A Phase 2 Study to Assess the Safety of EI-1071 and the Effects of EI-1071 on Neuroinflammation in Alzheimer's Disease Patients

Official title

An Open-label, Exploratory, Phase II, Proof-of Concept, Clinical Study to Assess the Safety and Tolerability of EI-1071 in Patients With Alzheimer's Disease (AD)

Overview

An open-label, exploratory, phase II, proof-of concept, clinical study to assess the safety and tolerability of EI-1071 and the effects of EI-1071 on neuroinflammation in patients with mild, moderate, or severe Alzheimer's disease

Detailed description

This is an open-label, phase II, exploratory, proof-of-concept study to assess the safety and tolerability of EI-1071 and the effects of EI-1071 on neuroinflammation in patients with mild, moderate, or sever Alzheimer's disease (AD). The main goals include:

1. to validate mechanism-engagement of EI-1071 by tracing the change of activated microglia in selected brain regions in AD patients using TSPO PET/MRI imaging. 2. to assess effects of EI-1071 on changes of inflammatory biomarkers associated with AD progression.

Interventions

• Drug EI-1071 tablet, oral
  Dose: 448.2 mg BID for 28 days

Primary outcome measures

• Change from Baseline to Week 4 [¹⁸F] FEPPA Binding in Selected Brain Regions of Interest [Time frame: Baseline, Week 4]

Secondary outcome measures (12)

• Number of Participants With at Least One Adverse Events (AEs) or Serious Adverse Events (SAEs) by CTCAE v5.0 [Time frame: From Day 1 up to Day 84]
• Change From Baseline to Week 12 as Measured by CDR-SB [Time frame: Baseline, Week 4, Week 12]
• Mean Change From Baseline to Week 12 in Mini Mental State Exam (MMSE) Score [Time frame: Baseline, Week 4, Week 12]
• Change From Baseline to Week 12 in Alzheimer Disease Assessment Scale-Cognition Subscale 11 (ADAS-Cog11) Score [Time frame: Baseline, Week 4, Week 12]
• Change From Baseline to Week 12 in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score [Time frame: Baseline, Week 4, Week 12]
• Change From Baseline to Week 12 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score [Time frame: Baseline, Week 4, Week 12]
• EI-1071 concentrations in plasma [Time frame: Predose and 2-3 hours post dose in Day1 and Day 14, predose and 2-4 hours post dose in Day 28]
• EI-1071 concentrations in cerebrospinal fluid [Time frame: Predose in Day 1 and 2-4 hours post dosing in Week 4]
• Neuroinflammation and/or neurodegeneration biomarkers levels in plasma and in cerebrospinal fluid [Time frame: Predose in Day 1 and 2-4 hours post dose in Day 28]
• Physical Examination (PE) [Time frame: Baseline, Day 1, Week 2, Week 4, Week 8, Week 12]
• Vital Sign [Time frame: Baseline, Day 1, week 2, week 4, week 8, week 12]
• Electrocardiograms (ECGs) changes from baseline for PR [Time frame: Baseline, Day 1, week 2, week 4, week 8, week 12]

Eligibility criteria

Inclusion criteria

• Must meet all the clinical criteria for mild to severe AD (i.e., probable or possible AD dementia by NIA-AA criteria; must have objective evidence of cognitive impairment at Screening
• Clinical Dementia Rating Scale (CDR)≧0.5
• If using drugs to treat symptoms related to AD, doses must be stable for at least 8 weeks prior to screening.
• Adequate hematologic, hepatic, and renal function at the screening visit defined by the following criteria:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
• Hemoglobin \[Hgb\] > 10 g/dL
• Platelet count ≥ 100 × 10⁹/L
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1 × upper limit of normal (ULN)
• Total bilirubin and direct bilirubin ≤ 1.0 × ULN
• Alkaline phosphatase (ALP) ≤ 1.0 × ULN
• Creatinine clearance (CCr) ≥ 60 mL/min
• Female subject with childbearing potential must have a negative serum pregnancy test at the screening visit (female subjects must be surgically confirmed sterile, i.e., had hysterectomy, bilateral oophorectomy, or tubal ligation procedures), post-menopausal for at least 1 year (documented in the medical history), or must commit to use two contraceptive methods during the study.
• Female subject with childbearing potential must be willing to implement adequate, highly effective contraceptive measure during the study period. Effective birth control includes:

• Intrauterine device plus one barrier method
• Oral, implantable, or injectable contraceptives plus one barrier method; or
• Two barrier methods

• Effective barrier methods are male or female condoms, diaphragms, or spermicides (creams or gels that contain a chemical to kill sperm). Women of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year.
• Male subject who agrees to use an adequate method of contraception during the study period \[e.g., barrier contraceptives (male condom)\].
• Subjects or his/her legal representative or guardian are willing to sign written informed consent and willing to comply with study requirements.

Exclusion criteria

• Body weight ≥ 150 kg or body mass index (BMI) ≥ 35 kg/m² at the screening visit.
• Prior use of pexidartinib (Turalio), other chemical entities, or any biologic treatment targeting colony stimulating factor 1 (CSF-1) or the CSF-1 receptor within 3-month of the first dose with EI-1071; previous uses of oral tyrosine kinase inhibitors are allowed (e.g., imatinib or nilotinib).
• AD patients with low binding affinity for tracer TSPO rs6971 SNP polymorphism at screening
• Pregnant, breast feeding or plan to be pregnant women during the study period
• Active tuberculosis (TB), active or chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or known active or chronic infection with human immunodeficiency virus (HIV) at screening or in the medical history.
• Any medical or neurological/neurodegenerative condition (including mental deficit, intracranial tumor, glioma or meningioma; head trauma, Lewy body dementia; other disease than AD) that, in the opinion of the Investigator, might be a contributing cause to the participant's cognitive impairment or could lead to discontinuation, lack of compliance, interference with study assessments, or safety concerns
• Clinically significant, unstable psychiatric illness or have contraindications to brain magnetic resonance imaging (MRI) or PET scans
• Have had a stroke or Transient Ischemic Attack (TIA), unexplained loss of consciousness or relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities in the past year based on medical history (with MRI imaging results as confirmation in the medical history) at screening. Subjects with clinically relevant cerebrovascular abnormalities in MRI will be excluded per PI's discretion.
• Evidence of clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, neoplastic, endocrine (including poor-controlled T2DM), neurological, immunodeficiency, pulmonary, or other disorder or disease at the screening visit (such as neurological or cognitive impairment/decline due to substance abuse, vitamin B12 deficiency, abnormal thyroid function, or other underlying condition might contribute to cognitive, functional or behavioral impairment will be excluded) by investigator's judgment at screening; subjects who have to be fed by enteral tube will be excluded.
• History of or ongoing malignancy or carcinoma (either concurrent or within the last year of starting study treatment) that requires therapy (e.g., surgical, chemotherapy, or radiation therapy), except for adequately treated basal or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ of the cervix or breast
• Currently participating in any other clinical study or have participated in clinical trial within the last 60 days prior to screening; had donated blood (≥ 250 mL) within 30 days at screening.
• Known allergy to EI-1071 or hypersensitivity to any component of the formulation (e.g., hydroxypropyl methylcellulose acetate succinate) or hypersensitivity to any radiochemical tracer or \[¹⁸F\]FEPPA radiochemical tracer
• Required to use strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) and is anticipated to use these inhibitors or inducers during the study period

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 2 centers

• Taipei Veterans General Hospital — Taipei
• Tri-Service General Hospital — Taipei

Identifiers

NCT: NCT06745583 · EI-1071-202 · PTC-22-973334

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗