Safety and Exploratory Efficacy Study of NEUROSTEM® Versus Placebo in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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This combined phase 1/2a clinical trial is to investigate the safety, dose limiting toxicity (DLT), and exploratory efficacy of three repeated intraventricular administrations of NEUROSTEM® (human umbilical cord blood-derived mesenchymal stem cells) versus placebo via an Ommaya reservoir at 4 week intervals in patients with Alzheimer's disease.

Detailed Description
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The study is divided into the 2 stages: dose-escalation in stage 1 and randomized and multiple-dose cohort parallel design in stage 2.The target population for enrollment in this study is patients with mild to moderate Alzheimer's disease.

Official Title
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A Double-blind, Single-center, Phase 1/2a Clinical Trial to Evaluate the Safety and Exploratory Efficacy of Intraventricular Administrations of NEUROSTEM® Versus Placebo Via an Ommaya Reservoir in Patients With Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Biological: human umbilical cord blood derived mesenchymal stem cells
* Other: Normal saline 2mL


Participation Criteria
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Eligibility Criteria
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1 stage Inclusion Criteria: Korean male or female at 50 -85 years of age Diagnosis of Probable Alzheimer type according to NINCDS-ADRDA criteria at Visit 1 (Screening) Korea Mini-Mental State Examination (KMMSE) score of 18 - 26 at Visit 1 (Screening) Positive for Amyloid on PIB-PET or Florbetaben PET A subject who is informed of the clinical trial and signs a consent form (if unable to sign, a consent from a legally acceptable representative is required) 2 stage Inclusion Criteria: Korean male or female at 50 -85 years of age Diagnosis of Probable Alzheimer type or mild cognitive impairment due to Alzheimer's disease (stage A) according to NIA-AA criteria at Visit 1(Screening) Korea Mini-Mental State Examination (KMMSE) score of over 18 at Visit 1 (Screening) Positive for Amyloid on Florbetaben PET A subject with neurodegeneration (mild atrophy of the brain) as confirmed by MRI A subject who is informed of the clinical trial and signs a consent form (if unable to sign, a consent from a legally acceptable representative is required) Exclusion Criteria: Concurrent mental disorder (such as schizophrenia, depression, bi-polar diseases or others) aside from dementia Concurrent dementia as a result of other neurodegenerative disorders (due to infectious disease of the central nervous system such as HIV, syphilis), head injury, Creutzfeld-Jacob disease, Pick's disease, Huntington's disease, or Parkinson's disease Diagnosis of severe white matter hyperintensitivity (WMH) according to CREDOS (Clinical REsearch Center for Dementia of South Korea), which is defined as ≥ 25mm of the deep white matter and ≥ 10mm of the periventricular capping/banding in lengths History of stroke within 3 months prior to study enrollment Severe liver disorder (equivalent to double the normal values of ALT and AST) at Visit 1 Severe kidney disorder (serum creatinine ≥1.5mg/dL) at Visit 1 Pregnant or lactating females Abnormal Laboratory findings at Visit 1 Hemoglobin < 9.5 g/dL for male and <9.0 g/dL for female Total WBC Count < 3000/mm3 Total Bilirubin >= 3 mg/dL Suspected active lung disease based on chest X-ray at Visit 1 Woman of childbearing age who refuses to practice medically acceptable contraceptive method (post menopausal patient with no menstruation for at least 12 months is considered as infertile) History of screening failure for the clinical trial of NEUROSTEM® in the past 6 months Participation in another clinical trial in the past 3 months prior to the beginning (Week 0) of this clinical trial Bleeding disorder (abnormal blood coagulation test result (i.e. platelet count of < 150,000/mm3, PT ≥ 1.5 INR, or aPTT ≥ 1.5 x control anti-coagulant or anti-platelet, without anticoagulant or anti-platelet therapy) Diagnosis of cancer (of any body system, including brain tumor) Substance/alcohol abuse Contraindicated for any of the tests performed during the clinical trial period (for example, MRI, CT, PET) A subject in whom Ommaya reservoir insertion is considered difficult Whom the principal investigator considers inappropriate for participation in the study due to any reasons other than those listed above

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Stage 1: 9 subjects (3 subjects for low dose and 6 subjects for high dose) Stage 2: 36 subjects ( 24 subjects for high dose and 12 subjects for placebo) A total of 45 subjects to be enrolled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NEUROSTEM (hUCB-MSCs)- low dose<br>human umbilical cord blood derived mesenchymal stem cells Low dose: 1 x 10^7cells/2mL 3 repeated intraventricular administrations via an Ommaya Reservoir at 4 week intervals | Biological: human umbilical cord blood derived mesenchymal stem cells<br>* Low dose: 1 x 10^7cells/2mL 3 repeated intraventricular administrations via an Ommaya Reservoir at 4 week intervals High dose: 3 x 10^7cells/2mL 3 repeated intraventricular administrations via an Ommaya Reservoir at 4 week intervals<br>* Other names: NEUROSTEM;|
| Experimental: NEUROSTEM (hUCB-MSCs) - high dose<br>human umbilical cord blood derived mesenchymal stem cells High dose: 3 x 10^7 cells/2mL 3 repeated intraventricular administrations via an Ommaya Reservoir at 4 week intervals | Biological: human umbilical cord blood derived mesenchymal stem cells<br>* Low dose: 1 x 10^7cells/2mL 3 repeated intraventricular administrations via an Ommaya Reservoir at 4 week intervals High dose: 3 x 10^7cells/2mL 3 repeated intraventricular administrations via an Ommaya Reservoir at 4 week intervals<br>* Other names: NEUROSTEM;|
| Placebo Comparator: Placebo<br>normal saline 2mL, doses separated by 4 weeks for a total of 3 doses | Other: Normal saline 2mL<br>* Intraventricular administrations of 2mL Normal Saline at 4 week intervals via an Ommaya Reservoir, for a total of 3 administrations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events | Number of subjects with adverse event, number of subjects with normal range of vital signs, mixed lymphocyte reaction result, and laboratory examination result | 24 weeks after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from the baseline in ADAS-Cog | Alzheimer's Disease assessment Scale-Cognitive Subscale | 24 weeks after the first dose | 
| Change from the baseline in S-IADL | Seoul Instrumental Activities of Daily Living | 24 weeks after the first dose | 
| Change from the baseline in K-MMSE | Mini Mental State Exmination Korean version | 24 weeks after the first dose | 
| Change from the baseline in CGA-NPI | Caregiver-administered Neuropsychiatric Inventory | 24 weeks from the first dose | 
| ADAS-Cog Response Rate | ADAS-cog response is defined as no worsening (no change or improvement on ADAS-cog score) of the ADAS-cog score at 24 weeks after the first administration compared to the baseline | 24 weeks after the first dose | 
| Change in CDR-SOB | Clinical Dementia Rating-Sum of Box | 24 weeks after the first dose | 
| Change in Florbetaben-PET | Florbetaben - Pittsburgh Compound B-positron emission tomography | 24 weeks after the first dose | 
| Change in FDG-PET (CMRglc: regional cerebral metabolic rate for glucose) | fluorodeoxyglucose positron emission tomography | 24 weeks after the first dose | 
| Change in CIBIC-plus | The Clinician's Interview Based Impression of Change-plus | 24 weeks after the first dose | 
| Change from baseline in MRI (DTI mapping) | MRI Analysis | 24 weeks after the first dose | 
| Change from the baseline in CSF biomarkers | biomakrer analysis | 24 weeks after the first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cord blood, stem cells, human umbilical cord blood derived mesenchymal stem cells, alzheimer's disease, cognitive ability, mesenchymal stem cells