Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients

• ClinicalTrials.gov Identifier: NCT03280056
• Recruitment Status: Completed
• First Posted: September 12, 2017
• Results First Posted: February 29, 2024
• Last Update Posted: February 29, 2024
• Sponsor: Brainstorm-Cell Therapeutics
• Collaborator: California Institute for Regenerative Medicine (CIRM)
• Information provided by (Responsible Party): Brainstorm-Cell Therapeutics

Tracking Information

• First Submitted Date: August 29, 2017
• First Posted Date: September 12, 2017
• Results First Submitted Date: December 1, 2023
• Results First Posted Date: February 29, 2024
• Last Update Posted Date: February 29, 2024
• Actual Study Start Date: August 28, 2017
• Actual Primary Completion Date: September 29, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 4, 2024)

The Proportion of NurOwn® Treated Participants With a ≥1.25 Points/Month Improvement in Post-treatment Slope vs. Pre-treatment Slope in ALSFRS-R Score at 28 Weeks Following the First Treatment as Compared to Placebo [ Time Frame: 28 weeks following the first intrathecal injection ]

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. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, as measured by quantitative neuromuscular strength testing, and with quality of life measures, and predicted survival. The total score of ALSFRS-R ranges from 0-48, with higher score being better.

Original Primary Outcome Measures (submitted: September 10, 2017)

To evaluate the efficacy and safety of NurOwn® (autologous MSC-NTF cells) as compared to placebo as measured by the amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) [ Time Frame: 28 weeks following the first treatment ]

To determine efficacy and safety of repeat intrathecal injections of NurOwn® as compared to Placebo given three times two months apart to participants with Amyotrophic Lateral Sclerosis

Current Secondary Outcome Measures (submitted: February 5, 2024)

• Number of Participants Whose Disease Progression is Halted or Improved as Measured by a 100% or Greater Improvement in Post-treatment Slope vs. Pre-treatment Slope in ALSFRS-R Score of NurOwn® Treatment vs. Placebo [ Time Frame: 28 weeks following the first intrathecal injection ]
  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. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, as measured by quantitative neuromuscular strength testing, and with quality of life measures, and predicted survival. The total score of ALSFRS-R ranges from 0-48, with higher score being better.
• Score of NurOwn® (MSC-NTF Cells) Treated Patients vs. Placebo Treated Patients as Measured by Change From Baseline in ALSFRS-R Score at Week 28 [ Time Frame: 28 weeks following the first intrathecal injection ]
  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. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, as measured by quantitative neuromuscular strength testing, and with quality of life measures, and predicted survival. The total score of ALSFRS-R ranges from 0-48, with higher score being better.
• NurOwn® (MSC-NTF Cells) Treated Patients vs. Placebo Treated Patients as Measured by the Combined Assessment of Function and Survival at 28 Weeks [ Time Frame: 28 weeks following the first intrathecal injection ]
  The combined Assessment of Function and Survival (CAFS) is a composite endpoint based on (1) the change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) score and (2) time to death. On the ALSFRS-R, 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a total score range (minimum and maximum score) of 0-48 (sum of all 12 items). The higher the score the better functioning. For the survival endpoint, the longer time the better outcome. A patient's CAFS score represents a patient's rank in the study based on comparing the patient's outcome for both the change in ALSFRS-R and the time to death to all other patients in the study in a pairwise fashion. The ranked scores range from 001 to 189 (the number of subjects in the mITT population) with larger rank score numbers associated with a better outcome. The reported values are the mean rank scores in each group for the composite endpoint.

Original Secondary Outcome Measures (submitted: September 10, 2017)

Biomarkers [ Time Frame: Through selected post-treatment time points up to 20 weeks post transplant ]

To evaluate biomarkers (such as cell-secreted neurothrophic factors, inflammatory factors, and cytokines in pg/ml) in the cerebrospinal fluid (CSF) as well as in serum samples throughout the study to evaluate their relationship to treatment with NurOwn® (MSC-NTF cells)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
• Official Title: A Phase 3, Randomized Double-Blind, Placebo-Controlled Multicenter Study to Evaluate Efficacy and Safety of Repeated Administration of NurOwn® (Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors) in Participants With ALS

Brief Summary

This study will evaluate the safety and efficacy of repeated administration of NurOwn® (MSC-NTF cells) therapy, which is based on transplantation of autologous bone marrow derived mesenchymal stromal cells (MSC), which are enriched from the patient's own bone marrow, propagated ex vivo and induced to secrete Neurotrophic factors (NTFs).

The autologous NurOwn® (MSC-NTF cells) are back-transplanted into the patient intrathecally by standard lumbar puncture where neurons and glial cells are expected to take up the neurotrophic factors secreted by the transplanted cells

Detailed Description

Neurotrophic factors (NTFs) are potent survival factors for embryonic, neonatal, and adult neurons and are considered potential therapeutic candidates for ALS. Delivery of multiple 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. NTF-secreting mesenchymal stromal cells (MSC-NTF cells) are a novel cell-therapeutic approach aimed at effectively delivering NTFs directly to the site of damage in ALS patients.

Participants meeting the inclusion and exclusion criteria will be randomized and will undergo bone-marrow aspiration. MSC of the participants randomized to the treatment group will be induced into MSC-NTF cells. Participants will undergo a total of three intrathecal (IT) transplantations with NurOwn® (MSC-NTF cells) or matching placebo at three bi-monthly intervals

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomized, Double-Blind, Placebo-Controlled Multicenter Study

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

This is a double-blind study where the investigators, participants and all sponsor and CRO personnel involved in the conduct, data management or analysis of the study will remain blinded to the treatment assignments

Primary Purpose: Treatment

• Condition: Amyotrophic Lateral Sclerosis (ALS)

Intervention

• Biological: NurOwn® (MSC-NTF cells)

  NurOwn® (MSC-NTF): One course of treatment that includes three separate intrathecal injections of 100-125 x 10^6 cells every 8 weeks

  NurOwn® (MSC-NTF): Autologous, bone marrow-derived, mesenchymal stem cells secreting neurotrophic factors

• Other: Placebo

  One course of treatment that includes three separate intrathecal injections of Placebo every 8 weeks

  Placebo: liquid solution in syringe for injection

• Other: Bone Marrow aspiration
  Bone Marrow aspiration

Study Arms

• Active Comparator: NurOwn® (MSC-NTF cells)
  Three Intrathecal administrations of NurOwn® (MSC-NTF cells) at bi-monthly intervals
  Interventions:

  • Biological: NurOwn® (MSC-NTF cells)
  • Other: Bone Marrow aspiration
• Placebo Comparator: Placebo
  Three Intrathecal administrations of Placebo at bi-monthly intervals
  Interventions:

  • Other: Placebo
  • Other: Bone Marrow aspiration

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 1, 2023): 196
• Original Estimated Enrollment (submitted: September 10, 2017): 200
• Actual Study Completion Date: September 29, 2020
• Actual Primary Completion Date: September 29, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria.
• Having onset of ALS disease symptoms, including limb weakness within 24 months at the Screening Visit.
• ALSFRS-R ≥ 25 at the screening Visit.
• Upright slow vital capacity (SVC) measure ≥ 65% of predicted for gender, height, and age at the screening Visit.
• Rapid progressors
• Participants taking a stable dose of Riluzole are permitted in the study
• Citizen or permanent resident of the United States or Canadian citizen able to travel to a US site for all follow-up study visits

Exclusion Criteria:

• Prior stem cell therapy of any kind
• History of autoimmune or other serious disease (including malignancy and immune deficiency) that may confound study results
• Current use of immunosuppressant medication or anticoagulants (per Investigator discretion)
• Exposure to any other experimental agent or participation in an ALS clinical trial within 30 days prior to Screening Visit
• Use of RADICAVA (edaravone injection) within 30 days of screening or intent to use edaravone at any time during the course of the study including the follow up period
• Use of non-invasive ventilation (BIPAP), diaphragm pacing system or invasive ventilation (tracheostomy)
• Feeding tube
• Pregnant women or women currently breastfeeding

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03280056
• Other Study ID Numbers: BCT-002-US
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Brainstorm-Cell Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Brainstorm-Cell Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: California Institute for Regenerative Medicine (CIRM)

Investigators

• Principal Investigator: Merit E. Cudkowicz, MD; Massachusetts General Hospital
• Principal Investigator: Robert H. Brown, MD, PhD; UMass Medical School
• Principal Investigator: Anthony J. Windebank, MD; Mayo Clinic
• Principal Investigator: Namita A. Goyal, MD; UC Irvine
• Principal Investigator: Robert G. Miller, MD; California Pacific Medical Center (CPM) Research Institute
• Principal Investigator: Robert Baloh, MD, Ph.D.; Cedars-Sinai Medical Center

• PRS Account: Brainstorm-Cell Therapeutics
• Verification Date: February 2024