italy
facility: Università di Roma "La Sapienza" - Stroke Unit
city: Udine
country: Italy
facility: Azienda Ospedaliera Universitaria "Santa Maria della Misericordia" Stroke Unit
city: Busan
country: Korea, Republic of
facility: Dong-A Medical Center
city: Busan
country: Korea, Republic of
facility: Inje University BUSAN Paik Hospital
city: Goyang
country: Korea, Republic of
facility: Inje University ILSAN Paik Hospital
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: ASAN Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St. Mary's hospital
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis Neurologie
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente Hoofd Afdeling Vasculaire Neurologie
city: Heerlen
country: Netherlands
facility: Atrium MC Parkstad
city: Zwolle
country: Netherlands
facility: Isala Klinieken Ploikliniek Neurologie
city: Gdansk
country: Poland
facility: Pomerania Traumatology Center, Regional Specialist Hospital im. Nicolaus Copernicus
city: Lublin
country: Poland
facility: Medical University of Lublin, Department of Neurology, Stroke Unit
city: Sandomierz
country: Poland
facility: Samodzielny Publiczny Zespol Zakladow Opieki Zdrowotnej w Sandomierzu
city: Skarżysko-Kamienna
country: Poland
facility: Szpital Powiatowy im. Marii Curie - Skłodowskiej w Skarżysku-Kamiennej
city: Tychy
country: Poland
facility: Wojewodzki Szpital Specjalistyczny Nr 1 im. Prof. Jozefa Gasinskiego
city: Warsaw
country: Poland
facility: Instytut Psychiatrii i Neurologii Oddział Neurologiczny z Pododdziałem Udarowym
city: Warsaw
country: Poland
facility: Medical University of Warsaw, Department of Neurology
city: Warsaw
country: Poland
facility: Szpital Wolski im. dr Anny Gostyńskiej Samodzielny Publiczny Zakład Opieki Zdrowotnej, Oddział Neurologii
city: Warsaw
country: Poland
facility: Wojskowy Instytut Medyczny, Oddział Neurologii
city: Amadora
country: Portugal
facility: Hospital Professor Doutor Fernando Fonseca, EPE
city: Coimbra
country: Portugal
facility: Centro Hospitalar de Coimbra EPE
city: Coimbra
country: Portugal
facility: Hospitais da Universidadde de Coimbra, EPE
city: Lisboa
country: Portugal
facility: Centro de Estudos Egas Moniz - Hospital de Santa Maria
city: Santa Maria da Feira
country: Portugal
facility: Hospital de São Sebastião, EPE
city: Martin
country: Slovakia
facility: Neurology Clinic, Faculty Hospital in Martin
city: Nitra
country: Slovakia
facility: University Hospital Nitra
city: Spisska Nova Ves
country: Slovakia
facility: Hospital un Poliklinic
city: Trnava
country: Slovakia
facility: Faculty Hospital Trnava
city: Zilina
country: Slovakia
facility: Neurology dept.,Hospital Zilina
city: Bloemfontein
country: South Africa
facility: Fichmed
city: Cape Town
country: South Africa
facility: Constantiaberg Medi-clinic
city: Gauteng
country: South Africa
facility: Union Hospital
city: Western Cape
country: South Africa
facility: Helderberg Research Institute
city: Western Cape
country: South Africa
facility: Triervlei Trial Centre
city: Worcester
country: South Africa
facility: Clinical Projects Research
city: Albacete
country: Spain
facility: Hospital Universitario de Albacete
city: Barcelona
country: Spain
facility: Hospital De La Santa Ta Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Germans Triasy Pujol
city: Barcelona
country: Spain
facility: Hospital Vall D'hebron
city: Madrid
country: Spain
facility: Hospital Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico Universitario de Santiago
city: Valencia
country: Spain
facility: Consorcio Hospital General Universitario Valencia
city: Valladolid
country: Spain
facility: Hospital Clinico Universitario De Valladolid
city: Basel
country: Switzerland
facility: Universitätsspital Basel, Neurologie
city: Zurich
country: Switzerland
facility: Universitätsspital Zürich, Klinik für Neurologie
Study officials:
affiliation: University of Alberta Hospital, Edmonton, Canada
name: Ashfaq Shuaib, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Professor Doutor Fernando Fonseca, EPE, Amadora, Portugal
name: Vasco Salgado, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsspital Basel, Neurologie, Basel, Switzerland
name: Philippe Lyrer, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Atrium MC Parkstad, Heerlen, Netherlands
name: Tobien Schreuder, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Santa Marcelina, Sao Paulo, Brasil
name: Maria S Rocha, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Lariboisière - Service Neurologie, Paris, France
name: Hugues Chabriat, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
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.
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. doi: 10.1111/j.1365-2125.2005.02378.x.
citation: 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.
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.
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. No abstract available.