A Phase IIa, Open Label, Proof of Concept Study to Evaluate the Safety of Aqueous Afamelanotide Solution in Patients with acute Arterial Ischaemic Stroke (AIS) who are ineligible for Intravenous Thrombolysis (IVT) or Endovascular Thrombectomy (EVT)

The primary objective of this study is to evaluate the **safety** of afamelanotide in patients with acute Arterial Ischaemic Stroke (AIS) who are ineligible for Intravenous Thrombolysis (IVT) or Endovascular Thrombectomy (EVT). This is clinically relevant as it addresses the need for alternative therapeutic options in AIS patients who cannot undergo standard revascularization procedures, potentially improving patient outcomes and expanding treatment possibilities.

Secondary objectives include:

• Evaluating the impact of afamelanotide on neurological functions in AIS patients using the National Institutes of Health Stroke Scale (NIHSS).
• Identifying changes in reperfusion of the ischaemic penumbra, specifically the ischaemic core and/or the penumbral ischaemic zone (salvageable tissue), following treatment with afamelanotide.
• Assessing cognitive functions and activities of daily living in AIS patients after treatment with afamelanotide.

The clinical trial focuses on evaluating the safety of afamelanotide in patients with **Arterial Ischaemic Stroke (AIS)**. The study population includes both male and female subjects, aged between 18 and 85 years, who have been diagnosed with their first AIS. The trial aims to recruit a total of twelve patients, with six experiencing mild to moderate stroke severity and six experiencing moderate to severe stroke severity. Participants are selected based on specific criteria, including an NIHSS score of 1-15 for at least three patients and a score greater than 15 for another three, with perfusion abnormalities observed on Computed Tomography Perfusion (CTP). The remaining patients may not show perfusion abnormalities but have clinically suspected AIS. All participants must have a pre-stroke modified Rankin Scale (mRS) score of less than 4. The trial includes a vulnerable population, and written informed consent is required from the patient or their medical treatment decision maker prior to study commencement. The sponsor has not provided information regarding the total number of participants.

The clinical trial is a **Phase IIa** open-label, proof-of-concept study designed to evaluate the safety of an aqueous solution of **afamelanotide** in patients with acute **Arterial Ischaemic Stroke (AIS)** who are ineligible for Intravenous Thrombolysis (IVT) or Endovascular Thrombectomy (EVT). The trial is set to commence on January 2, 2023, and is expected to conclude by February 2, 2025. The study involves the administration of afamelanotide as a **solution for injection**. The primary objective is to assess the safety of afamelanotide by monitoring and recording treatment-emergent adverse events (TEAEs). Secondary endpoints include evaluating changes in NIHSS scores, reperfusion volume of the ischaemic core and penumbral ischaemic zone, mRS scores, and MMSE scores compared to baseline and pre-stroke conditions.

Participants will be recruited based on specific inclusion criteria, including a diagnosis of first AIS, age between 18 and 85 years, and written informed consent. The study will enroll six patients with mild to moderate stroke severity and six with moderate to severe stroke severity. At least three patients will have an NIHSS score of 1-15, and at least three will have a score greater than 15, with perfusion abnormalities observed on Computed Tomography Perfusion (CTP). The trial will exclude individuals who do not meet these criteria.

The trial design does not include randomization or blinding, as it is an open-label study. Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility. Follow-up visits will be scheduled to monitor safety and efficacy outcomes, with the final visit marking the end of the study. The expected duration of participant involvement is aligned with the trial's overall timeline, from recruitment to the end-of-study visit. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or withdrawal of consent by the participant.

The clinical trial involves the administration of the experimental medication **afamelanotide**, marketed under the name **PRENUMBRA**. This medication is provided in the form of a **solution for injection**. The active substance, afamelanotide, is a protein of other origin, developed by CLINUVEL PHARMACEUTICALS LTD. The pharmaceutical form is specifically designed for injection, ensuring direct delivery into the bloodstream. The trial aims to evaluate the safety of afamelanotide in patients with acute Arterial Ischaemic Stroke (AIS) who are ineligible for Intravenous Thrombolysis (IVT) or Endovascular Thrombectomy (EVT). The dosing regimen is determined by the study protocol, with the maximum treatment period set at one day. The dosage is measured in milligrams per kilogram (mg/kg), although specific dosing amounts are not provided in the trial data.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus remains solely on the administration of afamelanotide to assess its safety profile in the specified patient population. Participant compliance with the dosing schedule is monitored as per the trial's protocol, ensuring adherence to the treatment regimen. The trial does not specify any additional medications or interventions, emphasizing the isolated evaluation of afamelanotide's effects.

Efficacy in this clinical trial will be assessed using several secondary endpoints. These include the National Institutes of Health Stroke Scale (NIHSS) scores, which will be compared to baseline measurements to evaluate changes in stroke severity. Additionally, the reperfusion volume of the ischaemic core and the penumbral ischaemic zone, which represents salvageable tissue, will be measured. The Modified Rankin Scale (mRS) scores will also be compared to both baseline and pre-stroke levels to assess functional outcomes. Furthermore, Activities of Daily Living (ADL) and Mini-Mental State Examination (MMSE) scores will be evaluated against baseline and pre-stroke values to determine improvements in daily functioning and cognitive status.