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CNS10-NPC-GDNF for the Treatment of ALS

Primary Purpose

Amyotrophic Lateral Sclerosis

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Stem cell (HPC) implantation

Stereotactic surgical device

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring stem cells, growth factor, ALS

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Confirmed diagnosis of ALS (Lab-supported Probable, Probable or Definite EI Escorial Criteria)
Duration of symptoms ≤ 36 months
Progressive weakness in lower extremities, with EMG supported evidence of denervation in both lower extremities.
Forced Vital Capacity >60% of predicted normal in supine.
Male/Female; Age: 18 and older
Able to provide Informed Consent
Be geographically accessible to the study site and able to travel to study site for required visits
Have caregiver to assist in the transportation and care required by participation in the study
Not taking riluzole or on a stable dose for ≥ 30 days
For women of child bearing capacity, negative pregnancy test prior to surgery
Medically able to undergo thoracolumbar laminectomy or laminoplasty as determined by the site PI and Neurosurgeon
Medically able to tolerate the immunosuppression regimen as determined by the site PI

Exclusion Criteria:

Using invasive ventilatory assistance
Diagnosis of another active or unstable medical illness that may interfere with study participation at discretion of PI
Presence of any of the following conditions:
1. Current drug or alcohol abuse
2. Any known immunodeficiency syndrome
3. Unstable medical condition
4. Unstable psychiatric illness including psychosis and untreated major depression within 90 days of screening
Persons of child bearing capacity not willing to practice birth control
Receiving any investigational device/biologic/drug in past 30 days or any previous exposure to stem cell therapy
Any condition in the lower extremities which precludes serial strength testing
Any condition that the Neurosurgeon feels may pose complications for the surgery
Any condition or ALS disease phenotype that the site PI feels may interfere with participation in the study or in the interpretation of study endpoints

Sites / Locations

Cedars-Sinai Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Stem cell implantation

Arm Description

Subjects meeting all Eligibility Criteria and providing Informed Consent will be enrolled in one of two sequential dosing groups (Group A and B). Subjects will be treated sequentially with a minimum of one month interval between surgeries for the first three subjects in each dosing cohort. The remaining subjects in the cohort will be treated with a minimum interval of at least one week between surgeries. There will be 9 subjects in each group. No control group is included. All patients will received unilateral lumbar spinal cord injections of CNS10-NPC-GDNF cells.

Outcomes

Primary Outcome Measures

Safety evaluated by Adverse Events and Serious Adverse Events, post-operative MRI, and clinical laboratory assessments

Safety, as evaluated by: Adverse Events and Serious Adverse Events Post-op MRI Clinical laboratory assessments, as clinically indicated (hematology, chemistry, immunology)

Secondary Outcome Measures

Compound Motor Action Potential (CMAP)

Compound Motor Action Potential - CMAP (Tibialis anterior)

Force Generation via ATLIS testing

Lower extremity Force Generation via ATLIS testing

Quantitative Muscle MRI

Quantitative Muscle MRI of bilateral lower extremities

Electrical Impedance Myography (EIM)

Lower Extremity Electrical Impedance Myography (EIM)

Assessment of glial cell line derived neurotrophic factor (GDNF) in the cerebral spianl fluid (CSF)

Assessment of GDNF in the CSF

Full Information

NCT ID

NCT02943850

First Posted

October 20, 2016

Last Updated

July 13, 2020

Sponsor

Cedars-Sinai Medical Center

Collaborators

California Institute for Regenerative Medicine (CIRM)

1. Study Identification

Unique Protocol Identification Number

NCT02943850

Brief Title

CNS10-NPC-GDNF for the Treatment of ALS

Official Title

Human Neural Progenitor Cells Secreting Glial Cell Line-Derived Neurotrophic Factor (CNS10-NPC-GDNF) for the Treatment of Amyotrophic Lateral Sclerosis

Study Type

Interventional

2. Study Status

Record Verification Date

July 2020

Overall Recruitment Status

Completed

Study Start Date

April 1, 2017 (Actual)

Primary Completion Date

October 18, 2019 (Actual)

Study Completion Date

October 18, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Cedars-Sinai Medical Center

Collaborators

California Institute for Regenerative Medicine (CIRM)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

The investigator is examining the safety of transplanting cells that have been engineered to produce a growth factor into the spinal cord of patients with Amyotrophic Lateral Sclerosis (ALS). The cells are called neural progenitor cells, which are a type of stem cell that can become several different types of cells in the nervous system. These cells have been derived to specifically become astrocytes, which is a type of neuronal cell. The growth factor is called glial cell line-derived neurotrophic factor, or GDNF. GDNF is a protein that promotes the survival of many types of neuronal cells. Therefore, the cells are called "CNS10-NPC-GDNF." The investigational treatment has been tested in animals, but it has not yet been tested in people. In this study, we want to learn if CNS10-NPC-GDNF cells are safe to transplant into the spinal cords of people.

Detailed Description

This study will be the first to use a genetically modified progenitor cells to treat a neurodegenerative disease. This is a Phase 1/2a, single-center, blinded (as to side of injection), safety study of two escalating doses of human neural progenitor cells expressing GDNF (CNS10-NPC-GDNF) delivered unilaterally to the lumbar region in ALS subjects with moderate leg involvement. Subjects meeting all Eligibility Criteria and providing Informed Consent will be enrolled in one of two sequential dosing groups. Subjects will be treated sequentially with a minimum of one month interval between surgeries for the first three subjects in each dosing cohort. The remaining subjects in the cohort will be treated with a minimum interval of at least two weeks between surgeries. Specific aims: Safety, as evaluated by: Adverse Events and Serious Adverse Events Clinical laboratory assessments, as clinically indicated (hematology, chemistry, immunology)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Amyotrophic Lateral Sclerosis

Keywords

stem cells, growth factor, ALS

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Stem cell implantation

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

Stem cell (HPC) implantation

Intervention Description

All patients will received unilateral lumbar spinal cord injections of CNS10-NPC-GDNF cells.

Intervention Type

Device

Intervention Name(s)

Stereotactic surgical device

Intervention Description

A newly developed stereotactic frame is being evaluated as a part of this trial

Primary Outcome Measure Information:

Title

Safety evaluated by Adverse Events and Serious Adverse Events, post-operative MRI, and clinical laboratory assessments

Description

Safety, as evaluated by: Adverse Events and Serious Adverse Events Post-op MRI Clinical laboratory assessments, as clinically indicated (hematology, chemistry, immunology)

Time Frame

Patients will be followed postoperatively for 12 months

Secondary Outcome Measure Information:

Title

Compound Motor Action Potential (CMAP)

Description

Compound Motor Action Potential - CMAP (Tibialis anterior)

Time Frame

CMAP will be performed 7 times over 15 months

Title

Force Generation via ATLIS testing

Description

Lower extremity Force Generation via ATLIS testing

Time Frame

ATLIS testing will be performed 7 times over 15 months

Title

Quantitative Muscle MRI

Description

Quantitative Muscle MRI of bilateral lower extremities

Time Frame

Muscle MRI will be performed 6 times over 15 months

Title

Electrical Impedance Myography (EIM)

Description

Lower Extremity Electrical Impedance Myography (EIM)

Time Frame

EIM will be performed 7 times over 15 months

Title

Assessment of glial cell line derived neurotrophic factor (GDNF) in the cerebral spianl fluid (CSF)

Description

Assessment of GDNF in the CSF

Time Frame

CSF will be collected at 3 time points over 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Confirmed diagnosis of ALS (Lab-supported Probable, Probable or Definite EI Escorial Criteria) Duration of symptoms ≤ 36 months Progressive weakness in lower extremities, with EMG supported evidence of denervation in both lower extremities. Forced Vital Capacity >60% of predicted normal in supine. Male/Female; Age: 18 and older Able to provide Informed Consent Be geographically accessible to the study site and able to travel to study site for required visits Have caregiver to assist in the transportation and care required by participation in the study Not taking riluzole or on a stable dose for ≥ 30 days For women of child bearing capacity, negative pregnancy test prior to surgery Medically able to undergo thoracolumbar laminectomy or laminoplasty as determined by the site PI and Neurosurgeon Medically able to tolerate the immunosuppression regimen as determined by the site PI Exclusion Criteria: Using invasive ventilatory assistance Diagnosis of another active or unstable medical illness that may interfere with study participation at discretion of PI Presence of any of the following conditions: Current drug or alcohol abuse Any known immunodeficiency syndrome Unstable medical condition Unstable psychiatric illness including psychosis and untreated major depression within 90 days of screening Persons of child bearing capacity not willing to practice birth control Receiving any investigational device/biologic/drug in past 30 days or any previous exposure to stem cell therapy Any condition in the lower extremities which precludes serial strength testing Any condition that the Neurosurgeon feels may pose complications for the surgery Any condition or ALS disease phenotype that the site PI feels may interfere with participation in the study or in the interpretation of study endpoints

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert H. Baloh, MD, PhD

Organizational Affiliation

Cedars-Sinai Medical Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Cedars-Sinai Medical Center

City

Los Angeles

State/Province

California

ZIP/Postal Code

90048

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

36064599

Citation

Baloh RH, Johnson JP, Avalos P, Allred P, Svendsen S, Gowing G, Roxas K, Wu A, Donahue B, Osborne S, Lawless G, Shelley B, Wheeler K, Prina C, Fine D, Kendra-Romito T, Stokes H, Manoukian V, Muthukumaran A, Garcia L, Banuelos MG, Godoy M, Bresee C, Yu H, Drazin D, Ross L, Naruse R, Babu H, Macklin EA, Vo A, Elsayegh A, Tourtellotte W, Maya M, Burford M, Diaz F, Patil CG, Lewis RA, Svendsen CN. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. Nat Med. 2022 Sep;28(9):1813-1822. doi: 10.1038/s41591-022-01956-3. Epub 2022 Sep 5.

Results Reference

derived

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CNS10-NPC-GDNF for the Treatment of ALS

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