Phase 2, Randomized, Double Blind, Placebo Controlled Multicenter Study of Autologous MSC-NTF Cells in Patients With ALS (NurOwn)

A Phase 2, Randomized, Double Blind, Placebo Controlled Multicenter Study to Evaluate Safety and Efficacy of Transplantation of Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors (MSC-NTF) in Patients With ALS

This is a multi-center, randomized, double blind, placebo controlled study to evaluate the safety and efficacy of autologous (self) transplantation of Neurotrophic factors-secreting Mesenchymal Stromal Cells (MSC-NTF, NurOwn™) in patients with ALS .

MSC-NTF cells are a novel cell-therapeutic approach which is expected to effectively deliver Neurotrophic factors, which are potent survival factors for neurons, directly to the site of damage.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis (ALS)
• Intervention / Treatment: Biological: Placebo; Biological: Nurown MSC-NTF cells

Detailed Description

The MSC-NTF cell therapy (NurOwn™) is based on transplantation of autologous bone marrow derived mesenchymal stromal cells (MSC), which are enriched from the patients' own bone marrow, propagated ex vivo and induced to secrete NTFs. The autologous MSC-NTF cells are back-transplanted into the ALS patient into the sites of damage, the spinal cord and the muscles.

NTFs are potent survival factors for embryonic, neonatal, and adult neurons and are considered potential therapeutic candidates for ALS. Delivery of appropriate NTFs to the immediate environment of afflicted neurons in ALS patients is expected to improve their survival and thus slow down disease progression and alleviate symptoms.

Previous open-label clinical trials have shown that MSC-NTF cells treatment was well tolerated and appears to be generally safe. Some initials indications of clinical benefit were also observed in some patients.

This multi-center, randomized, double blind, placebo controlled study will evaluate the safety and efficacy of a single combined intramuscular and intrathecal administration of MSC-NTF cells in early-stage ALS patients. Patients will be followed for approximately three months before transplantation with their autologous MSC-NTF cells or placebo. During this period of time, patient bone-marrow will be harvested and mesenchymal stromal cells will be isolated and expanded. Following treatment patients will be followed for a total of six months at monthly visits.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • UMass Medical School
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Males and females ages 18 to 75 years old, inclusive.
2. ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria.
3. Disease onset, as defined by first reported occurrence of symptomatic weakness, spasticity, or bulbar symptoms, of more than 12 months and less than or equal to 24 months.
4. Current disease symptoms must include limb weakness.
5. ALSFRS-R ≥30 at the Screening Visit.
6. Upright slow vital capacity (SVC) measure ≥65% of predicted for gender, height, and age at the Screening Visit.
7. Subjects must be taking a stable dose of riluzole for at least 30 days prior to enrolment or not be on riluzole, and not have been on it for at least 30 days prior to enrolment (riluzole-naïve subjects are permitted in the study).
8. Capable of providing informed consent and willing and able to follow study procedures, including willingness to undergo lumbar puncture.
9. Geographic accessibility to the study site and willingness and ability to comply with follow-up.
10. Women of child-bearing potential must agree not to become pregnant for the duration of the study. Women must be willing to consistently use two forms of contraceptive therapy throughout the course of the trial, and undergo a pregnancy test one week before bone marrow aspiration. Men must be willing to consistently use two forms of contraceptive if their partners are of child-bearing age.
11. Citizen or permanent resident of the United States.

Exclusion Criteria:

1. Prior stem cell therapy of any kind.
2. Inability to lie flat for the duration of intrathecal cell transplantation and/or bone marrow biopsy, or inability to tolerate study procedures for any other reason.
3. History of autoimmune disease (excluding thyroid disease) myelodysplastic or myeloproliferative disorder, leukemia or lymphoma, whole body irradiation, hip fracture, or severe scoliosis.
4. Any unstable clinically significant medical condition other than ALS (e.g., within six months of baseline, had myocardial infarction, angina pectoris, and/or congestive heart failure), treatment with anticoagulants that, in the opinion of the investigator, would compromise the safety of patients.
5. Any history of malignancy including any malignancy affecting the central nervous system and melanoma, within the previous 5 years, with the exception of localized skin cancers (with no evidence of metastasis, significant invasion, or re-occurrence within three years of baseline).
6. Serum AST or ALT value >3.0 times the upper normal limit.
7. Serum creatinine value >2.0 times the upper normal limit.
8. Positive test for Hepatitis B, Hepatitis C, HIV.
9. Current use of immunosuppressant medication or use of such medication within 4 weeks of Screening visit (Visit 1).
10. Any history of acquired or inherited immune deficiency syndrome.
11. Exposure to any other experimental agent (off-label use or investigational) or participation in a clinical trial within 30 days prior to Screening Visit (Visit 1).
12. Use of non-invasive ventilation (NIV), diaphragm pacing system or invasive ventilation (tracheostomy).
13. Any history of either substance abuse within the past year, or unstable psychiatric disease according to PI judgment.
14. Placement or usage of feeding tube.
15. Pregnant women or women currently breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nurown MSC-NTF cells; Single autologous MSC-NTF cells treatment by combined intramuscular and intrathecal administration	Biological: Nurown MSC-NTF cells; Single autologous MSC-NTF cells treatment by combined intramuscular and intrathecal administration; Other Names: NurOwn
Placebo Comparator: Excipient; Combined intramuscular and intrathecal placebo administration	Biological: Placebo; Excipient administration by combined intramuscular and intrathecal administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With at Least One Treatment Emergent Adverse Events	Safety assessed based on the incidence of treatment-emergent adverse events (TEAEs) (including serious adverse events [SAEs]) including clinically relevant changes in vital signs, clinical laboratory assessments, physical and neurological examinations, and electrocardiogram (ECG) tests, during transplantation of expanded autologous MSC-NTF cells administered on a single occasion via combined intrathecal (IT) administration and intramuscular (IM) injections	Up to 24 weeks following the first intrathecal injection, or End of Study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) Slopes From the Pre-transplantation Period to the Post-transplantation Period Between the Treatment and Placebo Groups Through 24 Weeks Post-transplantation.	The ALSFRS-R is a quickly administered (10 minutes) ordinal, validated rating scale (ratings 0-4) used to determine participants' assessment of their capability and independence in 12 functional activities. The total score of ALSFRS-R ranges from 0-48, with higher score being better. The slope of ALSFRS-R for the pre- and post-treatment is obtained from a linear regression model using all available data points in the corresponding period, respectively. The change in slope is obtained from a fixed-effect linear model which is defined as the post-treatment slope minus the pre-treatment slope. The unit of the slope is score on a scale per month. A positive change in slope, means that the patient's decline in the ALSFRS-R score is slower than pre-treatment. A negative change in slope, means that the patient decline in the ALSFRS-R score is faster than pre-treatment.	Up to 24 weeks following the first intrathecal injection
Change in SVC Slopes From the Pre-transplantation Period to the Post-transplantation Period Between the Treatment and Placebo Groups Through 24 Weeks Post-transplantation	SVC measures the maximum amount of air exhaled in a single breath, this lung function is influenced by gender, height, and age, in a complex, non-linear, way. The SVC reported is a normalized value obtained from a non-linear prediction model that accounts for the influence of participant's gender, height and age. SVC was done 3 times at each visit, in order to capture and report the maximal, effort-dependent, lung function that a participant can deliver. The slope of SVC is obtained from a linear regression model using all available data points in the corresponding period, respectively. The change in slope is from a fixed-effect linear model which is defined as the post-treatment slope minus the pre-treatment slope. The unit of the slope is score on a scale per month. Positive change in slope, means that the patient's decline in the SVC score is slower than pre-treatment. Negative change in slope, means that the patient decline in the SVC score is faster than pre-treatment.	Up to 24 weeks following the first intrathecal injection

Collaborators and Investigators

• Sponsor: Brainstorm-Cell Therapeutics
• Investigators: Principal Investigator: Robert H Brown, D.Phil, M.D., UMass Medical School; Principal Investigator: Anthony J. Windebank, M.D., Mayo Clinic; Principal Investigator: Merit Cudkowicz, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: December 17, 2013
• First Submitted That Met QC Criteria: December 17, 2013
• First Posted (Estimated): December 23, 2013

Study Record Updates

• Last Update Posted (Actual): June 6, 2024
• Last Update Submitted That Met QC Criteria: May 8, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: ALS; Cell therapy; Mesenchymal Stromal cells; MSC-NTF
• Additional Relevant MeSH Terms: Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: BCT-001-US