Treatment of Acute Ischemic Stroke (ReMEDy2 Trial)

Official title

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)

Overview

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.

Interventions

• Drug Recombinant human tissue kallikrein
  DM199 administered by a single intravenous (IV) dose 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
• Other Placebo for DM199 Solution for Injection
  Placebo administered by a single intravenous (IV) dose 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.

Primary outcome measures

• Stroke Recovery [Time frame: Day 90]

Secondary outcome measures (6)

• Effect on Disability [Time frame: Day 90]
• Independent Function [Time frame: Day 90]
• Mortality Rate [Time frame: Day 90]
• Neurological Outcome [Time frame: Day 90]
• Functional Independence [Time frame: Day 90]
• AIS Recurrence [Time frame: Day 90]

Eligibility criteria

Inclusion criteria

• Participant is between 18 and 90 years of age inclusive.
• Participant weight is 40 kg to 166 kg inclusive.
• Participant to be randomized and treatment initiated within 24 hours of last known normal/AIS stroke onset.
• 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.
• Participant had a pre-morbid mRS score of 0 to 1 (mRS score prior to AIS) as stated by participant or participant's representative.
• 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.
• Participant and/or legally authorized representative is able to provide informed consent.
• Participant is willing and able to comply with the study protocol, in the Investigator's judgment.

Exclusion criteria

• At screening, or with repeat imaging (see Inclusion 4 and 6), participant has imaging confirmed hemorrhage stroke.
• 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).
• Participant has large core of established infarction defined as ASPECTS 0-5.
• Participant has or will receive MT for their current AIS.
• Participant has suspected or confirmed extracranial arterial dissection.
• 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.
• 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.
• 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).
• 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.
• Participant has a history of clinically significant allergic reactions such as angioedema or anaphylaxis requiring hospitalization.
• 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.
• Life expectancy estimated at ≤1 year prior to enrollment.
• 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).

• Participant has known alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency).
• Participant is pregnant or nursing. NOTE: Participants who agree to stop nursing may be considered for inclusion at the discretion of the Investigator.
• 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.

• 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.
• Participant does not have sufficient venous access for infusion of study treatment or blood sampling.
• Participant is unable or unwilling to comply with protocol requirements, including assessments, tests, and follow-up visits.
• Participant has any other medical condition which in the opinion of the Investigator will make participation medically unsafe or interfere with the study results.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 35 centers

• Gulf Health Hospitals d/b/a Thomas Hospital — Fairhope
• USC Arcadia Hospital — Arcadia
• Glendale Adventist Medical Center d/b/a Adventist Health Glendale — Glendale
• Kaiser Permanente Los Angeles Medical Center — Los Angeles
• Ronald Reagan UCLA Medical Center — Los Angeles
• Stanford Health Care — Stanford
• The Lundquist Institute at Harbor UCLA Medical Center — Torrance
• Memorialcare Long Beach Medical Center — Torrance
• … and 27 more centers

Belgium · 5 centers

• Imeldaziekenhuis (Imelda Hospital) — Bonheiden
• UZ Gent — Ghent
• Jessa Ziekenhuis — Hasselt
• AZ Groeninge — Kortrijk
• Clinique St Pierre — Ottignies

Canada · 5 centers

• University of Alberta Hospital — Edmonton
• Vancouver General Hospital — Vancouver
• Health Sciences North — Hamilton
• Hamilton Health Sciences - Hamilton General Hospital — Hamilton
• Sunnybrook Research Institute — North York

Georgia · 5 centers

• West Georgia Medical Center LTD — Kutaisi
• Israel-Georgia Medical Research Clinic-Healthycore LTD — Tbilisi
• New Hospitals LTD — Tbilisi
• Pineo Medical Ecosystem LTD — Tbilisi
• JSC K. Eristavi National Center of Experimental and Clinical Surgery — Tbilisi

United Kingdom · 5 centers

• Royal Devon and Exeter Hospital — Exeter
• The Newcastle upon Tyne Hospitals NHS Foundation Trust - Royal Victoria Infirmary (RVI) — Newcastle upon Tyne
• Addenbrooke's Hospital — Cambridge
• St George's Hospital — London
• Royal Stoke University Hospital — Stoke-on-Trent

Hungary · 4 centers

• Bajcsy-Zsilinszky Hospital — Budapest
• St. Damjan Greek Catholic Hospital — Kisvárda
• B.-A.-Z. County Central Hospital — Miskolc
• Petz Aladár County Teaching Hospital — Győr

Spain · 4 centers

• Instituto de Investigacion Biomedica de A Coruna (INIBIC) — A Coruña
• Hospital Universitario Germans Trias i Pujol — Badalona
• Hospital Universitari Vall d'Hebron-Institut de Recerca — Barcelona
• Hospital Clínico Universitario de Santiago — Santiago de Compostela

Romania · 2 centers

• Fundeni Clinical Institute — Bucharest
• Elias Emergency University Hospital — Bucharest

France · 1 center

• CHU Pontchaillou /Hopital Sud Service de Neurologie — Rennes

Identifiers

NCT: NCT05065216 · DM199-2021-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗