Amyotrophic Lateral Sclerosis (ALS)
Conditions
Keywords
Mesenchymal Stromal cells, MSC-NTF, Cell therapy, ALS
Brief summary
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.
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.
Interventions
BIOLOGICALNurown MSC-NTF cells
Single autologous MSC-NTF cells treatment by combined intramuscular and intrathecal administration
BIOLOGICALPlacebo
Excipient administration by combined intramuscular and intrathecal administration
Sponsors
Brainstorm-Cell Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With at Least One Treatment Emergent Adverse Events | Up to 24 weeks following the first intrathecal injection, or End of Study | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Up to 24 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. 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. |
| 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 | Up to 24 weeks following the first intrathecal injection | 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. |
Countries
United States
Participant flow
Recruitment details
The subject population was planned to include up to 48 treated adults, aged 18 to 75 years, with ALS who were randomly assigned (3:1) to the treatment group (36 patients) or placebo group (12 patients). 48 patients were randomized and all 48 patients underwent treatment.
Pre-assignment details
Visit 1 was the Screening Visit. Visit 2 was the enrollment visit and the pre-transplantation follow-up period (Week 4-6). Visit 3 was the second visit of the pre-transplantation follow-up period (Week 8-10), and 1 week before BMA. Visit 3, patients were randomized into two arms at a 3:1 ratio. Any patient discontinuing the study prior to transplantation of cells (or placebo) injections was replaced with another subject to meet the target of 48 transplanted patients.
Participants by arm
| Arm | Count |
|---|---|
| Nurown MSC-NTF Cells Single autologous MSC-NTF cells treatment by combined intramuscular and intrathecal administration
Nurown MSC-NTF cells: Single autologous MSC-NTF cells treatment by combined intramuscular and intrathecal administration | 36 |
| Excipient Combined intramuscular and intrathecal placebo administration
Placebo: Excipient administration by combined intramuscular and intrathecal administration | 12 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | miscellaneous | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Excipient | Total | Nurown MSC-NTF Cells |
|---|---|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 9.11 | 51.1 years STANDARD_DEVIATION 11.27 | 50.3 years STANDARD_DEVIATION 11.9 |
| ALS Medical History since diagnosis | 9.01 months STANDARD_DEVIATION 4.637 | 9.00 months STANDARD_DEVIATION 5.311 | 9.00 months STANDARD_DEVIATION 5.578 |
| ALS Medical History since first symptom | 16.75 months STANDARD_DEVIATION 3.104 | 17.40 months STANDARD_DEVIATION 3.624 | 17.62 months STANDARD_DEVIATION 3.796 |
| El Escorial Criteria Definite | 3 Participants | 15 Participants | 12 Participants |
| El Escorial Criteria Laboratory-supported Probable | 1 Participants | 6 Participants | 5 Participants |
| El Escorial Criteria Possible | 1 Participants | 4 Participants | 3 Participants |
| El Escorial Criteria Probable | 7 Participants | 23 Participants | 16 Participants |
| Region of Enrollment United States | 12 participants | 48 participants | 36 participants |
| Sex: Female, Male Female | 2 Participants | 13 Participants | 11 Participants |
| Sex: Female, Male Male | 10 Participants | 35 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 12 |
| other Total, other adverse events | 36 / 36 | 12 / 12 |
| serious Total, serious adverse events | 8 / 36 | 1 / 12 |
Outcome results
Primary
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
Time frame: Up to 24 weeks following the first intrathecal injection, or End of Study
Population: The safety population includes all randomized participants who receive any study treatment (MSC-NTF or placebo) including those who do not complete the study. The safety population was analyzed based upon the treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nurown MSC-NTF Cells | Number of Patients With at Least One Treatment Emergent Adverse Events | 36 Participants |
| Excipient | Number of Patients With at Least One Treatment Emergent Adverse Events | 12 Participants |
Secondary
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.
Time frame: Up to 24 weeks following the first intrathecal injection
Population: The Full Analysis Set (FAS) includes all participants who were randomized. The FAS was analyzed based upon treatment group subjects were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nurown MSC-NTF Cells | 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. | -0.556 score on a scale per month | Standard Error 0.2784 |
| Excipient | 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. | -0.356 score on a scale per month | Standard Error 0.4821 |
p-value: 0.720895% CI: [-1.321, 0.92]Mixed Models Analysis
Secondary
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.
Time frame: Up to 24 weeks following the first intrathecal injection
Population: The Full Analysis Set (FAS) includes all randomized participants who were randomized. The FAS will be analyzed based upon treatment group subjects were randomized to.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Nurown MSC-NTF Cells | 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 | -0.73 score on a scale per month. | Standard Error 0.43 |
| Excipient | 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 | -0.31 score on a scale per month. | Standard Error 0.769 |
p-value: 0.64195% CI: [-2.187, 1.36]Mixed Models Analysis