Treatment of Acute Ischemic Stroke (ReMEDy2 Trial) (ReMEDy2)

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)

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 approximately 75 sites.

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. An interim analysis is planned at the end of Part A after 144 participants complete their Day 90 assessments. Following the interim analysis, the study may be stopped for futility, stopped for overwhelming efficacy, or the study may be continued with a Part B sample size re-estimation for a total enrollment at between 240-728 participants. For planning purposes, approximately 339 participants are estimated to be randomized in Part B.

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)

To minimize bias, the participant and PI will be blinded to treatment assignment. All Sub-Investigators and other members of the study team will also remain blinded except for a designated unblinded pharmacist or designee responsible for compounding the assigned study treatment. The study team will remain blinded until all data is collected and database lock occurs.

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).

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).

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.

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).

Change from baseline (normal or abnormal) in the HEENT (Head, Eye, Ear, Neck and Throat) category during a physical exam.

Change from baseline (normal or abnormal) in the Abdomen/Gastrointestinal category during a physical exam.

Change from baseline of total bilirubin value (umol/L) in the clinical chemistry laboratory assessment.

Change from baseline of alkaline phosphatase value (U/L) in the clinical chemistry laboratory assessment.

Change from baseline of gamma glutamyl transferase (gammaGT) value (U/L) n the clinical chemistry laboratory assessment.

Change from baseline of aspartate aminotransferase value (U/L) in the clinical chemistry laboratory assessment.

Change from baseline of alanine transaminase value (U/L) in the clinical chemistry laboratory assessment.

Change from baseline of lactate dehydrogenase value (U/L) in the clinical chemistry laboratory assessment.

Change from baseline of total random glucose value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total inorganic phosphate value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total potassium value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total calcium value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total chloride value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total magnesium value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total bicarbonate value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total blood urea nitrogen value (mmol/L) in the clinical chemistry laboratory assessment.

Change from baseline of total estimated glomerular filtration rate value (mL/min/1.73m2) in the clinical chemistry laboratory assessment.

Change from baseline of the partial automated differentiation value (%) in the hematology laboratory assessment.

Change from baseline of the mean corpuscular volume value (fL) in the hematology laboratory assessment.

Change from baseline of the mean corpuscular hemoglobin value (g/L) in the hematology laboratory assessment.

Change from baseline of the mean corpuscular hemoglobin concentration value (g/L) in the hematology laboratory assessment.

Change from baseline of the red blood cell distribution width value (%) in the hematology laboratory assessment.

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.

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.

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.

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.

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.

Inclusion Criteria: Participant is ≥18 years of age. Participant weight is 50 kg to 160 kg inclusive. Participant has been diagnosed with AIS last known normal within 24 hours (+ 2 hours). Participant has NIHSS ≥3 and ≤ 20. Participant had a pre-morbid mRS score of 0 to 1 (mRS score prior to AIS) as stated by participant or family. 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 hemorrhagic stroke. Participant has received or will receive fibrinolytics for their current AIS. Participant with imaging findings consistent with large vessel occlusion: Participants with vascular imaging demonstrating occlusion of the M1 or M2 branches of the middle cerebral artery (MCA), internal carotid artery (ICA), vertebral or basilar artery (BA) AND Participants with evidence of extensive brain injury, including Alberta Stroke Program Early Computed Tomography (ASPECTS) < 5 points if a hemispheric infarct or cerebellar infarct > 3 cm in maximal diameter (per SoC image). Participant has or will receive MT for their current AIS. 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. 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 hysterectomy, bilateral oophorectomy, etc.) must have a negative urine pregnancy test performed 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 a combination of 2 of the following methods: Condoms Diaphragm or cervical cap Intra-uterine device Stable hormonal-based contraception 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 urine 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.