Chronic Ischemic Stroke
Conditions
Keywords
Ischemic Stroke, Neural Stem Cells, Stroke, Allogeneic Cell Therapy, Stroke Rehabilitation, Neuroregeneration, Intracerebral Transplantation, Motor Recovery, Chronic Stroke, Stroke Impairment, Stroke Mobility Impairment, Regenerative Medicine, Cell Therapy
Brief summary
The suNR1se II Study is a Phase 2b randomized, controlled, multi-center clinical trial evaluating the efficacy and safety of stereotactic intracerebral administration of CC-101 (f/k/a NR1), an investigational allogeneic neural stem cell therapy, in adults with chronic ischemic stroke and persistent motor impairment. The study is designed to assess whether administration of CC-101 immediately adjacent to the region of prior stroke injury may improve motor function recovery compared with a sham surgical control procedure. The study will also evaluate the role of short-term anti-rejection therapy with tacrolimus in subjects receiving CC-101. Approximately 36 participants will be randomized in a 1:1:1 ration to receive CC-101 plus tacrolimus, sham surgery (no CC-101) plus tacrolimus-matched placebo, or CC-101 plus tacrolimus-matched placebo. Participants will be followed for safety and functional outcomes for at least 12 months following the study procedure.
Detailed description
CC-101 (f/k/a NR1) is an investigational allogeneic neural stem cell therapy being developed to support endogenous repair and regenerative mechanisms within the brain following ischemic injury and infarction (i.e., ischemic stroke). Rather than directly replacing stroke-damaged and dead brain cells and tissue, CC-101 is intended to promote recovery through local production of biologically active factors that support neurogenesis (i.e., new brain cell production), angiogenesis (i.e., new blood vessel formation), plasticity (i.e., rewiring of synaptic connections), extracellular matrix remodeling (i.e., change materials around brain cells), and modulation of inflammation. The suNR1se II Study is a prospective, randomized, controlled Phase 2b study designed to evaluate the efficacy and safety of stereotactic intracerebral administration of CC-101 in adults with chronic ischemic subcortical ischemic stroke, with or without adjacent cortical involvement. Participants will be randomized equally to one of three study arms: 1) CC-101 plus tacrolimus (Experimental Arm A), 2) sham surgery plus placebo (Control Arm B), or 3) CC-101 plus placebo (Exploratory Arm C). The inclusion of sham surgery control (Arm B) and tacrolimus-matched placebo anti-rejection therapy (Arms B & C) is intended to support rigorous evaluation of CC-101 treatment effect and further characterization of the role of tacrolimus in allogeneic neural stem cell therapy for chronic ischemic stroke. The primary efficacy assessment will evaluate changes in arm and leg motor functions between baseline and 12 months following intervention. Safety assessments will include adverse events, serious adverse events, neurosurgical complications, imaging findings, laboratory assessments, hospitalization events, and mortality.
Interventions
BIOLOGICALCC-101 (f/k/a NR1) Intracerebral Transplantation
Investigational allogeneic neural stem cell product administered stereotactically via intracerebral injection immediately adjacent to the prior stroke lesion.
DRUGTacrolimus
Oral tacrolimus or tacrolimus-matched placebo initiated prior to study intervention and continued for approximately 60 days following study intervention per protocol-defined dosing and taper schedule.
PROCEDURESham Surgical Control
Participants will undergo a partial thickness burr hole craniotomy without disruption of the meninges or transplantation of any cells as a means to maintain treatment masking.
Sponsors
Clarion Cells, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants; non-neurosurgeon investigators; study staff responsible for safety assessments; outcome raters; Sponsor personnel involved in study conduct, data review, and study management; and other Sponsor representatives with responsibility for trial oversight will remain blinded to treatment assignment throughout the study. Neurosurgical personnel performing the study procedures and other designated personnel with responsibilities requiring knowledge of treatment assignment (e.g., preparation and administration of investigational product) will be unblinded. Procedures will be implemented to maintain the blind.
Intervention model description
Participants will be randomized in a 1:1:1 allocation ratio to one of three parallel treatment groups evaluating CC-101 (f/k/a NR1) allogeneic neural stem cell therapy with or without active, short-term, oral anti-rejection drug therapy, compared with a sham surgical control. About two-thirds of study participants will receive intracerebral CC-101 transplantation, while one-third will receive sham surgery.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
KEY INCLUSION CRITERIA: 1. Confirmed diagnosis of completed ischemic subcortical stroke in the middle cerebral artery (MCA) distribution with or without cortical involvement based on magnetic resonance imaging (MRI) and/or computed tomography (CT) scan(s). 2. Index stroke occurred ≥ 6 months and ≤ 84 months prior to providing informed consent. 3. Age ≥ 18 years and ≤ 75 years at the time of providing informed consent. 4. Chronic motor neurological deficit due to the index stroke. 5. Total Fugl-Meyer Motor Scale (FMMS) \> 25 and ≤ 75 at baseline. 6. Modified Rankin Score (mRS) of 2-4 at baseline. 7. Subjects taking oral anti-spasticity agent (such as tizanidine hydrochloride or baclofen) must be on a stable dose for 90 days prior to a Screening/Baseline visit. KEY
Exclusion criteria
1. Stroke lesion \<1 cm3 or \>100 cm3 as measured by MRI. 2. Previous history of symptomatic stroke(s) with incomplete motor recovery (NOT including index stroke). 3. Complete or near complete lack of right and/or left upper extremity and/or right and/or left lower extremity movement as defined by the MRC Scale for Muscle Strength scores. 4. History of any neuromuscular, rheumatologic, autoimmune, orthopedic, or other disease or condition that limits motor function. 5. Acute myocardial infarction (heart attack), acute pulmonary embolism (blood clot to the lungs), acute proximal deep vein thrombosis (blood clot in the leg or arm), acute peripheral arterial occlusion, or any other type of acute blood clotting episode within six (6) months of study screening. 6. Intracoronary and/or other intra-arterial stent placement within 12 months of study Screening/Baseline visits requiring uninterrupted anticoagulant and/or anti-platelet therapy. 7. Contracture involving a shoulder, elbow, wrist, finger, hip, knee, and/or ankle. 8. Any contraindication to stereotactic brain surgery. 9. Presence of serum anti-Human Leukocyte Antigen (HLA) Class I and/or Class II antibodies to donor NR1 cells with a Luminex assay value greater than the larger of the central lab's reference ULN or 3,000 Maximum Fluorescence Intensity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Fugl-Meyer Motor Scale (FMMS) Score on Day +365 Following Neurosurgical Intervention (CC-101 transplantation or sham surgery) on Day 0. | Baseline to Day +365. | The total Fugl-Meyer Motor Scale (FMMS) score (0-100; the larger the better) reflects the sum of the upper extremity (0-66) and lower extremity (0-34) FMMS scores. For each study subject, this clinical assessment of motor function on Day +365 will be compared with the baseline total FMMS score to determine the interval change in motor function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Fugl-Meyer Motor Scale (FMMS) Score on Day +365 Following Neurosurgical Intervention (CC-101 transplantation or sham surgery) on Day 0. | Baseline to Day +365. | Each study subject will be categorized as having an increase in total FMMS score of ≥10 points or an increase of \<10 points (including unchanged scores and decreased scores) between baseline assessment and assessment on Day +365 following neurosurgical intervention. |
| Total Fugl-Meyer Motor Scale (FMMS) Score on Day +90 and Day +182 Following Neurosurgical Intervention (CC-101 transplantation or sham surgery) on Day 0. | Baseline to Day +90 and baseline to Day +182 | For each study subject, this clinical assessment of motor function on Day +90 and Day +182 will be compared with the baseline total FMMS score to determine the interval change in motor function. |
| Upper Extremity Motor Function as Assessed by the Action Research Arm Test (ARAT) on Day +365 Following Neurosurgical Intervention (CC-101 transplantation or sham surgery) on Day 0. | Baseline to Day +365. | Each study subject will be categorized as having an increase in ARAT score of ≥5.7 points or an increase of \<5.7 points (including unchanged scores and decreased scores) between baseline assessment and assessment on Day +365 following neurosurgical intervention. |
| Barthel Index on Day +90 and Day +182 Following Neurosurgical Intervention (CC-101 transplantation or sham surgery) on Day 0. | Baseline to Day +90 and baseline to Day +182. | For each study subject, this clinical assessment of functional independence on Day +90 and Day +182 will be compared with the baseline Barthel Index to determine the interval change. |
| Gait Velocity Using the Comfortable Gait Speed Test Measuring 10 Meters of Timed Gait Speed on Day +365 Following Neurosurgical Intervention (CC-101 transplantation or sham surgery) on Day 0.. | Baseline to Day +365. | Each study subject will be categorized as having or not having an improvement in gait function by at least one functional level using the 10-meter walk test between baseline assessment and assessment on Day +365 following neurosurgical intervention. |
| Overall Survival on Day +90, Day +182, and Day +365 Following Neurosurgical Intervention (CC-101 transplantation or sham surgery) on Day 0. | Survival rates at Day +90, Day +182, and Day +365. | Subject survival to key assessment milestones will be assessed. Time to all-cause subject death following study Day 0 neurosurgery will be estimated using the product-limit (Kaplan-Meier) method. |
Contacts
CONTACTRuth Antoine, MS, MBA
CONTACTSteven R Deitcher, MD
STUDY_CHAIRGary K Steinberg, MD, PhD
Stanford University School of Medicine, Department of Neurosurgery
Outcome results
None listed