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Evaluatiton the Efficacy and Safety of Mutiple Lenzumestrocel (Neuronata-R® Inj.) Treatment in Patients With ALS (ALSummit)

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ClinicalTrials.gov Identifier: NCT04745299
Recruitment Status : Recruiting
First Posted : February 9, 2021
Last Update Posted : June 3, 2021
Sponsor:
Information provided by (Responsible Party):
Corestem, Inc.

Brief Summary:
ALSUMMIT is a double-blind, randomized, placebo-controlled, muti-center, parallel, phase III clinical trial to evaluate and confirm the efficacy and long-term safety of repeated Lenzumestrocel (Neuronata-R® inj.) treatment.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Biological: Lenzumestrocel Drug: Riluzole Drug: Placebo Comparator Phase 3

Detailed Description:

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective and progressive loss of motor neurons. Disease progression leads to death within 2-4 years, but there exists no definite treatment so far.

Based on phase I/II clinical trial(NCT01363401), twice intrathecal autologous bone marrow-derived mesenchymal stem cells (Lenzumestrocel) injections showed significant therapeutic benefit lasting at least six months with safety in patients with ALS.

Additionally, the switch from pro- to anti-inflammatory conditions, which was indicated from the inverse correlation between TGF-β1 and MCP-1 levels after Lenzumestrocel injections in the good responder, has been considered a plausible beneficial action mechanism.

This study is designed to investigate the following. First, to reconfirm and evaluate the long-term efficacy of twice injections (single cycle) of Lenzumestrocel, group 1 will receive a single cycle injection with a 26-day interval.

Second, to evaluate the long-term safety and efficacy of Lenzumestrocel repeated injections, group 2 will receive a single cycle injection a 26-day apart followed by three times injections every three-month interval.

Group 3 will receive comparator injections.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 115 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Double-blind, Randomized, Multicenter, Placebo-Controlled, Parallel, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Lenzumestrocel(Neuronata-R® Inj.) in Patients With Amyotrophic Lateral Sclerosis
Actual Study Start Date : March 23, 2021
Estimated Primary Completion Date : October 30, 2023
Estimated Study Completion Date : May 3, 2026


Arm Intervention/treatment
Experimental: Single cycle administration group
Study drug injections twice in a 26-day interval followed by three times comparator injections every three months.
Biological: Lenzumestrocel
Single cycle administration group : injections twice in a 26-day interval Multiple administration group : injections twice in a 26-day interval followed by repeated three times injections every three months
Other Names:
  • Neuronata-R inj
  • Autologous Bone Marrow derived Mesenchymal Stem Cell

Drug: Riluzole
concomitant administration of Riluzole to all groups, except subjects to whom Riluzole administration is deemed impossible owing to adverse events as determined by medical experts
Other Name: Rilutek

Drug: Placebo Comparator

Single cycle administration group: Placebo comparator is injected three times every three months after injection of Lenzumestrocel twice in a 26-day interval.

Control group: Placebo comparator is injected twice in a 26-day interval followed by repeated three times injcections every three months

Other Name: Normal Saine Inj.

Experimental: Multiple administation group
Study drug injections twice in a 26-day interval followed by repeated three times study drug injections every three months.
Biological: Lenzumestrocel
Single cycle administration group : injections twice in a 26-day interval Multiple administration group : injections twice in a 26-day interval followed by repeated three times injections every three months
Other Names:
  • Neuronata-R inj
  • Autologous Bone Marrow derived Mesenchymal Stem Cell

Drug: Riluzole
concomitant administration of Riluzole to all groups, except subjects to whom Riluzole administration is deemed impossible owing to adverse events as determined by medical experts
Other Name: Rilutek

Placebo Comparator: Control group
Comparator injections twice in a 26-day interval followed by three times comparator injections every three months.
Drug: Riluzole
concomitant administration of Riluzole to all groups, except subjects to whom Riluzole administration is deemed impossible owing to adverse events as determined by medical experts
Other Name: Rilutek

Drug: Placebo Comparator

Single cycle administration group: Placebo comparator is injected three times every three months after injection of Lenzumestrocel twice in a 26-day interval.

Control group: Placebo comparator is injected twice in a 26-day interval followed by repeated three times injcections every three months

Other Name: Normal Saine Inj.




Primary Outcome Measures :
  1. Joint rank scores (CAFS, Combined Assessment of Functional and Survival) [ Time Frame: at 12 months, and 6 months ]

    Joint rank score is derived from Combined Assessment of Function and Survival. Functional assessment is based on ALSFRS-R scores and survival assessment is based on the period from randomization to physical death. Joint rank score will be calculated with ALSFRS-R score data and survival. For each pairwise comparison, a study participant is assigned a scocre and then the summed scores are ranked for all participants.

    The higher ranking, the higher score, and the lower ranking, the lower score. And the average rank score is then calculated for each treatment group. A higher mean rank score indicates that participants in that treatment group, on average, fared better.

    1. The difference in joint rank scores between multiple administration group and control group at 12 months.
    2. The difference in joint rank scores between single cycle administration group and control group at 6 months


Secondary Outcome Measures :
  1. Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score [ Time Frame: at 12 months, 6 months ]

    ALSFRS-R is an instrument designed to evaluate functional status of subjects with amyotrophic lateral sclerosis (Lou Gehrig's disease), such as gross motor activity, fine motor activity, bulbar function and respiration function. It consists of 12 items; 3 items for mouth functions, 4 items for upper limb and overall fine motor functions, 2 items for lower limb functions and 3 items for respiration functions. Each item is evaluated in 5-point scale (0~4). A higher score means a better functional status.

    1. Change of ALSFRS-R score measured at baseline and 12 months (multiple administration group and control group)
    2. Change of ALSFRS-R score measured at baseline and 6 months (single cycle administration and control group)

  2. Time to event [ Time Frame: at 12 months, 6 months ]
    1. The time taken for physical death, tracheostomy recognized as the point where disease progression functionally stops or chronic use of ventilator (chronic assisted ventilation; use of non-invasive ventilation for more than 20 hours in a day during the period of more than 30 consecutive days), whichever comes earlier, observed for 12 months after randomization (multiple administraion group and control group)
    2. Time to event for 6 months (single cycle administraion group and control group)

  3. Slow Vital Capacity (SVC) [ Time Frame: at 12 months ]

    SVC is a measure to identify change of respiration capability.

    Change in SVC measured at 12 months (multiple administration group and control group)



Other Outcome Measures:
  1. Slow Vital Capacity (SVC) [ Time Frame: 6 months, 36months ]
    Change to SVC measured at 6 months and 36 months

  2. Muscular strength [ Time Frame: 6 months, 12 months, 36 months ]
    Change of Muscular strength which is measured by Hand Held Dynanometer (HHD)

  3. Time to event [ Time Frame: 36 months ]
    Time to evnet for 36 months

  4. Time to death [ Time Frame: 6 months, 12 months, 36 months ]

    Time to death means the period from randomization of a subject to physical death.

    The comparison with the time to death between treatment groups and control group.


  5. EuroQol Short Form (EQ-5D-5L) [ Time Frame: 6 month, 12 months, 36 months ]

    EQ-5D-5L is designed to measure health conditions and it consists of 5 questions relating to mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 1~5 points are given for each question and a higher score means worse condition.

    Change of EQ-5D-5L from baseline to 6 month, 12 months, and 36 months.


  6. Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) [ Time Frame: 6 month, 12 months, 36 months ]
    ALSAQ-40 is designed to evaluate disease-specific health conditions of subjects with ALS/motor neural disease. It consists of 40 questions to evaluate 5 aspects of health conditions affected by the disease. Subjects are asked to think about the difficulties they may have experienced during the last 2 weeks. Subjects are asked to indicate the frequency of each event by selecting one of 5 options (0~4): never/rarely/sometimes/often/always or cannot do at all.

  7. Biological test [ Time Frame: up to 12 months after administration ]

    Tests on blood samples and cerebrospinal fluid samples for exploratory investigation of biological markers in plasma, blood and CSF.

    Comparison of change before and after treatment.

    • Measurement cytokines : TGF-β1, IL-10, IL-6, TNF-α, MCP-1, IL-8, IL-1RA, MIP-1β, RANTES and IP-10 etc.
    • Units of Measure: pg/mL
    • Comparative Analysis of how much each cytokine increases or decreases after treatment compared to before treatment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   25 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

[Inclusion Criteria]

  1. Subjects who show both upper motor neuron signs and lower motor neuron signs at the same time in neurological tests.
  2. Among subjects diagnosed with familial or sporadic ALS, subjects falling into clinically definite ALS, probable ALS and probable ALS-lab supported according to The revised World Federation of Neurology El Escorial Criteria[Rix Brooks, 2000], during 17-weeks period prior to the administration and ALSFRS-R score (progression rate) of 1.03 ± 50%/month (meaning mean value in that total period).
  3. For subjects who are under Riluzole treatment, those who have received stable dose of Riluzole for more than 28 days before screening visit.
  4. Subjects with duration of disease of no more than 2 years from the first diagnosis date.
  5. Subjects whose ALSFRS-R scores are in the range of 31~46 at the time of screening (P-V0).

[Exclusion Criteria]

  1. Subjects who received tracheostomy or use ventilators (including positive pressure ventilators; subjects who use non-invasive ventilation for sleep apnea may be allowed after review) at the time of screening (P-V0).
  2. Subjects who received gastrotomy at the time of screening (P-V0).
  3. Subjects for whom clinical efficacy evaluation is not possible because pulmonary functional tests cannot be conducted at the time of screening (P-V0) or subjects whose forced vital capacity is found to be not greater than 40%of the expected value.
  4. Subjects who fall into above Class II according to the New York Heart Association's functional classification, who have showed myocardial infarction, unstable arrhythmia and/or other significant cardiovascular diseases such as unstable angina in the past 3 months, or who show electrocardiographic signs of myocardial infarction or angina at the time of screening (P-V0) or who received stent insertion or coronary artery bypass grafting.
  5. Subjects who have received other investigational products or edaravone within 3 month or 5 half-lives at the time of screening (P-V0) and lead in period visit L-V1 (evaluated by whichever is longer).
  6. Subjects who have experienced epileptic seizure.
  7. Subjects with severe renal disorder (serum creatinine: not less than 2.0 mg/dL).
  8. Subjects with severe hepatic disorder (ALT, AST, or bilirubin: over 2.0 times of the normal upper limit).
  9. Subjects who show hemorrhagic tendency at the time of screening (PT and aPTT > 1.5 x ULN)
  10. Subjects who are found to have active viral infections (HBsAg, HCV Ab, HIV Ab, CMV IgM, EBV IgM, HSV IgM and Treponema pallidum) at the time of screening.
  11. Subjects with hypersensitivity to antibiotics (penicillin or streptomycin).
  12. Subjects who have ever received any cell therapy product for the same disease.
  13. Subjects with any malignant tumor in the past 5 years before screening, except malignant tumors with very low risk of metastasis or death.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04745299


Contacts
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Contact: Kwijoo Kim +82-2-497-3711 kwjkim@corestem.com
Contact: Yerim Jung +82-70-4706-9612 yrjung@corestem.com

Locations
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Korea, Republic of
Pusan National University Yangsan Hospital Recruiting
Yangsan, Kyungsangnam-do, Korea, Republic of, 50612
Contact: Jin-hong Shin, MD, PhD       shinzh@gmail.com   
Principal Investigator: Jin-hong Shin, MD, PhD         
Korea University Anam Hospital Recruiting
Seoul, Korea, Republic of, 02841
Contact: Byung-jo Kim, MD,PhD       neurokbj@gmail.com   
Principal Investigator: Byung-jo Kim, MD, PhD         
Hanyang university hospital Recruiting
Seoul, Korea, Republic of, 04763
Contact: Seung-hyun Kim, M.D.,PhD.       kimsh1@hanyang.ac.kr   
Principal Investigator: Seung-hyun Kim, MD, PhD         
Samsung Medical Center Recruiting
Seoul, Korea, Republic of, 06351
Contact: Byung-joon Kim, MD, PhD       bjmyo.kim@samsung.com   
Principal Investigator: Byung-joon Kim, MD, PhD         
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of
Contact: Jung-joon Sung, MD, PhD       jjsaint@snu.ac.kr   
Principal Investigator: Jung-joon Sung, MD, PhD         
Sponsors and Collaborators
Corestem, Inc.
Investigators
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Principal Investigator: Seung-hyun Kim, MD, PhD Hanyang University Seoul Hospital
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Responsible Party: Corestem, Inc.
ClinicalTrials.gov Identifier: NCT04745299    
Other Study ID Numbers: NEURONATA-R_ALS301
First Posted: February 9, 2021    Key Record Dates
Last Update Posted: June 3, 2021
Last Verified: February 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Corestem, Inc.:
Amyotrophic lateral sclerosis
Mesenchymal stem cell
cell therapy
ALS
neuroprotection
Phase 3 clinical trial
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Riluzole
Anticonvulsants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents