Safety and Efficacy Study of Autologous Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of autologous bone marrow-derived stem cells(HYNR-CS inj), through intrathecal delivery for the treatment in patients with ALS. This study consists of 2 steps. First step is a safety study of the intrathecal(IT) injection of HYNR-CS inj in 8 patients with ALS. In this phase 1 study, AE, laboratory test, physical examination, vital signs, Electrocardiogram, and Chest X-Ray examination were evaluated in terms of safety. Second step is to compare the efficacy and safety between test group and control group of total 64 patients with ALS.

Detailed Description
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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. We have performed the pre-clinical and clinical studies using autologous bone marrow-derived stem cells in ALS. We could get the evidence that autologous bone marrow-derived stem cells have dose-dependent effects on SOD1 mice via intrathecal injection. In our results of clinical trial, intrathecal injection of autologous bone marrow-derived stem cells could slow down disease progression and might be used as a disease modifying strategy in patients with ALS. This study was designed as a single center, randomized, open-label, parallel-group, 2-stage study, and targeted at patients diagnosed with Amyotrophic Lateral Sclerosis(Lou Gehrig's disease). The study consisted of Stage-1 study for safety evaluation and Stage-2 study for efficacy and safety evaluation of the study drug, and at Stage 1, 7 subjects eligible for the inclusion/exclusion criteria received safety evaluation for 28 days of study drug administration in twice under the protocol, and then followed Stage 2. To decide whether the study can be proceeded in 2 stages, ADR(CTCAE Version 3.0, ≥grade 3) should not appear in initial 7 subjects. Data obtained from subjects of this study were analyzed into three: Safety Analysis, ITT(Intent-To-Treat) Analysis, and PP(Per Protocol) Analysis. However, in case of phase 1, only safety analysis was conducted, and in case of phase 2, all of safety, ITT, and PP analyses were conducted. For ITT Analysis, all the subjects whose data on primary efficacy endpoint could be obtained following the administration of investigational drug were analyzed in analysis among subjects who were administered the investigational drug once at least. Also, Modified ITT Analysis, including 7 subjects at Stage 1, was carried out.

Official Title
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An Open-label, Phase I/II Trial for Safety and Efficacy Study of Autologous Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis, ALS

Intervention / Treatment
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* Biological: HYNR-CS inj
* Other: Control group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients between 25 and 75 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 who have taken Rilutek at stable background dose from 3 months ago at least before screening entry Patients whose duration of disease is within 5 years from the first diagnosis Patients with ALSFRS-R score within 31 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 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 30 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 PFT(Pulmonary Functional Test) or patients with suspected 40% or less of 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 thag can effect to bone marrow function Patients with any other neurological disease except ALS Patients with psychotic diseases

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test group<br>Treatment group with HYNR-CS inj. | Biological: HYNR-CS inj<br>* Intrathecal injection with 1ml/10kg of body weight at an interval of 26 days.<br>|
| Experimental: Control group<br>No treatment with HYNR-CS inj. | Other: Control group<br>* No treatment of HYNR-CS inj<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Difference in the Changes of Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Between Treatment Groups and Control Groups. | ALSFRS-R is ordinal rating scale questionnaire (rating 0-4 for each question, 4 is most functional, 0-48 total) of 12 functional activities. The most functional total score is 48. ALSFRS-R was evaluated at baseline and week 28.(The first injection was performed at 0 week) ALSFRS-R total score variation baseline(Visit 5) and week 16(Visit 9) | baseline(Visit 5) and week 16(Visit 9) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Appel Scale | To evaluate the disease change, Appel scale will be assessed. Appel scale is a test tool, which is devised to evaluate the functional condition and variation of ALS(Lou Gehrig's disease) patients (rating 6 to between 30 and 36 points for each of 5 functional conditions, 30-164 total). The higher the total score presents more severe disability. This was done at Visit 1, Visit 5 and Visit 9 (week -12,0,16). The first injection was performed at 0 week(Visit 5) Appel scale total score variation baseline(Visit 5) and week 16(Visit 9) | baseline(Visit 5) and week 16(Visit 9) | 
| Change in Forced Vital Capacity (FVC) (Percent of Predicted Normal) | Secondary efficacy was measured by comparing the rate of decline of mean FVC by treatment group. FVC which is a clinical scale to observe variation in patient's respiratory competence, was conducted at Visit 1, Visit 5 and Visit 9. (week -12,0,16) The first injection was performed at 0 week. FVC variation baseline(Visit 5) and week 16(Visit 9) | baseline(Visit 5) and week 16(Visit 9) | 
| Change in SF-36 (The Short Form (36) Health Survey is a 36 Item) | The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score presents more severe disability. The higher the score presents less disability. This was measured at Visit 5 and Visit 9. (week 0,16) The first injection was performed at 0 week. The score variation baseline(Visit 5) and week 16(Visit 9) | baseline(Visit 5) and week 16(Visit 9) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic lateral sclerosis, ALS, Motor neuron disease, MND, HYNR-CS inj, Autologous bone marrow derived stem cell, Intrathecal injection