A Phase 3 interventional study of NurOwn® (MSC-NTF cells) and Placebo in Amyotrophic Lateral Sclerosis (ALS), sponsored by Brainstorm-Cell Therapeutics. Completed at 6 sites in United States. Open to participants aged 18 Years to 60 Years. Per ClinicalTrials.gov, last updated 2024-02-29.
Sponsored by Brainstorm-Cell Therapeutics · Phase 3, Interventional, and Treatment
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
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
Exclusion Criteria:
Three Intrathecal administrations of NurOwn® (MSC-NTF cells) at bi-monthly intervals
Biological: NurOwn® (MSC-NTF cells) · Other: Bone Marrow aspiration
Three Intrathecal administrations of Placebo at bi-monthly intervals
Other: Placebo · Other: Bone Marrow aspiration
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
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
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
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
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
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
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.
| Milestone | NurOwn® (MSC-NTF Cells) | Placebo |
|---|---|---|
| Started | 95 | 94 |
| Completed | 71 | 73 |
| Not completed | 24 | 21 |
| Withdrew: Withdrawal by subject | 12 | 14 |
| Withdrew: Death | 9 | 2 |
| Withdrew: Adverse event | 1 | 3 |
| Withdrew: Lost to follow-up | 1 | 1 |
| Withdrew: Physician decision | 0 | 1 |
| Withdrew: Early discontinuation | 1 | 0 |
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.
| Participants | NurOwn® (MSC-NTF Cells) | Placebo |
|---|---|---|
| YES (%) | 31 | 26 |
| NO (%) | 64 | 68 |
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.
| Participants | NurOwn® (MSC-NTF Cells) | Placebo |
|---|---|---|
| YES (%) | 13 | 13 |
| NO (%) | 82 | 81 |
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 on a scale | NurOwn® (MSC-NTF Cells) | 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 | -5.52 ± 0.670 | -5.88 ± 0.665 |
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.
| score on a scale | NurOwn® (MSC-NTF Cells) | Placebo |
|---|---|---|
| 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 ± 5.210 | 72.21 ± 4.890 |
Collected over from the screening visit through the end of the study period (28 weeks after first treatment). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| NurOwn® (MSC-NTF Cells) | 10/95 (10.5%) | 23/95 (24.2%) | 93/95 (97.9%) |
| Placebo | 4/94 (4.3%) | 17/94 (18.1%) | 92/94 (97.9%) |
| Event | NurOwn® (MSC-NTF Cells) | Placebo |
|---|---|---|
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 5/95 | 3/94 |
| DysphagiaGastrointestinal disorders | 3/95 | 2/94 |
| Disease progressionGeneral disorders | 1/95 | 2/94 |
| PneumoniaInfections and infestations | 2/95 | 2/94 |
| Respiratory distressRespiratory, thoracic and mediastinal disorders | 2/95 | 0/94 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 1/95 | 1/94 |
| Acute respiratory failureRespiratory, thoracic and mediastinal disorders | 0/95 | 1/94 |
| Pneumonia aspirationRespiratory, thoracic and mediastinal disorders | 0/95 | 1/94 |
| Clostridium difficile infectionInfections and infestations | 0/95 | 1/94 |
| SepsisInfections and infestations | 0/95 | 1/94 |
| Event | NurOwn® (MSC-NTF Cells) | Placebo |
|---|---|---|
| Procedural painInjury, poisoning and procedural complications | 50/95 | 34/94 |
| HeadacheNervous system disorders | 45/95 | 32/94 |
| Back painMusculoskeletal and connective tissue disorders | 42/95 | 24/94 |
| FallInjury, poisoning and procedural complications | 28/95 | 34/94 |
| Procedural headacheInjury, poisoning and procedural complications | 31/95 | 30/94 |
| Post lumbar puncture syndromeInjury, poisoning and procedural complications | 22/95 | 29/94 |
| NauseaGastrointestinal disorders | 16/95 | 18/94 |
| Post procedural complicationInjury, poisoning and procedural complications | 16/95 | 7/94 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 16/95 | 11/94 |
| Musculoskeletal painMusculoskeletal and connective tissue disorders | 15/95 | 8/94 |
Demographic characteristics were balanced between NurOwn and placebo treatment groups with no statistically significant differences at baseline.
| Age, Categorical(Participants) | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 95 | 94 | 189 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| Mean | 48.1 ± 9.71 | 49.1 ± 8.38 | 48.6 ± 9.07 |
| Sex: Female, Male(Participants) | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| Female | 27 | 35 | 62 |
| Male | 68 | 59 | 127 |
| Ethnicity (NIH/OMB)(Participants) | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| Hispanic or Latino | 5 | 3 | 8 |
| Not Hispanic or Latino | 90 | 91 | 181 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 5 | 7 | 12 |
| Native Hawaiian or Other Pacific Islander | 0 | 1 | 1 |
| Black or African American | 3 | 3 | 6 |
| White | 87 | 81 | 168 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 2 | 2 |
| Region of Enrollment(participants) | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| United States | 95 | 94 | 189 |
| Baseline Amyotrophic Lateral Sclerosis Functional Rating ScaleScore(units on a scale) | NurOwn® (MSC-NTF Cells) | Placebo | Total |
|---|---|---|---|
| Mean | 30.3 ± 6.5 | 31.4 ± 6.1 | 30.9 ± 6.3 |
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