Amyotrophic Lateral Sclerosis (ALS)
Conditions
Keywords
MSC, Autologous, Neurotrophic factors
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
Interventions
BIOLOGICALNurOwn® (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
OTHERPlacebo
One course of treatment that includes three separate intrathecal injections of Placebo every 8 weeks Placebo: liquid solution in syringe for injection
OTHERBone Marrow aspiration
Bone Marrow aspiration
Sponsors
California Institute for Regenerative Medicine (CIRM)
Brainstorm-Cell Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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
Intervention model description
Randomized, Double-Blind, Placebo-Controlled Multicenter Study
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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 | 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. |
Countries
United States
Participant flow
Recruitment details
The first participant in Study BCT-002-US signed informed consent on 28 August 2017 The last participant visit took place on 29 September 2020. The study was conducted at 6 clinical sites in the USA. A total of 263 participants were screened for the study, and 196 participants (74.5% of participants screened) were randomly assigned (1:1) to treatment with either NurOwn or placebo.
Pre-assignment details
The most common reasons that participants did not meet inclusion criteria were failure to meet the SVC inclusion criterion at the Screening Visit or the required pre-treatment decline in ALSFRSR total score at the randomization visit. From the ITT population, 3 participants in the NurOwn group and 4 participants in the placebo group discontinued prior to treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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
Bone marrow aspiration | 95 |
| Placebo One course of treatment that includes three separate intrathecal injections of Placebo every 8 weeks
Placebo: liquid solution in syringe for injection
Bone marrow aspiration | 94 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 |
| Overall Study | Death | 9 | 2 |
| Overall Study | Early Discontinuation | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 14 |
Baseline characteristics
| Characteristic | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 95 Participants | 94 Participants | 189 Participants |
| Age, Continuous Mean | 48.1 years STANDARD_DEVIATION 9.71 | 49.1 years STANDARD_DEVIATION 8.38 | 48.6 years STANDARD_DEVIATION 9.07 |
| Baseline Amyotrophic Lateral Sclerosis Functional Rating ScaleScore | 30.3 units on a scale STANDARD_DEVIATION 6.5 | 31.4 units on a scale STANDARD_DEVIATION 6.1 | 30.9 units on a scale STANDARD_DEVIATION 6.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 90 Participants | 91 Participants | 181 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 87 Participants | 81 Participants | 168 Participants |
| Region of Enrollment United States | 95 participants | 94 participants | 189 participants |
| Sex: Female, Male Female | 27 Participants | 35 Participants | 62 Participants |
| Sex: Female, Male Male | 68 Participants | 59 Participants | 127 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 10 / 95 | 4 / 94 |
| other Total, other adverse events | 93 / 95 | 92 / 94 |
| serious Total, serious adverse events | 23 / 95 | 17 / 94 |
Outcome results
Primary
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
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.
Time frame: 28 weeks following the first intrathecal injection
Population: The modified intent-to-treat (mITT) population was defined as all participants who were randomized, treated and had at least three ALSFRS-R assessments: one pre-treatment assessments of ALSFRS-R prior to the baseline assessment, a baseline assessment and one post-treatment assessment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NurOwn® (MSC-NTF Cells) | 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 | YES (%) | 31 Participants |
| NurOwn® (MSC-NTF Cells) | 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 | NO (%) | 64 Participants |
| Placebo | 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 | YES (%) | 26 Participants |
| Placebo | 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 | NO (%) | 68 Participants |
p-value: 0.45395% CI: [0.632, 2.798]Chi-squared
Secondary
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
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.
Time frame: 28 weeks following the first intrathecal injection
Population: The modified intent-to-treat (mITT) population was defined as all participants who were randomized, treated and had at least three ALSFRS-R assessments: one pre-treatment assessments of ALSFRS-R prior to the baseline assessment, a baseline assessment and one post-treatment assessment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NurOwn® (MSC-NTF Cells) | 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 | YES (%) | 13 Participants |
| NurOwn® (MSC-NTF Cells) | 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 | NO (%) | 82 Participants |
| Placebo | 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 | YES (%) | 13 Participants |
| Placebo | 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 | NO (%) | 81 Participants |
p-value: 0.99795% CI: [0.416, 2.395]Chi-squared
Secondary
NurOwn® (MSC-NTF Cells) Treated Patients vs. Placebo Treated Patients as Measured by the Combined Assessment of Function and Survival at 28 Weeks
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.
Time frame: 28 weeks following the first intrathecal injection
Population: The modified intent-to-treat (mITT) population was defined as all participants who were randomized, treated and had at least three ALSFRS-R assessments: one pre-treatment assessments of ALSFRS-R prior to the baseline assessment, a baseline assessment and one post-treatment assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NurOwn® (MSC-NTF Cells) | NurOwn® (MSC-NTF Cells) Treated Patients vs. Placebo Treated Patients as Measured by the Combined Assessment of Function and Survival at 28 Weeks | 73.74 score on a scale | Standard Error 5.21 |
| Placebo | NurOwn® (MSC-NTF Cells) Treated Patients vs. Placebo Treated Patients as Measured by the Combined Assessment of Function and Survival at 28 Weeks | 72.21 score on a scale | Standard Error 4.89 |
p-value: 0.80495% CI: [-10.65, 13.72]ANCOVA
Secondary
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
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.
Time frame: 28 weeks following the first intrathecal injection
Population: The modified intent-to-treat (mITT) population was defined as all participants who were randomized, treated and had at least three ALSFRS-R assessments: one pre-treatment assessments of ALSFRS-R prior to the baseline assessment, a baseline assessment and one post-treatment assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| NurOwn® (MSC-NTF Cells) | 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 | -5.52 score on a scale | Standard Error 0.67 |
| Placebo | 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 | -5.88 score on a scale | Standard Error 0.665 |
p-value: 0.69395% CI: [-1.47, 2.2]Mixed Models Analysis