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

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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Biological: human umbilical cord blood derived mesenchymal stem cells; Other: Normal saline 2mL

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Samsung Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

1 stage Inclusion Criteria:

1. Korean male or female at 50 -85 years of age
2. Diagnosis of Probable Alzheimer type according to NINCDS-ADRDA criteria at Visit 1 (Screening)
3. Korea Mini-Mental State Examination (KMMSE) score of 18 - 26 at Visit 1 (Screening)
4. Positive for Amyloid on PIB-PET or Florbetaben PET
5. 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:

1. Korean male or female at 50 -85 years of age
2. 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)
3. Korea Mini-Mental State Examination (KMMSE) score of over 18 at Visit 1 (Screening)
4. Positive for Amyloid on Florbetaben PET
5. A subject with neurodegeneration (mild atrophy of the brain) as confirmed by MRI
6. 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:

1. Concurrent mental disorder (such as schizophrenia, depression, bi-polar diseases or others) aside from dementia
2. 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
3. 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
4. History of stroke within 3 months prior to study enrollment
5. Severe liver disorder (equivalent to double the normal values of ALT and AST) at Visit 1
6. Severe kidney disorder (serum creatinine ≥1.5mg/dL) at Visit 1
7. Pregnant or lactating females

8. 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
9. Suspected active lung disease based on chest X-ray at Visit 1
10. 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)
11. History of screening failure for the clinical trial of NEUROSTEM® in the past 6 months
12. Participation in another clinical trial in the past 3 months prior to the beginning (Week 0) of this clinical trial
13. 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)
14. Diagnosis of cancer (of any body system, including brain tumor)
15. Substance/alcohol abuse
16. Contraindicated for any of the tests performed during the clinical trial period (for example, MRI, CT, PET)
17. A subject in whom Ommaya reservoir insertion is considered difficult
18. Whom the principal investigator considers inappropriate for participation in the study due to any reasons other than those listed above

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NEUROSTEM (hUCB-MSCs)- low dose; 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; 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; Other Names: NEUROSTEM
Experimental: NEUROSTEM (hUCB-MSCs) - high dose; 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; 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; Other Names: NEUROSTEM
Placebo Comparator: Placebo; normal saline 2mL, doses separated by 4 weeks for a total of 3 doses	Other: Normal saline 2mL; Intraventricular administrations of 2mL Normal Saline at 4 week intervals via an Ommaya Reservoir, for a total of 3 administrations

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Medipost Co Ltd.
• Investigators: Study Director: Wonil Oh, MD, PhD, Medipost Co Ltd.

Publications and helpful links

General Publications

• Kim HJ, Cho KR, Jang H, Lee NK, Jung YH, Kim JP, Lee JI, Chang JW, Park S, Kim ST, Moon SW, Seo SW, Choi SJ, Na DL. Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: a phase I clinical trial. Alzheimers Res Ther. 2021 Sep 14;13(1):154. doi: 10.1186/s13195-021-00897-2.

Helpful Links

• first-in-man study of NEUROSTEM

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2014
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: January 29, 2014
• First Submitted That Met QC Criteria: February 3, 2014
• First Posted (Estimate): February 4, 2014

Study Record Updates

• Last Update Posted (Actual): August 28, 2020
• Last Update Submitted That Met QC Criteria: August 26, 2020
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: stem cells; cord blood; mesenchymal stem cells; human umbilical cord blood derived mesenchymal stem cells; alzheimer's disease; cognitive ability
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: MP-CR-010

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No