Treatment of Acute Ischemic Stroke (ReMEDy2 Trial)

Study Overview
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Brief Summary
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This is a Phase 2/3 study evaluating the safety and efficacy of DM199 in treating participants presenting within 24 hours of Acute Ischemic Stroke (AIS) onset for whom fibrinolytics and/or a catheter-based procedure, mechanical thrombectomy (MT), are not medically appropriate or available due to constraints of clot location, comorbidity risks, and/or time from estimated onset of stroke. The double-blinded study will be randomized, placebo controlled at up to approximately 100 sites.

Detailed Description
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This is a randomized, double-blind, placebo-controlled Phase 2/3 adaptive, multi-center study to evaluate the safety and efficacy of DM199 for the treatment of acute ischemic stroke. Participants with AIS will be randomized 1:1 to DM199 or placebo (placebo is normal saline given with the same route (IV or SC), volume and frequency as DM199), administered as a single intravenous (IV) dose followed by a subcutaneous (SC) dose within 2-12 hours of IV dose completion and then 2 times per week for three weeks (until Day 21). After dosing is complete, participants will be followed up by the investigator at approximately 30 and 90 days after their first dose. A formal interim analysis will be conducted after 144 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 size of between 240 up to 728. The futility rule will be non-binding.

Official Title
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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)

Conditions
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Acute Stroke, Ischemic Stroke, Stroke

Intervention / Treatment
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* Drug: Recombinant human tissue kallikrein


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is ≥18 years of age. Participant weight is 50 kg to 160 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. Participant had a pre-morbid mRS score of 0 to 1 (mRS score prior to AIS) as stated by participant or participant's representative. 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: Participant has any evidence of intracranial hemorrhage. Participant has received or will receive fibrinolytics for their current AIS. Participant has image findings with symptomatic large vessel occlusion at one or more of the following locations: Intracranial carotid I/T/L, M1 or M2 segment MCA, vertebral or basilar artery (BA). Participant has large core of established infarction defined as ASPECTS 0-4. Participant has or will receive MT for their current AIS. Participant has imaging findings and/or symptoms consistent with a posterior circulation stroke. Participant has any recorded SBP < 100 mm HG or MAP <65 mm Hg; 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). If 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. 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 (example treatment of an uncomplicated urinary tract infections or sinus infections with oral antibiotics would not be an exclusion). 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) 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DM199<br>DM199 administered by a single intravenous (IV) dose followed by a subcutaneous (SC) dose within 12 hours and then 2 times a week for three weeks (until Day 21). | Drug: Recombinant human tissue kallikrein<br>* Treatment is completed by week 3 (Day 21). After dosing is complete, participants will be followed up by the investigator at approximately 30 and 90 days after their first dose.<br>* Other names: DM199;|
| Placebo Comparator: Placebo<br>Placebo administered by a single intravenous (IV) dose followed by a subcutaneous (SC) dose within 12 hours and then 2 times a week for three weeks (until Day 21). | Drug: Recombinant human tissue kallikrein<br>* Treatment is completed by week 3 (Day 21). After dosing is complete, participants will be followed up by the investigator at approximately 30 and 90 days after their first dose.<br>* Other names: DM199;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Efficacy Endpoint: Modified Rankin Scores (mRS) of 0 or 1 represent responders | Stroke recovery as defined by participants with excellent functional outcomes at Day 90 (mRS of 0 or 1 represent responders) as assessed via the mRS score 0 - 6 (0 =no symptoms, 6 = death). | Day 90 | 
| Number of adverse events during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Severity of adverse events during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Causality of adverse events during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Number of serious adverse events during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Severity of serious adverse events during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Causality of serious adverse events during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Number of adverse events of special interest (AESI) during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Severity of adverse events of special interest (AESI) during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Causality of adverse events of special interest (AESI) during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Tolerability: incidence of injection site adverse reactions during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Tolerability: severity of injection site adverse reactions during treatment with DM199 or placebo | All participants | Up to 90 days | 
| Change from baseline in resting heart rate (HR) | All participants | At Day 1, Day 4, Day 21, Day 30, and Day 90 | 
| Change from baseline in systolic blood pressure (SBP) | All participants | At Day 1, Day 4, Day 21, Day 30, and Day 90 | 
| Change from baseline in diastolic blood pressure (DBP) | All participants | At Day 1, Day 4, Day 21, Day 30, and Day 90 | 
| Change from baseline in respiratory rate (RR) | All participants | At Day 1, Day 4, Day 21, Day 30, and Day 90 | 
| Change from baseline in body temperature (BT) | All participants | At Day 1, Day 4, Day 21, Day 30, and Day 90 | 
| Change from baseline (normal or abnormal) in the General Appearance category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Skin category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the HEENT (Head, Eye, Ear, Neck and Throat) category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Respiratory category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Cardiovascular category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Abdomen/Gastrointestinal category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Neurological category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Lymph Nodes category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Extremities category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline (normal or abnormal) in the Musculoskeletal category during a physical exam. | All Participants | Day 30 and Day 90 | 
| Change from baseline of total bilirubin value (umol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of alkaline phosphatase value (U/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of gamma glutamyl transferase (gammaGT) value (U/L) n the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of aspartate aminotransferase value (U/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of alanine transaminase value (U/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of lactate dehydrogenase value (U/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of creatine value (umol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of urea value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total protein value (g/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total random glucose value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total inorganic phosphate value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total sodium value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total potassium value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total calcium value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total chloride value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total magnesium value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total bicarbonate value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total blood urea nitrogen value (mmol/L) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of total estimated glomerular filtration rate value (mL/min/1.73m2) in the clinical chemistry laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the total leukocytes value (GI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the hemoglobin value (g/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the hematocrit value (count) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the platelets value (GI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the partial automated differentiation value (%) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the lymphocytes value (GI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the monocytes value (GI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the eosinophils value (GI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the basophils value (GI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the neutrophils value (GI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the red blood cells value (TI/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the mean corpuscular volume value (fL) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the mean corpuscular hemoglobin value (g/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the mean corpuscular hemoglobin concentration value (g/L) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the red blood cell distribution width value (%) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the red blood cell count value in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline of the hemoglobin A1C (mg/dL) in the hematology laboratory assessment. | All Participants | Day 4, Day 30, and Day 90 | 
| Change from baseline in overall 12-lead interpretation (normal, abnormal) confirmed by physician. | All Participants | Day 1 and Day 90 | 
| Change from baseline in RR interval (s) measured on 12 lead ECG. | All Participants | Day 1 and Day 90 | 
| Change from baseline in PR interval (ms) measured on 12 lead ECG. | All Participants | Day 1 and Day 90 | 
| Change from baseline in QT interval (ms) measured on 12 lead ECG. | All Participants | Day 1 and Day 90 | 
| Change from baseline in QRS interval (ms) measured on 12 lead ECG. | All Participants | Day 1 and Day 90 | 
| Change from baseline in QTcF (Frederica's formula) (ms) measured on 12 lead ECG. | All Participants | Day 1 and Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of effect on disability across the full spectrum of AIS by examining the distribution of Modified Rankin Scores (mRS) | Assessment of effect on disability across the full spectrum of AIS by examining the distribution of mRS scores (scale range = 0 = no symptoms to 6 = death) at Day 90 evaluated by shift analysis. | Day 90 | 
| Assessment of patients who experience recurrent stroke | Recurrent AIS as defined by by proportion of patients who experience a recurrent AIS by Day 90 as assessed by a new, persistent neurological deficit attributable to cerebrovascular ischemia. Imaging findings, if available, should support the diagnosis. | Day 90 | 
| Proportion of participants achieving independent function (able to look after own affairs without assistance) with or without minor disability | Proportion of participants achieving independent function (able to look after own affairs without assistance) with or without minor disability at Day 90 assessed as mRS 0-2 (dichotomized) mRS scores of 0, 1 or 2 represent responders, scale range of 0-6. | Day 90 | 
| Mortality rate | Mortality rate as defined by event rate (%) for mortality over 90 days. | Over 90 days | 
| Proportion of patients receiving excellent neurological outcome | Proportion of patients achieving an excellent neurological outcome defined by National Institutes of Health Stroke Scale (NIHSS) = 0-1 (scale range 0 No Stroke to 42 severe stroke) (dichotomized) at Day 90. | Day 90 | 
| Proportion of patients achieving an excellent functional independence in activities | Proportion of patients achieving an excellent functional independence in activities of daily living defined by Barthel Index (BI) score greater than or equal to 95 (scale range 0 = Dependent on care to 100 = Normal) (dichotomized) at Day 90. | Day 90 | 
| Pharmacokinetics: Plasma concentration (ng/mL) of KLK1 | All participants | Baseline, Day 1, Day 2, Day 21, and Day 90 | 
| Immunogenicity | Presence or absence of plasma DM199 anti-drug antibodies (ADA) (+/-) in all participants, and if positive, units per litre (U/L). | Baseline and Days 2, 21, and 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute, ischemic, stroke, AIS, tPA, LVO, MT, KLK1, Kallikreins