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)

The primary objective of this study is to evaluate the safety and efficacy of DM199 (rinvecalinase alfa) in participants with moderate acute ischemic stroke severity who present within 24 hours of symptom onset or last known normal, specifically in cases resulting from small and medium vessel occlusions. This trial targets a patient population with limited treatment options, excluding those who have undergone or will undergo mechanical thrombectomy. Participants who received fibrinolytic therapy are also excluded unless they demonstrate a persistent neurological deficit of moderate severity six or more hours following fibrinolytic treatment. The clinical relevance lies in addressing an unmet therapeutic need for patients with moderate stroke severity who are not candidates for standard interventions such as mechanical thrombectomy or who have not adequately responded to fibrinolytic therapy.

This clinical trial enrolled a total of **628 participants** diagnosed with **acute ischemic stroke** of moderate severity. The study population included both **male and female** adults aged **18 to 90 years**, with body weight ranging from **40 kg to 166 kg**. Participants were required to have a **National Institutes of Health Stroke Scale (NIHSS)** score between **5 and 15** at the time of randomization, indicating moderate stroke severity. The trial specifically targeted individuals with stroke due to **small and medium vessel occlusions** who presented within **24 hours** of stroke onset or last known normal time. Participants were required to have a **pre-morbid modified Rankin Scale (mRS)** score of **0 to 1**, reflecting functional independence prior to the stroke event. The selection criteria excluded individuals who had received or were planned to receive **mechanical thrombectomy**. Participants who had undergone **fibrinolytic treatment** were eligible only if they demonstrated a persistent neurological deficit of moderate severity at least **six hours** after fibrinolytic administration, with less than a **4-point improvement** in NIHSS score or worsening of symptoms. The trial focused on stroke patients with limited treatment options while ensuring that standard of care therapies were not withheld when clinically appropriate.

This Phase 2/3 adaptive design, randomized, double-blind, placebo-controlled clinical trial evaluates the safety and efficacy of DM199 (rinvecalinase alfa) in participants with moderate severity acute ischemic stroke. The study focuses on patients presenting within 24 hours of stroke onset or last known normal due to small and medium vessel occlusions who have limited treatment options. Participants who have received or will receive mechanical thrombectomy are not eligible. Participants who received fibrinolytics are excluded unless they exhibit a persistent neurological deficit of moderate severity six or more hours after fibrinolytic treatment. The trial is designed to ensure that participants are not denied standard of care therapies when appropriate.

The investigational product rinvecalinase alfa is administered as a solution for injection via parenteral route. The maximum daily dose is 548 micrograms, with a maximum total dose of 3536 micrograms over a maximum treatment period of 21 days. The control group receives a centrally blinded placebo product containing all the same manufactured ingredients and excipients as the DM199 formulation, except for the active pharmaceutical ingredient.

Eligible participants must be between 18 and 90 years of age with body weight ranging from 40 kg to 166 kg inclusive. Randomization and initiation of investigational product infusion must occur within 24 hours of last known normal or stroke onset. At the time of randomization, participants must have a National Institutes of Health Stroke Scale (NIHSS) score of 5 to 15 inclusive. Participants must have had a pre-morbid modified Rankin Scale (mRS) score of 0 to 1. For participants who received fibrinolytic treatment within 4.5 hours of stroke onset, specific criteria apply: the initial NIHSS score prior to fibrinolytics must have been 15 or below, at least six hours after fibrinolytic treatment the participant must demonstrate an NIHSS score of 5 to 15 with persistent deficit, the NIHSS score must show less than a 4-point improvement or have worsened after fibrinolytics, and repeat brain imaging must rule out hemorrhagic transformation. Hemorrhagic transformation is defined as PH1 or PH2 type hemorrhage based on Heidelberg Classification or hemorrhage resulting in neurologic deterioration, while HI1 and HI2 type hemorrhages are not exclusionary. Participants or their legally authorized representatives must be able to provide informed consent and willing to comply with the study protocol.

The primary efficacy endpoint is stroke recovery defined by participants achieving excellent functional outcomes at Day 90 as assessed via the modified Rankin Scale, with scores of 0 or 1 representing responders on a scale range of 0 to 6. Primary safety endpoints include the incidence, severity, and causality of adverse events and serious adverse events, adverse events of special interest, and tolerability assessed by incidence and severity of injection site adverse reactions. Additional safety assessments include changes from baseline in physical examination at Day 21 and Day 90, changes in vital sign measurements including resting heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature at Days 1, 4, 21, and 90, changes in hematology and chemistry parameters at Days 4, 21, and 90, and changes from baseline in 12-lead electrocardiogram at Day 1 and Day 90.

Secondary endpoints include assessment of disability across the full spectrum of acute ischemic stroke by examining the distribution of modified Rankin Scale shift scores at Day 90, proportion of participants achieving independent function with or without minor disability at Day 90 assessed as mRS 0 to 2, mortality rate defined by event rate percentage over 90 days, proportion of participants achieving excellent neurological outcome defined by NIHSS score of 0 to 1 at Day 90, proportion of participants achieving excellent functional independence in activities of daily living defined by Barthel Index score of 95 or greater on a scale range of 0 to 100 at Day 90, and recurrent acute ischemic stroke assessed as the proportion of participants who experience a recurrent stroke by Day 90 defined by a new persistent neurological deficit attributable to cerebrovascular ischemia with supportive imaging findings if available.

The estimated recruitment start date is December 25, 2025, with an estimated study completion date of December 31, 2026. Participant involvement spans approximately 90 days from randomization, with study visits scheduled at baseline, Days 1, 4, 21, and Day 90 for safety and efficacy assessments. Early termination from the study may occur based on safety concerns, participant withdrawal of consent, loss to follow-up, or at the investigator's discretion if continued participation is not in the participant's best interest.

The experimental treatment consists of **DM199** (**rinvecalinase alfa**), a recombinant **protein** therapeutic agent. DM199 is formulated as a **solution for injection** administered via **parenteral route**. The **active pharmaceutical ingredient** is rinvecalinase alfa, an engineered variant of human kallikrein-1 with specific amino acid modifications (E121>Q, A164>V), glycoform alfa. The **maximum daily dose** is 548 micrograms, with a **maximum total dose** of 3536 micrograms administered over a **maximum treatment period** of 21 days. The product is manufactured by DiaMedica Therapeutics Inc. and is designated with the sponsor product code DM199.

The **placebo** comparator is a centrally blinded product containing all the same manufactured ingredients and **excipients** as the DM199 formulation, except for the active pharmaceutical ingredient. This matching placebo ensures maintenance of study blinding throughout the trial. The placebo is administered using the same route and schedule as the experimental treatment to maintain consistency in study procedures and minimize potential bias.

The study employs a **randomized, double-blind, placebo-controlled** design to evaluate the safety and efficacy of DM199 in participants with **acute ischemic stroke** of moderate severity. Participants must present within 24 hours of stroke onset or last known normal time. The trial specifically targets patients with small and medium vessel occlusions who have limited treatment options. Participants who have received or will receive **mechanical thrombectomy** are excluded from participation. Additionally, participants who have received **fibrinolytics** are excluded unless they demonstrate a persistent neurological deficit of moderate severity six or more hours after fibrinolytic treatment. The study protocol ensures that participants are not denied access to **standard of care** therapies for acute ischemic stroke, such as fibrinolytics or mechanical thrombectomy, when clinically appropriate.

Efficacy will be assessed through multiple parameters evaluating stroke recovery and functional outcomes. The primary efficacy endpoint is stroke recovery defined by participants achieving excellent functional outcomes at Day 90 as assessed via the **modified Rankin Score** (mRS) dichotomized, where mRS scores of 0 or 1 represent responders on a scale range of 0 to 6. Secondary efficacy endpoints include the assessment of effect on disability across the full spectrum of **acute ischemic stroke** by examining the distribution of mRS shift scores (scale range 0 to 6) at Day 90. Additional secondary endpoints comprise the proportion of participants achieving independent function with or without minor disability at Day 90 assessed as mRS 0-2 dichotomized, where mRS scores of 0, 1, or 2 represent responders on a scale range of 0 to 6. Mortality rate will be evaluated as the event rate for mortality over 90 days. The proportion of participants achieving an excellent neurological outcome will be defined by **NIHSS** score of 0-1 dichotomized (scale range 0 to 42) at Day 90. Functional independence in activities of daily living will be assessed through the proportion of participants achieving a **Barthel Index** score dichotomized greater than or equal to 95 (scale range 0 to 100) at Day 90. Recurrent acute ischemic stroke will be evaluated as the proportion of participants who experience a recurrent event by Day 90, assessed by a new persistent neurological deficit attributable to cerebrovascular ischemia, with imaging findings supporting the diagnosis when available.