A phase 2b, multinational, randomized, double-blind study to investigate the efficacy and safety of redasemtide (S-005151) compared with placebo in adult participants with acute ischemic stroke

Trial ID: 2022-501890-38-00
Protocol: 2138P2231
Sponsor: Shionogi B.V.

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Diseases & Conditions

Ischaemic stroke

Objectives

The primary objective of this phase 2b, multinational, randomized, double-blind study is to compare the **efficacy** of redasemtide (S-005151) with that of placebo in adult participants with acute ischemic stroke who are not eligible for tissue plasminogen activator or thrombectomy. This objective is clinically relevant as it aims to determine the potential of redasemtide as a therapeutic option for patients with limited treatment alternatives, potentially improving outcomes in this patient population.

Secondary objectives include evaluating the **safety** and tolerability of redasemtide. These assessments are crucial to ensure that the therapeutic benefits of redasemtide do not come at the cost of unacceptable adverse effects, thereby supporting its overall clinical utility and informing future clinical practice.

Participants

The clinical trial involves a total of **192 participants** diagnosed with **acute ischemic stroke**. The study population includes both male and female adults aged 18 years and older, adhering to country-specific regulatory requirements. Participants are required to be medically stable at the time of enrollment, with a body weight ranging from 30 to 150 kg. The trial population was selected based on their ability to initiate study intervention within 25 hours of stroke onset and their ineligibility for recanalization thrombolysis or endovascular recanalization therapy. Participants must have a baseline NIHSS score between 8 and 22, and they should not require significant changes in therapy for three months following enrollment. The study includes individuals who are capable of providing informed consent or have consent provided by a legally authorized representative. Female participants must not be pregnant or breastfeeding and must adhere to contraceptive requirements if of childbearing potential. The trial considers vulnerable populations, ensuring ethical compliance and protection throughout the study.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy and safety of **redasemtide** (S-005151) compared to placebo in adult participants with **acute ischemic stroke** who are not eligible for tissue plasminogen activator or thrombectomy. The trial is set to last for approximately six months, with an estimated recruitment start date of August 1, 2023, and an estimated end date of December 31, 2024. Participants will be randomly assigned to receive either redasemtide or a placebo, administered via **intravenous infusion** once daily over 90 minutes for five consecutive days during hospitalization.

The study involves several key visits, beginning with an inclusion (screening) visit where eligibility is confirmed through criteria such as age, ability to provide informed consent, and a confirmed diagnosis of supratentorial ischemic stroke via CT or MRI. Participants must be able to initiate the study intervention within 25 hours of stroke onset and must not be eligible for recanalization therapies. The baseline NIHSS score must be between 8 and 22, and participants must be medically stable at the time of enrollment.

Following the treatment period, participants will undergo a series of follow-up visits at Day 30, Day 90, and Day 180 to assess primary and secondary endpoints, including the modified Rankin Scale (mRS) score and Barthel Index (BI) score. The primary endpoint is the mRS score at Day 90, while secondary endpoints include various measures of functional and neurological outcomes at each visit. The end-of-study visit will occur at Day 180, marking the conclusion of participant involvement.

Participant involvement is expected to last for the entire six-month duration of the trial, barring any conditions that may lead to early termination, such as significant adverse events or withdrawal of consent. The study is designed to ensure the safety and well-being of participants, with regular monitoring of treatment-emergent adverse events, clinical laboratory tests, vital signs, ECGs, and other safety assessments throughout the trial period.

Treatment

The clinical trial involves the administration of **redasemtide** (S-005151), an investigational medicinal product, in adult participants with acute ischemic stroke who are not eligible for tissue plasminogen activator or thrombectomy. Redasemtide is provided in the form of a **lyophilized powder** and is administered via **intravenous infusion**. The dosing regimen for redasemtide is based on body weight, with a maximum daily dose of 1.5 mg/kg and a total maximum dose of 7.5 mg/kg over a treatment period of up to 5 days. The active substance, redasemtide, is a polypeptide of protein origin, and the product is manufactured by SHIONOGI B.V. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** group to match S-005151, which serves as the comparator treatment. The placebo is designed to mimic the appearance and administration route of the investigational product, ensuring the study remains double-blind. The placebo does not contain any active pharmaceutical ingredients and is used to assess the efficacy and safety of redasemtide by providing a baseline for comparison. Participants are randomly assigned to receive either redasemtide or the placebo, and the administration schedule for the placebo mirrors that of the investigational product to maintain consistency across the study arms.

Efficacy

The efficacy of redasemtide (S-005151) in the treatment of acute ischemic stroke will be assessed through a series of primary and secondary endpoints. The primary endpoint is the **modified Rankin Scale (mRS) score** at Day 90. Secondary endpoints include the proportion of participants with an mRS score of 0 to 2 at Day 90, the proportion of participants with a Barthel Index (BI) score of ≥ 95 at Day 90, mRS scores at Day 30 and Day 180, and various other measures of neurological and functional outcomes at each visit. These include the proportion of participants with mRS scores of 0 or 1, 0 to 2, and 5 or 6, as well as changes in the National Institutes of Health Stroke Scale (NIHSS) scores and other patient-reported outcomes such as the SF-36 and SAQoL-39g.

Efficacy assessments will be conducted at multiple timepoints, including Day 30, Day 90, and Day 180, to evaluate both short-term and long-term outcomes. The mRS and NIHSS scores will be used to measure neurological function and recovery, while the BI score will assess the degree of independence in daily activities. Patient-reported outcomes will provide additional insights into the quality of life and perceived changes in health status. The analysis will involve comparing the outcomes between the redasemtide and placebo groups to determine the treatment's effectiveness in improving stroke-related symptoms and overall recovery.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1.Male or female adults ≥ 18 years of age (or complies with country-specific regulatory requirements) at the time of obtaining informed consent
10.Body weight of ≥ 30 to ≤ 150 kg
11.A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: - Is a woman of nonchildbearing potential (WONCBP) as defined in Section 10.4.1 (Appendix 4) OR - Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method as described in Section 10.4 (Appendix 4) during the 5-day Treatment Period. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. A WOCBP (defined in Section 10.4.1 [Appendix 4]) must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention are provided in Section 8.3.6. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
Cohort A: If a participant is not eligible for systemic thrombolysis and/or mechanical recanalization therapy, Screening and Baseline NIHSS score of to 22 (inclusive) is required and must be stable, defined as absence of an increase or decrease of ≥ 4 points within ≥ 1 hour to ≤ 3 hours Screening, and NIHSS score should be 6 to 22 at Baseline.
2.Capable of giving signed informed consent as described in the ICF that includes compliance with the national requirements and the requirements and restrictions listed in the ICF and in this protocol. If the participant cannot provide consent, consent from the participant’s proxy/legally authorized representative (LAR) is allowed according to local regulations. Note: Country-specific rules and local Ethics Committee approval for proxy/LAR will determine whether or not and how a participant unable to comprehend or sign the ICF is allowed to be enrolled in the study.
3.Diagnosis of supratentorial (including anterior and posterior circulation) ischemic stroke as the main infarction site, confirmed by computed tomography (CT) scan or magnetic resonance imaging (MRI) at the time of screening. The CT imaging criteria are hypodensity, perfusion deficit, or vessel occlusion in the anterior or posterior circulation.
4.Able to initiate study intervention within 25 hours of stroke onset (if the onset time is unknown, the last time at which the participant was known to be healthy is regarded as the onset time [“last known to be well”])
Cohort A: Determined by the investigator to not be eligible for systemic thrombolysis and/or mechanical recanalization therapy (ie, mechanical thrombectomy, local fibrinolytic therapy as per local standard of care) for the current stroke as detailed in the Participant Hospitalization Sheet. For every randomized participant, the investigator should complete the Participant Hospitalization Sheet (see Section 8) prior to randomization, including the reason for the participant not being eligible for thrombolytic therapy. (Note: Participants who underwent mechanical thrombectomy, but for whom a stent could not be placed to reach the occluded vessel site may be eligible for this study.) Please refer to the most recent tPA package for contraindications.
6 Cohort B: Determined by the investigator to be eligible for systemic thrombolysis and/or mechanical recanalization therapy (ie, mechanical thrombectomy, local fibrinolytic therapy as per local standard of care) for the current stroke as detailed in the Participant Hospitalization Sheet. Initiation of systemic thrombolysis must occur within the country-specific established clinical window from the onset of stroke and mechanical recanalization therapy must occur within 24 hours from the onset of stroke. Note: Thrombolytic agent includes not only recombinant human tPA, but also its engineered derivatives.
9.Medically stable at the time of enrollment except for primary disease and complications associated with it, according to the judgment of the investigator. In addition, hospitalization during the Follow-up Period is not anticipated, and the participant appears likely to be able to complete the study
8.Cohort B: In a participant who is eligible to receive or have received concomitant systemic thrombolysis and/or mechanical recanalization therapy, the NIHSS score must be 6 to 22 at Screening prior to systemic thrombolysis and/or mechanical recanalization therapy and the second /Baseline NIHSS score must be 6 to 22 and should be collected after systemic thrombolysis and/or mechanical recanalization therapy. The investigator should ensure the participant is fully recovered from sedation and/or anesthesia for mechanical recanalization therapy prior to confirmation of NIHSS score.

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Exclusion Criteria

Any disease or neurological disorder that, in the opinion of the investigator, would interfere with the conduct of the study
A severe decrease in consciousness level (defined as NIHSS item 1a score 3: Not alert, responds only with reflex motor or autonomic effects, or totally unresponsive, flaccid, and areflexic)
Disability corresponding to a mRS score of ≥ 2 before the onset of stroke
A history of stroke (excluding transient ischemic attack), history of or current intracranial hemorrhage, or head trauma that caused neurological effects within 90 days prior to obtaining informed consent
Participants with an ischemic stroke in cerebellum and/or brain stem as the main infarction site
Diagnosis of a current transient ischemic attack
Unable to undergo either CT or MRI
Considered by the investigator to be inappropriate to participate due to a history or complication of serious cardiovascular disease within 1 month of screening (eg, history of acute myocardial infarction, current acute myocardial infarction, uncontrollable heart failure, infective endocarditis requiring treatment, or acute aortic dissection, or requiring or likely to require hospitalization for severe arrhythmia during the study)
Blood glucose level < 50 or > 400 mg/dL after glycemic control
Systolic blood pressure ≥ 220 mm Hg or diastolic blood pressure ≥ 120 mm Hg after antihypertensive treatment
Any malignant tumor except nonmelanoma skin cancer or lesions equivalent to intramucosal cancer or carcinoma in situ curable by endoscopic resection. OR if the participant with a malignant tumor is undergoing or has completed systemic anti-cancer treatment (chemotherapy, immunotherapy) or radiotherapy within 1 month prior to Screening and is not medically stable based on the assessment of the investigator
Sensitivity to any of the study interventions, or components thereof, or clinically significant drug or other severe allergy that, in the opinion of the investigator, contraindicates participation in the study
Use of prohibited concomitant medications or therapies listed in Section 6.8 for the treatment of current AIS
Participants who have previously received redasemtide
Participants who have received any investigational product within 90 days of Screening

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	01 Aug 2023	1
Czechia	Not Recruiting	01 Aug 2023	8
Denmark	Not Recruiting	01 Aug 2023	1
Finland	Not Recruiting	01 Aug 2023	11
France	Not Yet Recruiting	01 Aug 2023	32
Germany	Not Recruiting	01 Aug 2023	4
Greece	Not Recruiting	01 Aug 2023	65
Hungary	Not Recruiting	01 Aug 2023	35
Spain	Not Recruiting	01 Aug 2023	81