A Phase II, Open-label, Dose Escalation and Safety Study of Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis
Trial Snapshot
- Phase
- Phase 2
- Sponsor
- Neuralstem Inc.
- Enrollment
- 18
- Locations
- 3
- Primary Endpoint
- To determine the safety of the maximum tolerated dose of human spinal cord-derived neural stem cell transplantation for the treatment of amyotrophic lateral sclerosis (ALS) assessed by the number and severity of adverse events.
Study Overview
Brief Summary
The study is to determine the feasibility, safety, toxicity, and maximum tolerated (safe) dose of human spinal derived neural stem cell transplantation for the treatment of Amyotrophic Lateral Sclerosis (ALS).
Detailed Description
These stem cells are called Human Spinal Stem Cells (HSSC) and have been engineered from the spinal cord of a single fetus electively aborted after 8 weeks of gestation. The tissue was obtained with the mother's consent. The cells will be transplanted into the ALS patient's spinal cord after laminectomy, an operation that removes bone surrounding the spine. After the spinal cord is exposed, a device manufactured for this purpose will be mounted onto the patient and will hold a syringe filled with the cells. The syringe will have a needle attached and the needle will enter the spinal cord at 5-10 locations injecting the cells. The device will minimize trauma to the spinal cord by the needle by making the puncture precise and steady and injecting the material at a slow and steady speed.
ALS is a universally fatal neurodegenerative condition that causes weakness leading to paralysis and death. Life expectancy is 2-5 years. The cause is unknown and there is no effective treatment. Previous research has shown that on autopsy, ALS patients are found to have increased levels of the amino acid glutamate accumulated in the brain and spinal cord. This increase is thought to be caused by a decrease in the glutamate transporter which normally "cleans up" glutamate from the cells. HSSC are known to express amino acid transporters and it is hoped that this action will reduce the toxicity of accumulated glutamate and benefit ALS patients. There is a second hypothesized benefit of the HSSC and that is their ability to secrete neurotrophic support factors. Neurotrophic factors support the health of nerves.
There will be 5 sequential cohorts (Groups A - E) with 3 subjects in each cohort. New patients will be enrolled into each group. No control group is included. All subjects will receive spinal cord injections of HSSC. All subjects will also be ambulatory with respiratory function greater than or equal to 50% supine and 60% seated of predicted normal and will receive bilateral injections at the C3 through C5 cervical segments. Subjects in Group E will receive bilateral injections at the L2 through L5 lumbar segments and then return approximately one-three months later to receive bilateral injections at the C3 through C5 cervical segments.
The dose escalation plan is as follows:
- Group A: 3 ambulatory early-stage subjects with arm weakness but not paralysis, to receive bilateral C3 through C4 injections of 2x106 cells (10 injections x 2x105 cells/ injection)
- Group B: 3 ambulatory early-stage subjects with arm weakness but not paralysis, to receive bilateral C3 through C5 injections of 4x106 cells (20 injections x 2x105 cells/ injection)
- Group C: 3 ambulatory early-stage subjects with arm weakness but not paralysis, to receive bilateral C3 through C5 injections of 6x106 cells (20 injections x 3x105 cells/ injection)
- Group D: 3 ambulatory early-stage subjects with arm weakness but not paralysis, to receive bilateral C3 through C5 injections of 8x106 cells (20 injections x 4x105 cells/ injection)
- Group E: 3 ambulatory early-stage subjects with arm weakness but not paralysis, to receive bilateral L2 through L5 injections of 8x106 cells (20 injections of 4x105 cells/ injection) and then approximately 4-12 weeks later to receive bilateral C3 through C5 injections of 8x106 cells (20 injections of 4x105 cells/ injection.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Have the ability to understand the requirements of the study, provide written informed consent, understand and provide written authorization for the use and disclosure of Protected Health Information (PHI) [per Health Insurance Portability and Accountability Act (HIPAA) Privacy Ruling] and comply with the study procedures.
- •Subjects with sporadic or familial ALS, meeting the definition of laboratory-supported probable, probable or definite ALS according to the World Federation of Neurology El Escorial Criteria (Appendix A). At the time of enrollment subjects should be within 24 months of symptom onset.
- •Age 18 years or older.
- •Females must have a negative serum pregnancy test and practice an acceptable method of contraception or be of non-childbearing potential (post-menopausal for at least 2 years or surgically sterile [hysterectomy, oophorectomy or surgical sterilization]).
- •Geographic accessibility to the study center and the ability to travel to the clinic for study visits.
- •Presence of a willing and able caregiver.
- •Medically able to undergo lumbar and/or cervical laminectomy or laminoplasty as determined by the site Principal Investigator and neurosurgeon.
- •Medically able to tolerate the immunosuppression regimen consisting of basiliximab, tacrolimus, mycophenolate mofetil, prednisone and methylprednisolone as determined by the site PI.
- •Agrees to the visit schedule as outlined in the informed consent.
- •Not taking riluzole (Rilutek®) or on a stable dose for ≥ 30 days.
- •Vital capacity ≥ 60% of predicted normal for age, height and gender measured in the seated position and ≥50% in supine position during the 7 days prior to surgery.
- •Ambulatory subjects with extremity weakness and/or spasticity due to ALS. Patients undergoing lumbar surgery must have demonstrable weakness or spasticity in one or both lower extremities. Patients undergoing cervical surgery must have demonstrable weakness or spasticity in one or both upper extremities, with at least antigravity strength. Subjects must have normal neck extensor and flexor strength.
Exclusion Criteria
- •Etiology of paraplegia or weakness is due to causes other than ALS.
- •A positive result on the Panel Reactive Antibody (PRA) test, with the presence of specific HLA antibodies matching the HLA DNA profile of the donor cells.
- •Any known immunodeficiency syndrome.
- •Receipt of any investigational drug, device or biologic within 30 days of surgery.
- •Any concomitant medical disease or condition limiting the safety to participate:
- •Coagulopathy
- •Active uncontrolled infection
- •Hypotension requiring vasopressor therapy
- •Previous spinal surgery that the neurosurgeon deems to be an obstacle to the planned transplantation
- •Skin breakdown over the site of surgery
- •Malignancy (except for non-melanoma skin cancer)
- •Spinal stenosis severe enough to preclude surgery (as determined by the neurosurgeon)
- •Pre-existing kyphosis by preoperative MRI or X-ray
- •Less than 5/5 grade in neck extension and strength test at the time of surgery.
- •Creatinine >1.5, liver function tests (SGOT/SGPT, Bilirubin, Alk Phos) > 2x upper limit of normal, hematocrit/hemoglobin < 30/10, total WBC < 4000, uncontrolled hypertension (systolic > 180 or diastolic > 100) or uncontrolled diabetes (defined as hemoglobin A1C >8), evidence of GI bleeding by hemoccult test, tuberculosis (TB test: PPD), serologic evidence of current infection with a hepatitis virus or human immunodeficiency virus (HIV).
- •Presence of any of the following conditions:
- •Current drug abuse or alcoholism
- •Unstable medical conditions
- •Unstable psychiatric illness including psychosis and untreated major depression within 90 days of screening
- •Any condition or ALS disease phenotype that the site PI feels may interfere with participation in the study or in the interpretation of study endpoints.
- •Any condition that the neurosurgeon feels may pose complications for the surgery.
- •Known hypersensitivity to basiliximab, tacrolimus, mycophenolate mofetil, prednisone or methylprednisolone.
- •Inability to provide informed consent as determined by the site PI.
- •Inadequate family or caregiver support as determined by the site PI.
Arms & Interventions
Surgery
There will be 5 sequential cohorts (Groups A-E) with 3 subjects in each cohort. Each cohort will follow a dose escalation plan. New patients will be enrolled into each group. No control group is included. All patients will received spinal cord injections of HSSC.
Intervention: Human spinal cord stem cell implantation (Device)
Outcomes
Primary Outcomes
To determine the safety of the maximum tolerated dose of human spinal cord-derived neural stem cell transplantation for the treatment of amyotrophic lateral sclerosis (ALS) assessed by the number and severity of adverse events.
Time Frame: Patients will be followed postoperatively for 24 months.
The primary objective of the study is to determine the feasibility, safety, toxicity, and maximum tolerated (safe) dose of human spinal cord-derived neural stem cell transplantation for the treatment of amyotrophic lateral sclerosis (ALS).
Secondary Outcomes
- To evaluate neurologic deficits post spinal stem cell transplantation therapy.(Patients will be followed postoperatively for 24 months.)