Study to Assess the Safety and Efficacy of Sovateltide in Patients With Acute Cerebral Ischemic Stroke

Any unfavorable sign, symptom, or disease that occurs while using sovateltide will be reported as an adverse event (AE), including the worsening of pre-existing medical conditions. A severe medical occurrence, such as death, life-threatening situations, hospitalization, significant disability, or congenital anomalies will be reported as a serious adverse event (SAE). All AEs will be collected on CRFs from when the patient signs the informed consent form (ICF) until the study exit. Any SAE that is ongoing at the time the patient exits the study must be followed until the event is resolved or there is a satisfactory explanation that meets one of the following outcomes: 1. Resolved (With sequelae or without sequelae). 2. Death and 3. Unknown (Despite adequate follow-up).

The mRS measures independence rather than the performance of specific tasks. It accounts for both mental and physical adaptations to neurological deficits. The scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death (1: No significant disability despite symptoms; able to carry out all usual duties and activities, 2: Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, 3: Moderate disability; requiring some help, but able to walk without assistance, 4: Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability; bedridden, incontinent, and requiring constant nursing care and attention). A score of ≤ 2 on the mRS is considered a favorable outcome with minimal or no disability. In our study, mRS will be assessed on day 1, day 2, day 3, day 6, day 30, and 3 months.

NIHSS is the most widely used scale to assess stroke severity and subsequent stroke outcome.

It is a 42-point scale that measures neurological deficits and contains 15 items, including the level of consciousness, language function neglect, visual fields, eye movements, facial symmetry, motor strength, sensation, and coordination. The examination can be performed quickly. The NIHSS scoring is as follows: • Score 25: Very severe neurological impairment • Score 15-24: Severe impairment • Score 5-14: Moderately severe impairment • Score < 5: Mild impairment. NIHSS has been used extensively in clinical studies to measure stroke outcomes and has been validated and standardized to reduce inter-observer error. It will be assessed on day 1, day 2, day 3, day 6, day 30, and 3 months. In the case of dosing days (day 1, day 3, and day 6), the NIHSS score will be measured before administering the first study dose.

The BI is considered a reliable disability scale for stroke patients. It is a 10-item scale on which disability is assessed by various aspects of self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and a group related to mobility (ambulation, transfers, and stair climbing). Patients who score 100 (maximum score) on BI are fully independent in physical functioning. They are continent, can feed and dress themselves, get out of bed, walk more than 1 block, and perform activities of daily living. The lowest score is 0, representing a totally dependent bedridden state. Barthel index will be assessed on day 1, day 2, day 3, day 6, day 30, and 3 months.

NIHSS is the most widely used scale to assess stroke severity and subsequent stroke outcome.

It is a 42-point scale that measures neurological deficits and contains 15 items, including the level of consciousness, language function neglect, visual fields, eye movements, facial symmetry, motor strength, sensation, and coordination. The examination can be performed quickly. The NIHSS scoring is as follows: • Score 25: Very severe neurological impairment • Score 15-24: Severe impairment • Score 5-14: Moderately severe impairment • Score < 5: Mild impairment.

It will be assessed on day 1, day 2, day 3, day 6, day 30, and 3 months. In the case of dosing days (day 1, day 3, and day 6), the NIHSS score will be measured before administering the first study dose. Relative change at various time points will be calculated in each patient and improvement will be analyzed.

The mRS scale consists of 7 grades, from 0 to 6, with 0 corresponding to no symptoms and 6 corresponding to death (1: No significant disability despite symptoms; able to carry out all usual duties and activities, 2: Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance, 3: Moderate disability; requiring some help, but able to walk without assistance, 4: Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance, 5: Severe disability; bedridden, incontinent, and requiring constant nursing care and attention).

The mRS scoring will be assessed on day 1, day 2, day 3, day 6, day 30, and 3 months. Relative change in mRS at various time points will be calculated in each patient and improvement will be analyzed.

BI (Barthel Index) score is a 10-item scale on which disability is assessed by various aspects of self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and a group related to mobility (ambulation, transfers, and stair climbing). Patients who score 100 (maximum score) on BI are fully independent in physical functioning. They are continent, can feed and dress themselves, get out of bed, walk more than 1 block, and perform activities of daily living. The lowest score is 0, representing a totally dependent bedridden state.

BI will be assessed on day 1, day 2, day 3, day 6, day 30, and 3 months. Relative change in BI at various time points will be calculated in each patient and improvement will be analyzed.

EuroQol-EQ-5D is a generic measure of health status developed by an international research group, the EuroQol Group. EuroQol-EQ-5D defines health in terms of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is divided into 5 levels: no problem, slight problem, moderate problem, severe problem, and extreme problem. The scale is numbered from 0 to 100; 100 means the best health you imagine, and 0 is the worst health you imagine. The patient indicated his/her health by marking it on a numbered scale.

EuroQol will be assessed on day 1, day 6, day 30, and 3 months. Relative change in EuroQol at various time points will be calculated in each patient and improvement will be analyzed.

The SS-QOL is a self-report questionnaire consisting of 49 items in the 12 domains of energy, family roles, language, mobility, mood, personality, self-care, social roles, thinking, upper extremity function, vision, and work/productivity. The domains are scored separately, and a the total score is provided, with a minimum value of 1 (meaning the worst outcome) and a the maximum value of 5 (meaning the best outcome).

SS-QOL will be assessed on days 6, day 30, and 3 months. Relative change in SS-QOL at various time points will be calculated in each patient and improvement will be analyzed.

The data on stroke recurrence are helpful in examining trends, risk factors, and treatment effects.

Our study will assess the proportion of patients with recurrent cerebral ischemic stroke in sovateltide treated versus placebo-treated patients within 90 days of post-randomization.

Mortality or death is an indicator of the treatment risk factors as well as its effects on ischemic stroke.

Mortality will be assessed and compared in the placebo and sovateltide patients within 90 days post-randomization.

Intravenous thrombolysis (e.g., use of t-PA) is the most prevalent treatment strategy for acute ischemic stroke; however, it is associated with thrombolysis-related symptomatic intracerebral hemorrhage (ICH), which occurs in nearly 6% of patients and carries close to 50% mortality. Hence, an assessment of ICH is recommended for the development of new therapeutics to treat ischemic stroke.

In our study, radiographic or symptomatic ICH will be assessed in the placebo as well as in sovateltide-treated patients and their proportion will be analyzed.

The Alberta Stroke Programme Early Computed Tomography Score (ASPECTS) is widely used to determine the extent of early ischemic changes in brain imaging for acute stroke and is recognized by the American Heart Association guidelines for managing acute stroke. The ASPECT score is a 10-point quantitative score wherein 1 point is deducted for each defined middle cerebral artery (MCA) area showing any evidence of early ischemic change. The ten defined MCA regions include M1 - Anterior MCA cortex, M2 - MCA cortex lateral to the insular ribbon, M3 - posterior MCA cortex, M4 - anterior MCA territory, M5 - lateral MCA territory, M6 - posterior MCA territory, C - Caudate, L - Lentiform Nucleus, I - Insula, and IC - Internal Capsule. A score of 0 would indicate infarction of all 10 regions.