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Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis

Primary Purpose

Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neuromuscular Disease

Status
Completed
Phase
Phase 1
Locations
Korea, Republic of
Study Type
Interventional
Intervention
HYNR-CS-Allo
Sponsored by
Hanyang University Seoul Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Amyotrophic Lateral Sclerosis, ALS, Neurodegenerative disease, Motor Neuron Disease, Central Nervous System Disease, Neuromuscular Disease, Bone marrow derived stem cell, stem cell therapy, intrathecal injection

Eligibility Criteria

25 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients between 25 and 80 years old
  • Patients who have both signs of lower motor neuron(LMN) and upper motor neuron(UMN) degeneration by clinical, electrophysiological or neuropathologic examination
  • Patients diagnosed as 'Probable' or 'Definite' ALS according to the World Federation of Neurology El Escorial criteria
  • Patients whose duration of disease is within 5 years from the first diagnosis
  • Patients with ALSFRS-R score within 21 to 46 at screening
  • Patients who can visit to a hospital by walk personally or by protector's help
  • Patients who provide the written consent by oneself or his/her legal representative
  • Patients who has HLA-haplo matched Bone marrow donor

Exclusion Criteria:

  • Patients who doesn't appropriate to the diagnostic criteria of ALS
  • Patients who are diagnosed as primary lateral sclerosis(PLS) or progressive muscular atrophy(PMA)
  • Patients suspected of adverse effect after stem cell injection(patients suspected of malignant tumor, risk group of psychogenic shock, patients with serious hypertension)
  • Patients with ALSFRS-R score below 21 at screening
  • Patients performed ventilator or tracheostomy at screening
  • Patients performed gastrostomy at screening
  • Patients unable to assess the efficacy of this clinical trial due to unattainable Pulmonary Functional Test(PFT) or patients with suspected 40% or less of Forced vital capacity(FVC) at screening
  • Patients with finding of myocardial infarction or angina pectoris according to ECG, patients who have been performed Stenting or Bypass operation at screening
  • Patients who have taken any other drug for clinical trial within the past 3 months at screening entry
  • Patients with epilepsy
  • Patients with severe renal dysfunction(serum creatinine≥2.0mg/dl)
  • Patients with severe liver dysfunction(ALT, AST, bilirubin≥upper limit of normal X 2)
  • Pregnant woman, lactating woman, female patients who has a pregnancy planning or who doesn't agree with adoption of contraception methods proper medically, male patients who doesn't agree with adoption of contraception methods proper to his partner during participating this study
  • Patients with hemorrhagic tendency at screening
  • Patients with virus infection at screening
  • Patients with a known history of hypersensitivity/allergy to penicillin and streptomycin
  • Patients with previous stem cell therapy
  • Patients diagnosed with cancer
  • Patients who have taken any drug that can effect to bone marrow function
  • Patients with any other neurological disease except ALS
  • Patients with psychotic diseases

Sites / Locations

  • Hanyang University Seoul Hospital, Cell Therapy Center for Neurologic Disorders

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HYNR-CS-Allo

Arm Description

HYNR-CS-Allo inj. 2 times by intrathecal administration with 28 days interval.

Outcomes

Primary Outcome Measures

Serious Adverse Events(SAE)
The Incidence of any treatment related serious adverse events(SAE)

Secondary Outcome Measures

ALS-Functional rating scales(ALS-FRS)
Changes in ALS-Functional rating scales(ALS-FRS)
Adverse Events(AE)
Incidence & Degree of Adverse Events(AE)

Full Information

First Posted
December 10, 2012
Last Updated
May 15, 2019
Sponsor
Hanyang University Seoul Hospital
Collaborators
Corestemchemon, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01758510
Brief Title
Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
Official Title
An Open-label, Phase 1 Trial for Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell("HYNR-CS-Allo Inj") Treatment in Amyotrophic Lateral Sclerosis(ALS)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
December 2012 (Actual)
Primary Completion Date
April 10, 2017 (Actual)
Study Completion Date
April 10, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hanyang University Seoul Hospital
Collaborators
Corestemchemon, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety of HLA-haplo matched Allogenic Bone Marrow Derived stem cells("HYNR-CS-Allo inj"), through intrathecal delivery for the treatment in patients with amyotrophic lateral sclerosis(ALS). This study is an open label, dose up and down study using the 3+3 design to assess the safety of HLA-haplo matched Allogenic Bone Marrow Derived stem cells("HYNR-CS-Allo inj")
Detailed Description
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by motor neuron loss. Despite of many trials for disease-modifying, no treatment has so far changed natural course of disease. The investigators had performed the pre-clinical and clinical studies using autologous bone marrow-derived stem cells in ALS. In the investigators' results of clinical trial, intrathecal injection of autologous bone marrow-derived stem cells is safe and could slow down disease progression and might be used as a disease modifying strategy in patients with ALS. In the new field, like cell therapy, it is an important issue whether a bone marrow derived mesenchymal stem cells can be used as an allograft. Many investigators had showed that the immunoprivileged and immunosuppressive properties of mesenchymal stem cells result from the absence of major histocompatibility class II antigens and the secretion of T helper type 2 cytokines. One potential advantage of allogenic bone marrow derived cells could be avoiding the need for procedural delay before treatment. And it is also hypothesized that the function of autologous bone marrow derived cells could be impaired in patients with co-morbidities or advanced age. This study is to evaluate safety of HYNR-CS-Allo inj(HLA-haplo matched Allogenic bone marrow-derived stem cells) in patients with ALS. The patients enrolled in the trial will be successively allocated into three cohorts for HYNR-CS-Allo inj., 0.25 X 10^6 cells/kg, 0.5 X 10^6 cells/kg, 1 X 10^6 cells/kg, according to the 3+3, up and down protocol design. The first treatment cohort will be 0.5 X 106 cells/kg dose cohort. Only a maximum of six patients will be given a particular dosage. The scheduled assessments and visits will be carried out over three periods: run-in period, treatment period, and follow-up period. The run-in period includes the screening visit where a written informed consent is obtained and the screening period where patients are assessed for eligibility. It will be completed within 30 days prior to enrollment. The patients meeting inclusion criteria will start the treatment period. During the treatment period, subjects will be administered HYNR-CS-Allo inj. 2 times by intrathecal administration with 28 days interval. The Follow-up period starts once subjects complete the treatment period and will continue until the final follow-up visit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neuromuscular Disease, Neurodegenerative Disease, Central Nervous System Disease
Keywords
Amyotrophic Lateral Sclerosis, ALS, Neurodegenerative disease, Motor Neuron Disease, Central Nervous System Disease, Neuromuscular Disease, Bone marrow derived stem cell, stem cell therapy, intrathecal injection

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HYNR-CS-Allo
Arm Type
Experimental
Arm Description
HYNR-CS-Allo inj. 2 times by intrathecal administration with 28 days interval.
Intervention Type
Genetic
Intervention Name(s)
HYNR-CS-Allo
Intervention Description
The patients enrolled in the trial will be successively allocated into three cohorts for HYNR-CS-Allo inj., 0.25 X 10^6 cells/kg, 0.5 X 10^6 cells/kg, 1 X 10^6 cells/kg, according to the 3+3, up and down protocol design. The first treatment cohort will be 0.5 X 10^6 cells/kg dose cohort.
Primary Outcome Measure Information:
Title
Serious Adverse Events(SAE)
Description
The Incidence of any treatment related serious adverse events(SAE)
Time Frame
6 months
Secondary Outcome Measure Information:
Title
ALS-Functional rating scales(ALS-FRS)
Description
Changes in ALS-Functional rating scales(ALS-FRS)
Time Frame
6 months
Title
Adverse Events(AE)
Description
Incidence & Degree of Adverse Events(AE)
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients between 25 and 80 years old Patients who have both signs of lower motor neuron(LMN) and upper motor neuron(UMN) degeneration by clinical, electrophysiological or neuropathologic examination Patients diagnosed as 'Probable' or 'Definite' ALS according to the World Federation of Neurology El Escorial criteria Patients whose duration of disease is within 5 years from the first diagnosis Patients with ALSFRS-R score within 21 to 46 at screening Patients who can visit to a hospital by walk personally or by protector's help Patients who provide the written consent by oneself or his/her legal representative Patients who has HLA-haplo matched Bone marrow donor Exclusion Criteria: Patients who doesn't appropriate to the diagnostic criteria of ALS Patients who are diagnosed as primary lateral sclerosis(PLS) or progressive muscular atrophy(PMA) Patients suspected of adverse effect after stem cell injection(patients suspected of malignant tumor, risk group of psychogenic shock, patients with serious hypertension) Patients with ALSFRS-R score below 21 at screening Patients performed ventilator or tracheostomy at screening Patients performed gastrostomy at screening Patients unable to assess the efficacy of this clinical trial due to unattainable Pulmonary Functional Test(PFT) or patients with suspected 40% or less of Forced vital capacity(FVC) at screening Patients with finding of myocardial infarction or angina pectoris according to ECG, patients who have been performed Stenting or Bypass operation at screening Patients who have taken any other drug for clinical trial within the past 3 months at screening entry Patients with epilepsy Patients with severe renal dysfunction(serum creatinine≥2.0mg/dl) Patients with severe liver dysfunction(ALT, AST, bilirubin≥upper limit of normal X 2) Pregnant woman, lactating woman, female patients who has a pregnancy planning or who doesn't agree with adoption of contraception methods proper medically, male patients who doesn't agree with adoption of contraception methods proper to his partner during participating this study Patients with hemorrhagic tendency at screening Patients with virus infection at screening Patients with a known history of hypersensitivity/allergy to penicillin and streptomycin Patients with previous stem cell therapy Patients diagnosed with cancer Patients who have taken any drug that can effect to bone marrow function Patients with any other neurological disease except ALS Patients with psychotic diseases
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Seung Hyun Kim, M.D., Ph.D
Organizational Affiliation
Hanyang University Seoul Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hanyang University Seoul Hospital, Cell Therapy Center for Neurologic Disorders
City
Seoul
State/Province
Haengdang-dong, Seongdong-gu
ZIP/Postal Code
133-792
Country
Korea, Republic of

12. IPD Sharing Statement

Citations:
PubMed Identifier
22244934
Citation
Kwon MJ, Baek W, Ki CS, Kim HY, Koh SH, Kim JW, Kim SH. Screening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALS. Neurobiol Aging. 2012 May;33(5):1017.e17-23. doi: 10.1016/j.neurobiolaging.2011.12.003. Epub 2012 Jan 15.
Results Reference
background
PubMed Identifier
22119626
Citation
Koh SH, Baik W, Noh MY, Cho GW, Kim HY, Kim KS, Kim SH. The functional deficiency of bone marrow mesenchymal stromal cells in ALS patients is proportional to disease progression rate. Exp Neurol. 2012 Jan;233(1):472-80. doi: 10.1016/j.expneurol.2011.11.021. Epub 2011 Nov 19. Erratum In: Exp Neurol. 2012 Apr;234(2):527.
Results Reference
background
PubMed Identifier
22087847
Citation
Koh SH, Huh YM, Noh MY, Kim HY, Kim KS, Lee ES, Ko HJ, Cho GW, Yoo AR, Song HT, Hwang S, Lee K, Haam S, Frank JA, Suh JS, Kim SH. beta-PIX is critical for transplanted mesenchymal stromal cell migration. Stem Cells Dev. 2012 Jul 20;21(11):1989-99. doi: 10.1089/scd.2011.0430. Epub 2012 Jan 26.
Results Reference
background
PubMed Identifier
20117176
Citation
Choi MR, Kim HY, Park JY, Lee TY, Baik CS, Chai YG, Jung KH, Park KS, Roh W, Kim KS, Kim SH. Selection of optimal passage of bone marrow-derived mesenchymal stem cells for stem cell therapy in patients with amyotrophic lateral sclerosis. Neurosci Lett. 2010 Mar 19;472(2):94-8. doi: 10.1016/j.neulet.2010.01.054. Epub 2010 Feb 1.
Results Reference
background
PubMed Identifier
20030561
Citation
Cho GW, Noh MY, Kim HY, Koh SH, Kim KS, Kim SH. Bone marrow-derived stromal cells from amyotrophic lateral sclerosis patients have diminished stem cell capacity. Stem Cells Dev. 2010 Jul;19(7):1035-42. doi: 10.1089/scd.2009.0453.
Results Reference
background
PubMed Identifier
19879334
Citation
Kim H, Kim HY, Choi MR, Hwang S, Nam KH, Kim HC, Han JS, Kim KS, Yoon HS, Kim SH. Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett. 2010 Jan 14;468(3):190-4. doi: 10.1016/j.neulet.2009.10.074. Epub 2009 Oct 29.
Results Reference
background
PubMed Identifier
24995608
Citation
Kwon MS, Noh MY, Oh KW, Cho KA, Kang BY, Kim KS, Kim YS, Kim SH. The immunomodulatory effects of human mesenchymal stem cells on peripheral blood mononuclear cells in ALS patients. J Neurochem. 2014 Oct;131(2):206-18. doi: 10.1111/jnc.12814. Epub 2014 Jul 31.
Results Reference
background
PubMed Identifier
25934946
Citation
Oh KW, Moon C, Kim HY, Oh SI, Park J, Lee JH, Chang IY, Kim KS, Kim SH. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med. 2015 Jun;4(6):590-7. doi: 10.5966/sctm.2014-0212. Epub 2015 May 1.
Results Reference
background
PubMed Identifier
24966156
Citation
Kim HY, Kim H, Oh KW, Oh SI, Koh SH, Baik W, Noh MY, Kim KS, Kim SH. Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study. Stem Cells. 2014 Oct;32(10):2724-31. doi: 10.1002/stem.1770.
Results Reference
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Links:
URL
http://hyctc.hyumc.com/
Description
home page for Hanyang University Seoul Hospital, Cell Therapy Center for Neurologic Disorders
URL
http://www.corestem.com
Description
collaborator and stem cell provider
URL
https://www.hyumc.com/
Description
Hanyang University Medical center
URL
http://seongdong.seouldementia.or.kr/
Description
home page of dementia center in Seoul Seongdong-gu

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Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis

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