This study is for adults who have difficulty moving a few months after a stroke. In this study, ASP2246 will be given to people for the first time. This is known as a "first in human" study.
The main aims of the study are to check the safety of ASP2246, how well people tolerate it, and to find suitable doses of ASP2246 to use later in this study and in future studies.
This study has 2 parts. In Part 1, people will have brain surgery. During the surgery, different small groups of people will receive a lower to a higher dose of ASP2246. Each dose will be given slowly through a special tube to the damaged part of the brain (intracerebral parenchymal infusion). Any medical problems will be recorded at each dose. This is done to find suitable doses to use in Part 2 of the study.
In Part 2, other different groups of people will undergo the same type of brain surgery. Some people will receive a higher dose of ASP2246, and some people will receive a lower dose of ASP2246. These are the doses from Part 1. Also, another group of people won't be given ASP2246 during brain surgery. This is known as a sham procedure. This is done so neither the people taking part in Part 2, nor the study doctors (apart from the surgeons) know who will be given ASP2246.
After brain surgery, people will be observed for about 2 weeks. For people in Part 1, this will take place in the hospital. For people in Part 2, the observation in hospital may be longer or shorter, depending on the results from Part 1. People in both Parts 1 and 2 will have physical therapy for 12 weeks after surgery and continue to have safety checks for about 1 year after their brain surgery.
Participant should have had an ischemic cerebral infarction at least 3 months, but not more than 12 months, before signing informed consent. This stroke must be the first-ever stroke for the participant.
Participant has current neuromotor dysfunction with a modified Rankin Scale (mRS) score between 2 to 4 at screening.
Participant has Fugl-Meyer Assessment (FMA)- upper extremity (UE) score ≥ 20 to ≤ 50 and FMA-lower extremity (LE) score < 21 at screening.
Participant has supratentorial perforator area infarction (single lacunar infarction or branch-atheromatous disease [BAD]), as assessed clinically and by magnetic resonance imaging (MRI) at screening.
Participant has a cerebral infarct volume > 3.4 cm^3 or < 0.37 cm^3, as measured by MRI (use of either a central or local reading is acceptable).
Participant has a primary intracerebral or intracranial hemorrhage.
Participant has a history of central nervous system (CNS) malignancy or a known presence of any malignancy, unless in remission for > 5 years. Exception: The participant with basal or squamous cell skin cancer that has been successfully treated will be considered eligible even if they have been in remission for < 5 years.
Participant had motor dysfunction of mRS > 2 before the onset of the stroke (premorbid mRS).
Parallel
ASP2246
DrugIntracerebral parenchymal infusion via SmartFlow Neuro cannula.
Brain surgery
Procedure/SurgeryStereotactic brain surgery
Sham surgery
Procedure/SurgerySham surgery without the dura incised.
Rehabilitation therapy
Other interventionRehabilitation 3 days per week for up to 12 weeks.
Number of participants with Dose-Limiting Toxicity (DLT)
A DLT will be defined as an Adverse Event (AE) ≥ 3 Grade that occurs during the 2-week DLT evaluation period and is attributed to study intervention or surgical procedure. This determination will be based on the investigator's initial assessment of causality and will be confirmed by the Dose Escalation and Safety Committee (DESC). A Grade 3 AE is defined as a severe or medically significant event that is not immediately life-threatening, but may cause hospitalization or prolongation of hospitalization, be disabling, or limit a patient's ability to perform self-care activities of daily living (ADL).
Number of participants with Treatment-Emergent Adverse Events (TEAEs)
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. This includes events related to the comparator, if applicable, and events related to the (study) procedures. A TEAE is defined as an AE observed until 52 weeks after surgery on day 1.
Number of participants with Serious Adverse Events (SAEs)
A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other situations.
Number of participants with an Adverse Event of Special Interest (AESI)
An AESI includes intracranial hemorrhage, cerebral edema (local or extensive), meningitis/encephalitis/encephalopathy (infectious or aseptic), seizures, worsening or new onset of neurologic deficits, intracranial malignancies/tumor formation, and immunogenic reactions.
Pharmacokinetics (PK) of ASP2246 in whole blood: Area under the concentration-time curve (AUC) from the time of dosing extrapolated to time infinity (AUCinf)
AUCinf will be recorded from the PK whole blood samples collected.
PK of ASP2246 in whole blood: AUC from the time of dosing up to the time of the last measurable concentration (AUClast)
AUClast will be recorded from the PK whole blood samples collected.
PK of ASP2246 in whole blood: maximum concentration (Cmax)
Cmax will be recorded from the PK whole blood samples collected.
PK of ASP2246 in plasma: AUCinf
AUCinf will be recorded from the PK plasma samples collected.
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