This study will include adults (ages 18-80) who have had a stroke caused by a large blood clot blocking blood flow in the brain. All patients in the study must have already had a treatment called a thrombectomy, where doctors remove the clot to help blood flow return to the brain.

The goal of this study is to test the safety of a drug called EMPAVELI (pegcetacoplan). This drug is meant to lower swelling and inflammation that can happen after blood flow returns. The hope is that it may help protect the brain from more damage and improve recovery.

People in the study will get three doses of EMPAVELI through an EMPAVELI-designed pump 0-3 hours post thrombectomy surgery and 24 and 48 hours after the initial dose. Doctors will check them with exams, blood tests, brain scans, and other tests while they are there. Patients will also have follow-up visits at 30 and 90 days to see how they are doing, per the usual standard of care.

This research is important because, even with current stroke treatments, many patients still have problems like disability. If this drug is found to be safe, it could lead to better treatments to protect the brain and help people recover more fully after a stroke.

Acute ischemic stroke (AIS) remains the primary cause of disability worldwide. Advances in revascularization therapies such as pharmacologic thrombolysis and intra-arterial endovascular thrombectomy (EVT) have improved outcomes, yet >50% of patients remain functionally disabled at 90 days post-ictus onset despite high recanalization rates. One major reason for this limited recovery is the activation of thrombo-inflammatory processes beyond the initial vessel occlusion. These processes contribute to reperfusion injury and secondary brain damage, which current standard-of-care treatments fail to address. EMPAVELI (Pegcetacoplan) is a targeted C3 inhibitor developed by Apellis Pharmaceuticals. It is FDA-approved for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH) and has demonstrated effective inhibition of complement-mediated inflammation. By selectively inhibiting C3, EMPAVELI prevents excessive complement activation while preserving key immune functions, making it an attractive candidate for neuroprotection in AIS patients.

This is a prospective, single-center, open-label, single-arm, interventional clinical trial. It is designed to assess the safety and tolerability of a single subcutaneous dose of the complement C3 inhibitor EMPAVELI (pegcetacoplan) in adult patients with AIS due to anterior circulation LVO who have undergone successful or near-complete EVT. The study is classified as a Phase 1experimental trial with a primary focus on safety. There is no randomization, no control group, and no blinding. The design is non-randomized and non-comparative, using historical controls for contextual reference only. All enrolled subjects will receive the same intervention: three subcutaneous injections of EMPAVELI (1,080 mg) administered within 3 hours post-reperfusion and at 24 and 48 hours after the initial dose, aligning with the acute thrombo-inflammatory phase of stroke recovery.

The study involves serial clinical and laboratory assessments over a 90-day period, including pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcome measurements (e.g., NIHSS, mRS, GCS, Barthel Index). Safety assessments will include adverse event (AE) monitoring, laboratory studies (CBC, BMP, liver function tests), vital signs, and imaging. Imaging includes MRIs and TCDs, both in the standard of care at CUIMC. Follow-up evaluations will be conducted in person (up to 72 hours or hospital discharge) and via telephone at Days 30 and 90.

The study does not involve any ethnographic or qualitative methodology and is not observational in nature. Its primary purpose is to generate foundational safety data to inform future randomized controlled trials assessing the efficacy of EMPAVELI in AIS patients.

Inclusion Criteria:

• Adults (18-80 years old)
• Diagnosis of AIS due to anterior circulation (Intracranial ICA, M1 MCA) LVO with evidence of complete/near-complete revascularization following EVT (mTICI ≥2b).
• Enrollment within 24 hours of reperfusion, with reperfusion occurring within 24 hours of ictus onset.
• Body weight ≥ 50 kg.
• Absolute reticulocyte count >1.0 x ULN
• Platelet count of >50,000/mm³
• Absolute neutrophil count (ANC) ≥ 1500/mm³ at
• Vaccination against Neisseria meningitidis types A, C, W, Y and B, Streptococcus pneumoniae and Haemophilus influenzae Type B (Hib) either within 2 years prior to Day1 dosing, or within 14 days after EMPAVELI. Unless documented evidence exists, that subjects are non-responders to vaccination as evidenced by titers or display titer levels within acceptable local limits
• Women of child-bearing potential (WOCBP) must have a negative pregnancy test and must agree to use protocol defined methods of contraception for the duration of the study and 90 days after study drug administration.
• Males must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study and 90 days after study drug administration.
• English/Spanish-speaking patients or legally authorized representatives (LARs).
• Signed informed consent from the patient or LAR.

Exclusion Criteria:

• Pregnant or lactating female
• Suspected pregnancy.
• Renal insufficiency (GFR<30mL/minute OR creatinine >2 mg/dL OR need for renal replacement therapy (RRT) at time of admission).
• Platelet count < 50,000/mm³
• Absolute neutrophil count <1500/mm³
• Baseline mRS >2
• Presence of concomitant serious illness that would confound study, including but not limited to serious psychiatric or autoimmune disease, sepsis, or trauma.
• Immunocompromised status (e.g., subjects with Human Immunodeficiency Virus [HIV] infection, neutropenia, complement deficiency, etc.)
• Autoimmune disorder (Sjogren's Disease, Psoriasis, hediak-Higashi Syndrome)
• Presence of any intracranial bleed (ICH, SAH, SDH, hemorrhagic lesion).
• Active hepatic failure as defined by AST >160 units/L and/or ALT >180 units/L, or total bilirubin levels greater than four times normal levels (>4.8mg/dL).
• Continued use of digoxin or amlodipine (as recommended by the manufacturer due to CYP3A inhibition).
• Patients with DNR orders.
• Known infection at the time of admission (elevated WBC with identified infection source)
• Evidence of blood dyscrasia.
• Episode of fever > 38.5 degrees Celsius during admission and prior to enrollment.
• History of any clinically significant disease or disorder which, in the opinion of the Investigator, could have either put the subject at risk because of participation in the study, or interfered with interpretation of the subject's study results