Evaluate the Safety of Neuronata-R® Inj. Suspended With HypoTHermosol® FRS (HTS-FRS) in Patients With ALS

A Phase I Clinical Trial to Evaluate the Safety of Neuronata-R® Inj. Suspended With HypoTHermosol® FRS (HTS-FRS) in Patients With Amyotrophic Lateral Sclerosis

This clinical trial is a single-center, open-label, and phase I clinical trial to Evaluate the Safety of Neuronata-R® Inj. suspended with HypoTHermosol® FRS (HTS-FRS) in Patients with Amyotrophic Lateral Sclerosis.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Biological: Lenzumestrocel; Drug: Riluzole

Detailed Description

Neuronata-R is produced by mixing the patient's own cerebrospinal fluid with cultured mesenchymal stem cells the day before administration. Therefore, as autologous cerebrospinal fluid is collected from the patient for drug production at each administration, the patient must endure the occurrence of adverse events (headache, pain, etc.) and pain caused by collection, and problems such as fatigue and time consumption of the medical staff's procedure have continuously emerged.

Therefore, a comparative equivalence tests and stability tests were conducted with HypoThermosol® FRS (HTS-FRS) as a suspension agent for Neuronata-R, and it was confirmed that there was no difference in the quality of the finished product depending on the type of additive and Neuronata-R using autologous cerebrospinal fluid as a suspension agent, and it was confirmed that it was safe as an additive through non-clinical trials.

The dose determination for the safety evaluation of HypoThermosol® FRS (HTS-FRS), which will be used as a suspension, was determined in consultation with the MFDS to use a 1:1 mixture of autologous CSF and HypoThermosol® FRS (HTS-FRS) as a suspension in the first stage dose, and only HypoThermosol® FRS (HTS-FRS) was used as a suspension in the second stage dose without cerebrospinal fluid. And, the administration period is follow-up for 4 weeks after administration twice every 26 days.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 04763
    • Hanyang University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Among subjects diagnosed with familial or sporadic amyotrophic lateral sclerosis
2. Subjects whose ALSFRS-R scores are in the range of 25~46 at the time of screening (Visit 1).
3. Subjects who are able to visit the site by themselves or with other's support.
4. When subjects and/or their legal guardians consent to participating in this clinical study.
5. Subjects deemed, by the investigator, capable of complying with the clinical study protocol
6. For child-bearing aged female subjects: Subjects who consent to sexual abstinence (refraining from sexual intercourse) or use of contraception method with annual failure rate of < 1% during the study period.

A female subject who has experienced the menarche, does not reach the menopause (or 12-month or longer amenorrhea for unknown reasons except menopause) and does not receive surgical sterilization (ovariectomy and/or hysterectomy) is regarded as the child-bearing aged woman.

Examples of contraception methods with annual failure rate of < 1% include bilateral tubal ligation, vasectomy, appropriate use of hormonal contraceptives that inhibit ovulation (supplemented by barrier method and spermicide), hormone-releasing intrauterine device and copper intrauterine device.

Based on clinical study period and subject's preferred lifestyle, the reliability of sexual abstinence should be evaluated. Periodic abstinence (e.g., calendar method, ovulation and post-ovulation symptothermal method) and extravaginal ejaculation are not acceptable contraception methods.

For male subjects: Subjects who, as described below, consent to sexual abstinence (refraining from sexual intercourse) or use of contraception method and consent to refrain from donation of sperm.

When a male subject has his child-bearing aged female partner or pregnant female partner, he should maintain sexual abstinence or use condom to avoid exposure to embryo. Such male subject should not donate sperm during this period.

Based on clinical study period and subject's preferred lifestyle, the reliability of sexual abstinence should be evaluated. Periodic abstinence and extravaginal ejaculation are not acceptable contraception methods.

Exclusion Criteria:

1. Subjects who fail to satisfy ALS diagnosis criteria according to the revised World Federation of Neurology El Escorial Criteria [Rix Brooks, 2000].
2. Subjects expected to have side effects on administration of cell therapy (such as subjects suspected to have malignant tumor, high-risk subjects vulnerable to psychogenic shock and severe hypertension subjects).
3. ALSFRS-R score of less than 25 and 47 or higher during screening (visit 1)
4. Subjects who fall into above Class II according to the New York Heart Association's functional classification (see the attachment), 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 (Visit 1) or who received stent insertion or coronary artery bypass grafting.
5. Subjects who have experienced epileptic seizure.
6. Subjects with severe renal disorder (serum creatinine: not less than 3.0 mg/dL).
7. Subjects with severe hepatic disorder (ALT, AST, or bilirubin: over 2.0 times of the normal upper limit).
8. Subjects who show hemorrhagic tendency at the time of screening (PT and aPTT > 1.5 x ULN)
9. Subjects who are found to have active viral infections (such as HBsAg, HCV Ab, HIV Ab, CMV IgM, EBV IgM, HSV IgM and Treponema pallidum) at the time of screening.
10. Subjects with hypersensitivity to antibiotics (penicillin or streptomycin).
11. Subjects with any malignant tumor in the past 5 years before screening, except malignant tumors with very low risk of metastasis or death (such as appropriately treated cervical intraepithelial neoplasia, skin basal or squamous cell carcinoma, localized prostate cancer or ductal carcinoma in situ).
12. Subjects who are receiving any medicinal products that may affect bone marrow functions.
13. Subjects with severe mental disorders (such as schizophrenia and bipolar disorder. However, exception applies to mild ALS-related cognitive impairment and secondary emotional trauma).
14. Subjects for whom administration of investigational product is prohibited, subjects with conditions that may affect interpretation of results or subjects with conditions that may result in high risk of complications, such as the rest diseases, metabolic disorders, physical examination results and/or laboratory test results as diseases or such conditions are reasonably suspected.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Groups/Cohorts; In the first-stage dose, a 1:1 mixture of autologous CSF and HypoThermosol® FRS (HTS-FRS) is used as a suspension, and in the second-stage dose, only HypoThermosol® FRS (HTS-FRS) is used as a suspension without cerebrospinal fluid. Mix 1.0 ⅹ 10^6 cells per kg of body weight with the suspension at the dose level below; First stage dose: HTS-FRS 0.5mL/10kg + cerebrospinal fluid 0.5mL/10kg; Second stage dose: HTS-FRS 1.0mL/10kg

Biological: Lenzumestrocel; 1.0 ⅹ 10^6 cells/kg of Neuronata-R mixed with HTS-FRS suspension are administered twice in the cerebrospinal fluid at intervals of 26 days; Other Names: Neuronata-R; Autologous Bone Marrow derived Mesenchymal Stem cell; Drug: Riluzole; In the case of a subject who is not taking Riluzole at the time of screening (visit 1), Riluzole should be taken except when discontinued due to Adverse events. The dose can be changed within the authorization according to the medical expert's judgement; Other Names: Rilutek

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
tolerability Assessment	HTS-FRS DLT expression for each dose step	through study period, an average of 8week
Safety Assessment	Adverse Events(including DLT)	through study period, an average of 8week
Safety Assessment	Clinical Laboratory Analysis(Change in laboratory test results at the time of visit after IP administration compared to baseline)	Baseline and 26day, 8week
Safety Assessment	Cerebrospinal Fluid Analysis(Changes in cerebrospinal fluid results at 26day compared to 0day)	0 Day, 26 Day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Assessment	Change in total ALSFRS-R score from before treatment (screening) to after administration	baseline and 26day , 8week
Exploratory Assessment	Change rate in ALSFRS-R score from before treatment (screening) to after administration	within -8week and 0day, 8week

Collaborators and Investigators

• Sponsor: Corestemchemon, Inc.
• Investigators: Principal Investigator: Seung Hyun Kim, MD, PhD, Hanyang University Seoul Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2022
• Primary Completion (Actual): November 27, 2023
• Study Completion (Actual): November 27, 2023

Study Registration Dates

• First Submitted: June 16, 2024
• First Submitted That Met QC Criteria: November 4, 2024
• First Posted (Actual): November 6, 2024

Study Record Updates

• Last Update Posted (Actual): November 6, 2024
• Last Update Submitted That Met QC Criteria: November 4, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; ALS; Mesenchymal stem cell; Phase 1 clinical trial; cell theraphy; HypoThermosol(HTS-FRS)
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Protective Agents; Anticonvulsants; Neuroprotective Agents; Excitatory Amino Acid Agents; Excitatory Amino Acid Antagonists; Riluzole
• Other Study ID Numbers: NEURONATA-ALSHT122

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes