A Study of ASP2246 for People Who Have Movement Problems Caused by Brain Injury After a Stroke

Official title

A Phase 1/2 Multicenter, Open-label, Dose Escalation Study Followed by a Randomized, Double-blind Sham-controlled Dose Expansion Study to Evaluate the Safety, Tolerability and Efficacy of ASP2246 in Adult Participants Who Have Motor Dysfunction Associated With Late Subacute to Chronic Ischemic Stroke Due to Supratentorial Perforator Area Infarction

Overview

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.

Interventions

• Drug ASP2246
  Intracerebral parenchymal infusion via SmartFlow Neuro cannula.
• Procedure Brain surgery
  Stereotactic brain surgery
• Procedure Sham surgery
  Sham surgery without the dura incised.
• Other Rehabilitation therapy
  Rehabilitation 3 days per week for up to 12 weeks.

Primary outcome measures

• Number of participants with Dose-Limiting Toxicity (DLT) [Time frame: Up to 2 Weeks]
• Number of participants with Treatment-Emergent Adverse Events (TEAEs) [Time frame: Up to 52 Weeks]
• Number of participants with Serious Adverse Events (SAEs) [Time frame: Up to 52 Weeks]
• Number of participants with an Adverse Event of Special Interest (AESI) [Time frame: Up to 52 Weeks]
• Number of Participants with Suicidal Ideation and/or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) [Time frame: Up to 52 Weeks]

Secondary outcome measures (12)

• Pharmacokinetics (PK) of ASP2246 in whole blood: Area under the concentration-time curve (AUC) from the time of dosing extrapolated to time infinity (AUCinf) [Time frame: Up to 52 Weeks]
• PK of ASP2246 in whole blood: AUC from the time of dosing up to the time of the last measurable concentration (AUClast) [Time frame: Up to 52 Weeks]
• PK of ASP2246 in whole blood: maximum concentration (Cmax) [Time frame: Up to 52 Weeks]
• PK of ASP2246 in plasma: AUCinf [Time frame: Up to 52 Weeks]
• PK of ASP2246 in plasma: AUClast [Time frame: Up to 52 Weeks]
• PK of ASP2246 in plasma: Cmax [Time frame: Up to 52 Weeks]
• Number of participants with anti-polyethylene glycol (PEG) antibodies [Time frame: Up to 52 Weeks]
• Number of participants with anti-neurogenic differentiation 1 transcription factor (NeuroD1) antibodies [Time frame: Up to 52 Weeks]
• Change from baseline in proinflammatory cytokine response [Time frame: Baseline and up to Day 8]
• Change from baseline in complement activation [Time frame: Baseline and up to Day 8]
• Change from baseline in Fugl-Meyer Assessment (FMA) (motor function) total score [Time frame: Baseline, Week 24 and Week 52]
• Change from baseline in FMA-UE total score [Time frame: Baseline, Week 24 and Week 52]

Eligibility criteria

Inclusion criteria

• 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 completed recovery phase rehabilitation after cerebral infarction and spontaneous improvement is not expected during the study period.
• Participant is willing and physically able to participate in the designated rehabilitation therapy during the study period.
• Female participant is not pregnant and at least 1 of the following conditions apply:

• Not a woma(e)n of childbearing potential (WOCBP)
• WOCBP who has a negative urine or serum pregnancy test at screening (Unique to Japan: with a medical interview) and agrees to follow contraceptive guidance from the time of giving informed consent to at least 180 days after surgery.
• Female participant must not be breastfeeding or lactating starting at screening and for 180 days after surgery.
• Female participant must not donate ova after undergoing surgery and for 180 days after surgery.
• Male participant must agree to use contraception with female partner(s) of childbearing potential (including breastfeeding partner) for a minimum of 180 days after surgery.
• Male participant must agree to remain abstinent or use a condom with pregnant partner(s) for a minimum of 180 days after surgery.
• Male participant must not donate sperm for a minimum of 180 days after surgery.
• Participant agrees not to participate in another interventional study (including rehabilitation) while receiving study intervention/participating for up to 52 weeks in the present study.
• Participant agrees that the use of antiplatelet, oral anticoagulant or nonsteroidal anti-inflammatory drugs (NSAIDs) will be determined by the local medical staff in accordance with the American College of Chest Physicians Clinical Pharmacy 2022 Guidelines and the Japanese Guidelines for the Management of Stroke 2021. The Japanese guidelines specify that no antiplatelet, oral anticoagulant or NSAIDs are to be restarted post-surgery until results of the day 1 head MRI or computerized tomography (CT) are reviewed and restarting medication is deemed safe.

Exclusion criteria

• 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).
• Participant has a history of seizures.
• Participant has apparent contractures impeding joint movement at shoulder, elbow, forearm, wrist, hand, hip, knee or ankle.
• Participant with spasticity of grade 2 or higher on the modified Ashworth Scale.
• Participant has any other neurologic, neuromuscular or orthopedic disease that limits motor function.
• Participant has an active infection.
• Participant has a history of or current diagnosis of immunodeficiency.
• Participant has been deemed to have a high risk of recurrent stroke during the study period (e.g., a family history strongly suggestive of hereditary cerebrovascular disease, such as moyamoya disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).
• Participant has an uncontrolled systemic illness, including, but not limited to, hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 95 mmHg), resistant hypertension (systolic blood pressure \[BP\] ≥ 140 mmHg or diastolic BP ≥ 90 mmHg in a participant who is taking 3 or more medications for hypertension), bleeding disorders, hypercoagulability, diabetes, renal, hepatic or cardiac failure, morbid obesity, or uncontrolled sleep apnea.
• Participant has any positive findings on tests for occult malignancy, unless a nonmalignant etiology is confirmed.
• Participant has an uncontrolled major psychiatric illness, including depression (Hamilton Score of > 14).
• Participant has a presence of craniectomy (without bone flap replacement) or other contraindication for stereotactic surgery.
• Participant has signs and symptoms of intracranial herniation or increased intracranial pressure.
• Participant with a history of, or electrocardiogram (ECG) evidence suggestive of, recent myocardial infarction (within 6 months of surgery), major dysrhythmia, atrial fibrillation or congestive heart failure.
• Participant has a substance-related and addictive disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders-5 criteria, including drug or alcohol use.
• Participant has contraindications to MRI or MRI contrast agent(s).
• Participant has Montreal Cognitive Assessment (MoCA) score < 26.
• Participant has a history of suicide attempt(s), suicidal behavior, or suicidal ideation (indicated by a 'yes' response to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale \[C-SSRS\]) within 12 months prior to study enrollment, or who is assessed at screening to be at a significant risk of committing suicide.
• Participant has a history of using warfarin or direct oral anticoagulant (DOAC). Exception: The participant will be considered eligible if the medication was discontinued at least 6 months prior to study enrollment, and the embolic source has resolved without recurrence.
• Participant has a history of neuroleptic drug use. Exception: The participant will be considered eligible if they are neuroleptic medication-free for at least 6 months and their psychiatric symptoms remain mild, stable and do not meet the exclusion criteria.
• Participant has a history of antiepileptic drug use for seizures. Note: For the participant who has used or is using antiepileptic medications for conditions other than seizures, a detailed risk assessment needs to be conducted to determine eligibility.
• Participant has had botulinum toxin injection, phenol injection, intrathecal baclofen, or any other interventional treatments for spasticity (except bracing and splinting) within the previous 3 months.
• Participant has present or previous history of participation in a study with ASP2246.
• Participant has received any investigational therapy within 28 days or 5 half-lives, whichever is longer, prior to screening.
• Participant has inadequate organ function as indicated by the laboratory values at screening.
• Participant has any condition that makes the participant unsuitable for study participation.
• Participant has known or suspected hypersensitivity to ASP2246 or any components of the formulation used.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Japan · 5 centers

• Tohoku University Hospital — Sendai
• Juntendo University Hospital — Bunkyo-ku
• Toyama University Hospital — Toyama
• Kyoto University Hospital — Kyoto
• Tokushima University Hospital — Tokushima

Identifiers

NCT: NCT07318714 · 2246-CL-0101 · jRCT2033250653

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗