History of Changes for Study: NCT03280056

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

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Study Record Versions

Version	Submitted Date	Changes
1	September 10, 2017	None (earliest Version on record)
2	September 15, 2017	Contacts/Locations and Study Status
3	December 5, 2017	Contacts/Locations, Eligibility and Study Status
4	March 6, 2018	Contacts/Locations and Study Status
5	March 7, 2018	Contacts/Locations and Study Status
6	May 24, 2018	Eligibility and Study Status
7	November 29, 2018	Contacts/Locations and Study Status
8	March 24, 2019	Study Status
9	July 4, 2019	Study Status
10	October 22, 2019	Recruitment Status, Study Status, Contacts/Locations and Study Design
11	January 25, 2021	Recruitment Status and Study Status
12	October 3, 2021	Study Status and Study Design
13	October 5, 2021	Arms and Interventions and Study Status
14	December 1, 2023	Quality Control Review has not concluded Returned: December 20, 2023 Study Status, Outcome Measures, Document Section, Adverse Events, Baseline Characteristics, Participant Flow, Arms and Interventions and Study Design
15	January 4, 2024	Quality Control Review has not concluded Returned: January 4, 2024 Study Status, Outcome Measures, Baseline Characteristics and Participant Flow
16	January 9, 2024	Quality Control Review has not concluded Returned: January 31, 2024 Outcome Measures and Study Status
17	February 5, 2024	Study Status, Outcome Measures and More Information

Comparison Format:

Merged
Side-by-Side

Study Identification


Unique Protocol ID:	BCT-002-US
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
Secondary IDs:

Study Status


Record Verification:	February 2024
Overall Status:	Completed
Study Start:	August 28, 2017
Primary Completion:	September 29, 2020 [Actual]
Study Completion:	September 29, 2020 [Actual]

First Submitted:	August 29, 2017
First Submitted that Met QC Criteria:	September 10, 2017
First Posted:	September 12, 2017 [Actual]

Results First Submitted:	December 1, 2023
Results First Submitted that Met QC Criteria:	February 5, 2024
Results First Posted:	February 29, 2024 [Actual]

Certification/Extension First Submitted:	October 3, 2021
Certification/Extension First Submitted that Met QC Criteria:
Certification/Extension First Posted:	February 29, 2024 [Actual]

Last Update Submitted that Met QC Criteria:	February 5, 2024
Last Update Posted:	February 29, 2024 [Actual]

Sponsor/Collaborators


Sponsor:	Brainstorm-Cell Therapeutics
Responsible Party:	Sponsor
Collaborators:	California Institute for Regenerative Medicine (CIRM)

Oversight


U.S. FDA-regulated Drug:	Yes
U.S. FDA-regulated Device:	No
Data Monitoring:	Yes

Study Description

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

Conditions


Conditions:	Amyotrophic Lateral Sclerosis (ALS)
Keywords:	MSC Autologous Neurotrophic factors

Study Design


Study Type:	Interventional
Primary Purpose:	Treatment
Study Phase:	Phase 3
Interventional Study Model:	Parallel Assignment
	Randomized, Double-Blind, Placebo-Controlled Multicenter Study
Number of Arms:	2
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:	Randomized
Enrollment:	196 [Actual]

Arms and Interventions

Arms	Assigned Interventions
Active Comparator: NurOwn® (MSC-NTF cells) Three Intrathecal administrations of NurOwn® (MSC-NTF cells) at bi-monthly intervals	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 Bone Marrow aspiration Bone Marrow aspiration
Placebo Comparator: Placebo Three Intrathecal administrations of Placebo at bi-monthly intervals	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 Bone Marrow aspiration

Outcome Measures

[See Results Section.]


Primary Outcome Measures:
1.	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.
Secondary Outcome Measures:
1.	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.
2.	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.
3.	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.

Eligibility


Minimum Age:	18 Years
Maximum Age:	60 Years
Sex:	All
Gender Based:
Accepts Healthy Volunteers:	No
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

Contacts/Locations


Study Officials:	Merit E. Cudkowicz, MD Principal Investigator Massachusetts General Hospital
	Robert H. Brown, MD, PhD Principal Investigator UMass Medical School
	Anthony J. Windebank, MD Principal Investigator Mayo Clinic
	Namita A. Goyal, MD Principal Investigator UC Irvine
	Robert G. Miller, MD Principal Investigator California Pacific Medical Center (CPM) Research Institute
	Robert Baloh, MD, Ph.D. Principal Investigator Cedars-Sinai Medical Center
Locations:	United States, California
	University of California Irvine Alpha Stem Cell Clinic Irvine, California, United States, 92697
	Cedars-Sinai Medical Center Los Angeles, California, United States, 90048
	California Pacific Medical Center San Francisco, California, United States, 94115
	United States, Massachusetts
	Massachusetts General Hospital Boston, Massachusetts, United States, 02115
	University of Massachusetts Medical School Worcester, Massachusetts, United States, 01655
	United States, Minnesota
	Mayo Clinic Rochester, Minnesota, United States, 55905

IPDSharing


Plan to Share IPD:	No

References


Citations:
Links:
Available IPD/Information:

Document Section


	Study Protocol Document Date: March 1, 2020 Uploaded: 11/22/2023 11:43 File Name: Prot_000.pdf
	Statistical Analysis Plan Document Date: June 19, 2020 Uploaded: 12/01/2023 14:05 File Name: SAP_001.pdf

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.

Arm/Group Title	NurOwn® (MSC-NTF Cells)	Placebo
Arm/Group Description	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	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

Period Title: Overall Study
Started	95	94
Completed	71	73
Not Completed	24	21
Reason Not Completed
Withdrawal by Subject	12	14
Death	9	2
Adverse Event	1	3
Lost to Follow-up	1	1
Physician Decision	0	1
Early Discontinuation	1	0

Baseline Characteristics

Arm/Group Title

NurOwn® (MSC-NTF Cells)

Placebo

Total

Arm/Group Description

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

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

Total of all reporting groups

Overall Number of Baseline Participants

189

Baseline Analysis Population Description

Age, Categorical

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

95 Participants

94 Participants

189 Participants

<=18 years

Between 18 and 65 years

100%

189

100%

>=65 years

Age, Continuous

Mean (Standard Deviation)
Unit of measure: years

Number Analyzed

95 Participants

94 Participants

189 Participants

Mean

48.1(9.71)

49.1(8.38)

48.6(9.07)

Sex: Female, Male

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

95 Participants

94 Participants

189 Participants

Female

28.42%

37.23%

32.8%

Male

71.58%

62.77%

127

67.2%

Ethnicity (NIH/OMB)

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

95 Participants

94 Participants

189 Participants

Hispanic or Latino

5.26%

3.19%

4.23%

Not Hispanic or Latino

94.74%

96.81%

181

95.77%

Unknown or Not Reported

Race (NIH/OMB)

Measure Type: Count of Participants
Unit of measure: Participants

Number Analyzed

95 Participants

94 Participants

189 Participants

American Indian or Alaska Native

Asian

5.26%

7.45%

6.35%

Native Hawaiian or Other Pacific Islander

1.06%

0.53%

Black or African American

3.16%

3.19%

3.17%

White

91.58%

86.17%

168

88.89%

More than one race

Unknown or Not Reported

2.13%

1.06%

Region of Enrollment

Measure Type: Number
Unit of measure: participants

Number Analyzed

95 Participants

94 Participants

189 Participants

United States

189

Baseline Amyotrophic Lateral Sclerosis Functional Rating ScaleScore^[1]

Mean (Standard Deviation)
Unit of measure: units on a scale

Number Analyzed

95 Participants

94 Participants

189 Participants

30.3(6.5)

31.4(6.1)

30.9(6.3)

[1]

Measure Description: 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.

Outcome Measures

1. Primary Outcome:

Title

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

Description

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

Outcome Measure Data

Analysis Population Description

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/Group Title		NurOwn® (MSC-NTF Cells)	Placebo
Arm/Group Description		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	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
Overall Number of Participants Analyzed		95	94
Measure Type: Count of Participants Unit of Measure: Participants	YES (%)	31 32.6%	26 27.7%
	NO (%)	64 67.4%	68 72.3%

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	NurOwn® (MSC-NTF Cells), Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.453
	Comments	[Not specified]
	Method	Chi-squared
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.330
	Confidence Interval	(2-sided) 95% 0.632 to 2.798
	Estimation Comments	[Not specified]

2. Secondary Outcome:

Title

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

Description

Time Frame

28 weeks following the first intrathecal injection

Outcome Measure Data

Analysis Population Description


Arm/Group Title		NurOwn® (MSC-NTF Cells)	Placebo
Arm/Group Description		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	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
Overall Number of Participants Analyzed		95	94
Measure Type: Count of Participants Unit of Measure: Participants	YES (%)	13 13.7%	13 13.8%
	NO (%)	82 86.3%	81 86.2%

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	NurOwn® (MSC-NTF Cells), Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.997
	Comments	[Not specified]
	Method	Chi-squared
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.998
	Confidence Interval	(2-sided) 95% 0.416 to 2.395
	Estimation Comments	[Not specified]

3. Secondary Outcome:

Title

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

Description

Time Frame

28 weeks following the first intrathecal injection

Outcome Measure Data

Analysis Population Description


Arm/Group Title	NurOwn® (MSC-NTF Cells)	Placebo
Arm/Group Description	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	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
Overall Number of Participants Analyzed	95	94
Least Squares Mean (Standard Error) Unit of Measure: score on a scale	-5.52(0.670)	-5.88(0.665)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	NurOwn® (MSC-NTF Cells), Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.693
	Comments	[Not specified]
	Method	Mixed Models Analysis
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.37
	Confidence Interval	(2-sided) 95% -1.47 to 2.20
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.926
	Estimation Comments	[Not specified]

4. Secondary Outcome:

Title

NurOwn® (MSC-NTF Cells) Treated Patients vs. Placebo Treated Patients as Measured by the Combined Assessment of Function and Survival at 28 Weeks

Description

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

Outcome Measure Data

Analysis Population Description


Arm/Group Title	NurOwn® (MSC-NTF Cells)	Placebo
Arm/Group Description	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	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
Overall Number of Participants Analyzed	95	94
Least Squares Mean (Standard Error) Unit of Measure: score on a scale	73.74(5.210)	72.21(4.890)

Statistical Analysis 1


Statistical Analysis Overview	Comparison Group Selection	NurOwn® (MSC-NTF Cells), Placebo
	Comments	[Not specified]
	Type of Statistical Test	Superiority
	Comments	[Not specified]


Statistical Test of Hypothesis	P-Value	0.804
	Comments	[Not specified]
	Method	ANCOVA
	Comments	[Not specified]


Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.53
	Confidence Interval	(2-sided) 95% -10.65 to 13.72
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.176
	Estimation Comments	[Not specified]

Adverse Events


Time Frame	from the screening visit through the end of the study period (28 weeks after first treatment)
Adverse Event Reporting Description	AE means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality.

Arm/Group Title	NurOwn® (MSC-NTF Cells)		Placebo
Arm/Group Description	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		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
All-Cause Mortality
	NurOwn® (MSC-NTF Cells)		Placebo
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	10 / 95 (10.53%)		4 / 94 (4.26%)
Serious Adverse Events
	NurOwn® (MSC-NTF Cells)		Placebo
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	23 / 95 (24.21%)		17 / 94 (18.09%)
Cardiac disorders
Cardiac arrest ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Palpitations ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Gastrointestinal disorders
Dysphagia ^∗	3 / 95 (3.16%)	3	2 / 94 (2.13%)	2
Gastrointestinal haemorrhage ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
General disorders
Asthenia ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Disease progression ^∗	1 / 95 (1.05%)	1	2 / 94 (2.13%)	2
Euthanasia ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Pain ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Immune system disorders
Anaphylactic reaction ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Infections and infestations
Clostridium difficile infection ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Intervertebral discitis ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Pneumonia ^∗	2 / 95 (2.11%)	2	2 / 94 (2.13%)	3
Sepsis ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Injury, poisoning and procedural complications
Facial bones fracture ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Fall ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Procedural complication ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Procedural headache ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Procedural nausea ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Procedural pain ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Skull fracture ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Subdural haematoma ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Metabolism and nutrition disorders
Dehydration ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Malnutrition ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Nervous system disorders
Cerebral haemorrhage ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Cerebrospinal fluid leakage ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Dizziness ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Loss of consciousness ^∗	1 / 95 (1.05%)	1	1 / 94 (1.06%)	1
Syncope ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Renal and urinary disorders
Renal colic ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Urinary retention ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Dyspnoea ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Pneumonia aspiration ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Pulmonary embolism ^∗	1 / 95 (1.05%)	1	1 / 94 (1.06%)	1
Respiratory arrest ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Respiratory distress ^∗	2 / 95 (2.11%)	2	0 / 94 (0%)	0
Respiratory failure ^∗	5 / 95 (5.26%)	6	3 / 94 (3.19%)	3
Respiratory muscle weakness ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
Vascular disorders
Deep vein thrombosis ^∗	0 / 95 (0%)	0	1 / 94 (1.06%)	1
Haemorrhage ^∗	1 / 95 (1.05%)	1	0 / 94 (0%)	0
∗Indicates events were collected by non-systematic methods.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	NurOwn® (MSC-NTF Cells)		Placebo
	Affected / At Risk (%)	# Events	Affected / At Risk (%)	# Events
Total	93 / 95 (97.89%)		92 / 94 (97.87%)
Gastrointestinal disorders
Constipation ^∗	7 / 95 (7.37%)	7	6 / 94 (6.38%)	6
Diarrhoea ^∗	5 / 95 (5.26%)	6	7 / 94 (7.45%)	9
Dysphagia ^∗	9 / 95 (9.47%)	9	5 / 94 (5.32%)	5
Nausea ^∗	16 / 95 (16.84%)	20	18 / 94 (19.15%)	22
Vomiting ^∗	3 / 95 (3.16%)	4	6 / 94 (6.38%)	6
General disorders
Chills ^∗	2 / 95 (2.11%)	3	5 / 94 (5.32%)	5
Fatigue ^∗	0 / 95 (0%)	0	8 / 94 (8.51%)	8
Injection site pain ^∗	8 / 95 (8.42%)	13	9 / 94 (9.57%)	10
Pyrexia ^∗	9 / 95 (9.47%)	10	9 / 94 (9.57%)	9
Infections and infestations
Nasopharyngitis ^∗	8 / 95 (8.42%)	8	5 / 94 (5.32%)	6
Upper respiratory tract infection ^∗	6 / 95 (6.32%)	7	12 / 94 (12.77%)	12
Injury, poisoning and procedural complications
Contusion ^∗	9 / 95 (9.47%)	9	9 / 94 (9.57%)	16
Fall ^∗	28 / 95 (29.47%)	61	34 / 94 (36.17%)	76
Laceration ^∗	7 / 95 (7.37%)	7	11 / 94 (11.7%)	12
Limb injury ^∗	6 / 95 (6.32%)	7	1 / 94 (1.06%)	2
Post lumbar puncture syndrome ^∗	22 / 95 (23.16%)	36	29 / 94 (30.85%)	48
Post procedural complication ^∗	16 / 95 (16.84%)	22	7 / 94 (7.45%)	10
Postoperative fever ^∗	7 / 95 (7.37%)	7	1 / 94 (1.06%)	2
Procedural anxiety ^∗	5 / 95 (5.26%)	7	1 / 94 (1.06%)	1
Procedural headache ^∗	31 / 95 (32.63%)	58	30 / 94 (31.91%)	51
Procedural pain ^∗	50 / 95 (52.63%)	145	34 / 94 (36.17%)	52
Skin abrasion ^∗	3 / 95 (3.16%)	3	5 / 94 (5.32%)	8
Musculoskeletal and connective tissue disorders
Arthralgia ^∗	10 / 95 (10.53%)	11	7 / 94 (7.45%)	7
Back pain ^∗	42 / 95 (44.21%)	78	24 / 94 (25.53%)	33
Coccydynia ^∗	11 / 95 (11.58%)	14	1 / 94 (1.06%)	1
Muscle spasms ^∗	9 / 95 (9.47%)	14	6 / 94 (6.38%)	6
Muscle tightness ^∗	7 / 95 (7.37%)	7	1 / 94 (1.06%)	1
Muscular weakness ^∗	11 / 95 (11.58%)	15	12 / 94 (12.77%)	16
Musculoskeletal pain ^∗	15 / 95 (15.79%)	16	8 / 94 (8.51%)	9
Musculoskeletal stiffness ^∗	3 / 95 (3.16%)	4	5 / 94 (5.32%)	5
Myalgia ^∗	7 / 95 (7.37%)	8	2 / 94 (2.13%)	2
Neck pain ^∗	7 / 95 (7.37%)	9	8 / 94 (8.51%)	8
Pain in extremity ^∗	16 / 95 (16.84%)	29	11 / 94 (11.7%)	15
Nervous system disorders
Balance disorder ^∗	1 / 95 (1.05%)	1	5 / 94 (5.32%)	5
Dizziness ^∗	5 / 95 (5.26%)	6	5 / 94 (5.32%)	5
Dysarthria ^∗	2 / 95 (2.11%)	3	5 / 94 (5.32%)	6
Headache ^∗	45 / 95 (47.37%)	85	32 / 94 (34.04%)	57
Psychiatric disorders
Anxiety ^∗	5 / 95 (5.26%)	5	5 / 94 (5.32%)	5
Insomnia ^∗	5 / 95 (5.26%)	5	3 / 94 (3.19%)	3
Respiratory, thoracic and mediastinal disorders
Cough ^∗	4 / 95 (4.21%)	5	7 / 94 (7.45%)	7
Dyspnoea ^∗	4 / 95 (4.21%)	4	6 / 94 (6.38%)	8
∗Indicates events were collected by non-systematic methods.

Limitations and Caveats


This trial had a unique and atypical trial population that included more participants than anticipated with advanced ALS, who had a low ALSFRS-R score. As compared with recent large ALS clinical trials, this study population is an outlier, with a mean overall ALSFRS-R score at baseline lower than other studies, and this impacted the power of this study.

More Information


Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study. There is NOT an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact:
Name/Official Title:	Chief Medical Officer
Organization:	Brainstorm Cell Therapeutics
Phone:	+1-201-488-0460
Email:	ClinicalTrial@brainstorm-cell.com