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NCT05065216PHASE2, PHASE3Recruiting

Treatment of Acute Ischemic Stroke (ReMEDy2 Trial)

DiaMedica Therapeutics Inc

Start Date

11/7/2021

Completion Date

12/1/2026

Summary

This is a Phase 2/3 study evaluating the safety and efficacy of DM199 (rinvecalinase alfa) in treating participants with moderate stroke severity, who present within 24 hours of Acute Ischemic Stroke (AIS) onset due to small and medium vessel occlusions. This study focuses on participants with limited treatment options. Participants who have or will receive mechanical thrombectomy (MT) are not eligible for participation. Additionally, participants who have received fibrinolytics are excluded unless they experience a persistent neurological deficit of moderate severity six or more hours after fibrinolytic treatment. Participants considered for this trial should not be denied the use of standard of care (SoC) AIS therapies, such as fibrinolytics or MT, when appropriate. The double-blinded study will be randomized and placebo-controlled at up to approximately 100 sites.

Detailed Description

This is a Phase 2/3 Adaptive Design, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of DM199 for the Treatment of Acute Ischemic Stroke (ReMEDy2 Trial). Participants with AIS will be randomized 1:1 to DM199 or placebo. DM199 will be administered as a single intravenous (IV) dose (0.5 μg/kg; not to exceed 50 μg) followed by subcutaneous (SC) doses at 2 hours (+10 hours) of the IV dose completion and then 2 times per week up to Day 21. The duration of each individual's participation in the study will be approximately 90 days from the time of initial treatment to completion of all study activities. A formal interim analysis will be conducted after 200 participants complete their Day 90 assessment in Part A. The purposes of this interim analysis are to assess safety, allow early stopping of the study for futility, or continuing the study with a revised final sample up to a maximum of 728 participants.

Eligibility Criteria

Age Range: 18 years to 90 years

Inclusion Criteria: 1. Participant is between 18 and 90 years of age inclusive. 2. Participant weight is 40 kg to 166 kg inclusive. 3. Participant to be randomized and treatment initiated within 24 hours of last known normal/AIS stroke onset. 4. Participant has NIHSS ≥5 and ≤15 at approximately the time of randomization. This criterion also applies to participants who meet the following conditions: * The participant initially presents with an NIHSS score below 5 but clinically worsens, including cases of progressing stroke / stroke-in-evolution, resulting in a subsequent persistent NIHSS score of ≥5 and ≤15; and * Participant meets all other inclusion and exclusion criteria, including repeat brain imaging to rule out hemorrhagic transformation. 5. Participant had a pre-morbid mRS score of 0 to 1 (mRS score prior to AIS) as stated by participant or participant's representative. 6. If participant has received fibrinolytic treatment for AIS within 4.5 hours of last know normal/AIS stoke onset and at least 6 hours after completing fibrinolytic treatment, and the participant meets all of the following criteria: * Participant's initial NIHSS score prior to fibrinolytics was ≤15; and * At least six hours after fibrinolytics, the participant has NIHSS score of ≥5 and ≤15 with a persistent deficit; and * The participant's NIHSS score showed less than a 4-point improvement, or worsened, after receiving fibrinolytics; and * Participant meets all other inclusion and exclusion criteria including repeat brain imaging to rule out hemorrhagic transformation. 7. Participant and/or legally authorized representative is able to provide informed consent. 8. Participant is willing and able to comply with the study protocol, in the Investigator's judgment. Exclusion Criteria: 1. At screening, or with repeat imaging (see Inclusion 4 and 6), participant has imaging confirmed hemorrhage stroke. 2. Participant has image findings with symptomatic large vessel occlusion at one or more of the following locations: Intracranial carotid I/T/L or M1 segment MCA, vertebral or basilar artery (BA). 3. Participant has large core of established infarction defined as ASPECTS 0-5. 4. Participant has or will receive MT for their current AIS. 5. Participant has suspected or confirmed extracranial arterial dissection. 6. Participant has imaging findings and/or symptoms consistent with a brain stem or cerebellar stroke. Posterior cerebral artery strokes without any associated brain stem or cerebellar involvement are allowable. 7. Participant has any recorded SBP \<100 mmHg or MAP \<65 mmHg; MAP = DBP + \[1/3 (SBP - DBP)\] (measured with noninvasive BP cuff type monitor) after stroke symptom onset and prior to randomization. 8. Participant is currently prescribed angiotensin-converting enzyme inhibitor (ACEi) and is unable or unwilling to convert to another antihypertensive pharmacological treatment through Day 29 ±1 day (8 days after last treatment). 9. Participant is currently prescribed an ACEi, and the last dose of the ACE inhibitor medication is reported to have been taken \< 24 hours before start of IV study drug infusion as stated by participant or participant's representative. 10. Participant has a history of clinically significant allergic reactions such as angioedema or anaphylaxis requiring hospitalization. 11. Participant has a diagnosis or suspected diagnosis of hereditary angioedema (HAE) or is taking or prescribed medications commonly used as prophylaxis/treatment of HAE, such as C1-esterase inhibitors (Cinryze, Berinert, Ruconest, Haegarda), Danazol, kallikrein inhibitors (Ecallantide, Berotralstat, Lanadelumab), Bradykinin B2 Receptor Antagonists (Icatibant), or other medication designed to influence the kallikrein-kinin system. 12. Life expectancy estimated at ≤1 year prior to enrollment. 13. Participant has clinical evidence of an active infection at the time of enrollment requiring parenteral treatment or hospitalization to monitor or manage the infection. NOTE: Treatment of uncomplicated infections with oral antibiotics would not be an exclusion (for example, the treatment of uncomplicated urinary tract infections or sinus infections with oral antibiotics would not be exclusionary). 14. Participant has known alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency). 15. Participant is pregnant or nursing. NOTE: Participants who agree to stop nursing may be considered for inclusion at the discretion of the Investigator. 16. Participants of child-bearing potential must agree to use medically acceptable contraceptive measures to prevent pregnancy. All participants of childbearing potential (defined as sexually mature participants who have had menses within the preceding 24 months and have not undergone permanent sterilization methods such as hysterectomy, bilateral oophorectomy, bilateral salpingectomy, etc.) must have a negative serum pregnancy test performed locally at screening. Participants of childbearing potential must agree not to attempt to become pregnant or undergo in vitro fertilization. If participating in sexual activity that could lead to pregnancy, participants must use 2 reliable methods (1 per partner is acceptable) of contraception simultaneously while receiving protocol-specified medication and during the study follow-up period. Participants participating in sexual activity must agree to use, or for their partner to use highly effective birth control methods (those with a failure rate of less than 1% per year when used consistently and correctly) until they have completed the study (after the Day 90 visit). Such methods include: * Combined (estrogen and progesterone containing) hormonal oral, intravaginal, or transdermal contraception associated with the inhibition of ovulation * Progesterone-only oral, injectable, or implantable hormonal contraception associated with the inhibition of ovulation * Intrauterine device (IUD) * Intrauterine hormone-releasing system (IUS) * Bilateral tubal occlusion * Vasectomized partner * Sexual abstinence Participants who are not of reproductive potential (who have been postmenopausal for more than 24 consecutive months or have undergone hysterectomy, bilateral oophorectomy, bilateral salpingectomy, etc.) are not required to use contraception. Participants are prohibited from sperm donation. NOTE: A negative serum pregnancy test will be documented during screening if a participant is of child-bearing potential. 17. Participant is currently participating in or has participated in a study using an investigational device or drug or received an investigational drug or investigational use of a licensed drug within 30 days prior to screening. 18. Participant does not have sufficient venous access for infusion of study treatment or blood sampling. 19. Participant is unable or unwilling to comply with protocol requirements, including assessments, tests, and follow-up visits. 20. Participant has any other medical condition which in the opinion of the Investigator will make participation medically unsafe or interfere with the study results.

Interventions

DRUG

Recombinant human tissue kallikrein

OTHER

Placebo for DM199 Solution for Injection

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Conditions

Acute StrokeIschemic StrokeStroke

Locations

Gulf Health Hospitals d/b/a Thomas Hospital

Fairhope, Alabama 36532

United States

USC Arcadia Hospital

Arcadia, California 91007

United States

Glendale Adventist Medical Center d/b/a Adventist Health Glendale

Glendale, California 91206-4152

United States

Kaiser Permanente Los Angeles Medical Center

Los Angeles, California 90027-5209

United States

Ronald Reagan UCLA Medical Center

Los Angeles, California 90095

United States

Stanford Health Care

Stanford, California 94305

United States

The Lundquist Institute at Harbor UCLA Medical Center

Torrance, California 90502

United States

Memorialcare Long Beach Medical Center

Torrance, California 90806

United States

HCA Florida - JFK Medical Center

Atlantis, Florida 33462-1149

United States

Boca Raton Regional Hospital Marcus Neuroscience Institute

Boca Raton, Florida 33486

United States

Holy Cross Health

Fort Lauderdale, Florida 33308

United States

University of Florida Jacksonville

Jacksonville, Florida 32209

United States

Sarasota Memorial Hospital

Sarasota, Florida 34239-2617

United States

Tampa General Hospital (TGH) - The Stroke Center

Tampa, Florida 33606-3603

United States

OSF HealthCare Saint Francis Medical Center

Peoria, Illinois 61637

United States

Ascension Via Christi Hospitals Wichita Inc.

Wichita, Kansas 67214

United States

Ochsner Clinic Foundation

New Orleans, Louisiana 70121

United States

UMASS Chan Medical School

Worcester, Massachusetts 01655

United States

Trinity Health Grand Rapids Hospital

Grand Rapids, Michigan 49503

United States

Abbott Northwestern Hospital

Minneapolis, Minnesota 55407

United States

University Medical Center of Southern Nevada

Las Vegas, Nevada 89102

United States

The University of New Mexico - School of Medicine

Albuquerque, New Mexico 87131

United States

Northwell Health Physician Partners - Neurology at Lenox Hill

New York, New York 10075

United States

Summa Health Clinical Research Center

Akron, Ohio 44304

United States

The Clinical Neuroscience Institute

Dayton, Ohio 45431

United States

Mercy Health - St. Vincent Medical Center

Toledo, Ohio 43608

United States

The University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma 73104

United States

Ascension St. John

Tulsa, Oklahoma 74104

United States

Oregon Health & Science University

Portland, Oregon 97239

United States

The Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania 19104

United States

Prisma Health-Greenville Memorial Hospital

Greenville, South Carolina 29605

United States

Erlanger Hospital

Chattanooga, Tennessee 37403

United States

Chattanooga Center for Neurologic Research

Chattanooga, Tennessee 37404-1163

United States

Houston Methodist Neurological Institute

Houston, Texas 77030

United States

Memorial Hermann Hospital, Texas Medical Center

Houston, Texas 77030

United States

Imeldaziekenhuis (Imelda Hospital)

Bonheiden, Belgium 015 50 50 11

Belgium

UZ Gent

Ghent, Belgium 9000

Belgium

Jessa Ziekenhuis

Hasselt, Belgium 3500

Belgium

AZ Groeninge

Kortrijk, Belgium 8500

Belgium

Clinique St Pierre

Ottignies, Belgium 1340

Belgium

University of Alberta Hospital

Edmonton, Alberta T6G 2G3 7802481660

Canada

Vancouver General Hospital

Vancouver, British Columbia V5Z1M9

Canada

Health Sciences North

Hamilton, Ontario L8L2X2

Canada

Hamilton Health Sciences - Hamilton General Hospital

Hamilton, Ontario L8L8E7

Canada

Sunnybrook Research Institute

North York, Ontario M4N 3M5

Canada

CHU Pontchaillou /Hopital Sud Service de Neurologie

Rennes, Brittany Region 35033

France

West Georgia Medical Center LTD

Kutaisi, Georgia 4600

Georgia

Israel-Georgia Medical Research Clinic-Healthycore LTD

Tbilisi, Georgia 0112

Georgia

New Hospitals LTD

Tbilisi, Georgia 0114

Georgia

Pineo Medical Ecosystem LTD

Tbilisi, Georgia 0114

Georgia

JSC K. Eristavi National Center of Experimental and Clinical Surgery

Tbilisi, Georgia 0159

Georgia

Bajcsy-Zsilinszky Hospital

Budapest, Hungary 1106

Hungary

St. Damjan Greek Catholic Hospital

Kisvárda, Hungary 4600

Hungary

B.-A.-Z. County Central Hospital

Miskolc, Hungary 3526

Hungary

Petz Aladár County Teaching Hospital

Győr, Vasvári Pál U. 2-4 9024

Hungary

Fundeni Clinical Institute

Bucharest, Bucharest (Sector 2) 022328

Romania

Elias Emergency University Hospital

Bucharest, Romania 011461

Romania

Instituto de Investigacion Biomedica de A Coruna (INIBIC)

A Coruña, Spain 15006

Spain

Hospital Universitario Germans Trias i Pujol

Badalona, Spain 8916

Spain

Hospital Universitari Vall d'Hebron-Institut de Recerca

Barcelona, Spain 8035

Spain

Hospital Clínico Universitario de Santiago

Santiago de Compostela, Spain 15706

Spain

Royal Devon and Exeter Hospital

Exeter, Devon EX25DW

United Kingdom

The Newcastle upon Tyne Hospitals NHS Foundation Trust - Royal Victoria Infirmary (RVI)

Newcastle upon Tyne, England NE1 4LP

United Kingdom

Addenbrooke's Hospital

Cambridge, United Kingdom CB2 0QQ

United Kingdom

St George's Hospital

London, United Kingdom SW17 0QT

United Kingdom

Royal Stoke University Hospital

Stoke-on-Trent, United Kingdom ST4 6QG

United Kingdom