Clinical trial NCT01151124: Pilot Investigation of Stem Cells in Stroke
Official title: A Phase I Safety Trial of CTX0E03 Drug Product Delivered Intracranially in the Treatment of Patients With Stable Ischemic Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Stroke
Lead sponsor: ReNeuron Limited
Sponsor class: INDUSTRY
First posted: 2010-06-25
Enrollment: 11
Sex: MALE
Minimum age (years): 60
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The study is designed to test the safety of a manufactured neural stem cell line (CTX cells) delivered by injection into the damaged brains of male patients 60 years of age or over who remain moderately to severely disabled 6 months to 5 years following an ischemic stroke. In addition the trial will evaluate a range of potential efficacy measures for future trials. Treatment will involve a single injection of one of four doses of CTX cells into the patient's brain in a carefully controlled neurosurgical operation performed under general anesthetic. The trial is designed to treat 12 patients and measure outcomes over 24 months. Patients will be invited to participate in a long-term follow-up trial for a further 8 years.

Detailed description: Design: The trial is an open label, single administration, ascending dose, single site trial using CTX neural stem cells with 24-month patient monitoring following treatment.

Pre-treatment selection of patients : Males aged ≥60 years with unilateral ischaemic stroke affecting sub-cortical white matter and/or basal ganglia 6 months to 5 years prior to entry into the study, with persistent unilateral hemiparesis, a minimum infarct diameter of 1 cm and stable neurological functional deficit as determined by the NIH Stroke Scale, (measured twice at least 1 month apart), will be eligible for treatment.

Treatment: The CTX cells will be injected by stereotaxic procedures into the putamen region of the brain of the patient under general anesthesia with imaging guidance to locate injection site. Four ascending doses of CTX cells will be tested in 12 patients (4 dosage groups of three patients at each dose level receiving 2 million, 5 million, 10 million or 20 million cells). Patients will be admitted to hospital the day before surgery and prepared for CTX cell implantation to take place. Patients will be discharged two days after surgery.

One patient will be treated at a time. An independent Data Safety Monitoring Board (DSMB) will make the decision to continue dosing at each dose level following satisfactory review of the 28 day safety data for the first patient at that dose level; and to increase the dose to the next level following satisfactory review of the 3 month safety data for all three patients in the previous dose group.

Post treatment follow-up of patients: There will be 6 scheduled visits to clinic for monitoring and neurofunctional testing and 5 scheduled telephone contacts to monitor adverse events (AEs) and concomitant medications over the 2 year follow-up period.

End-points: The primary end-point of the trial is safety, measured by numbers of relevant Serious Adverse Events, health screening, neurological assessment and scanning abnormalities. The secondary aim is to evaluate various MRI and other test measures for their potential as efficacy markers for subsequent trials.

Post trial follow up: All trial patients will be flagged by the National Health Service Central Register (NHSCR) Scotland for life-long follow-up. In addition, all patients will be invited to take part in an 8-year follow up trial requiring an annual review by a suitable physician.

Eligibility criteria: Inclusion Criteria:

* Males
* 60 years or over
* Unilateral ischemic stroke involving subcortical white matter or Basal Ganglia 6 months to 5 years before entry
* NIHSS score minimum 6 with hemiparesis (2 or more for motor arm and leg)
* Neurologically stable for 2 m
* modified Rankin score of 2-4
* Fit for general anesthesia, neurosurgery
* Capacity to consent
* Infarct at least 1cm diameter

Exclusion Criteria:

* Structural brain vascular lesions requiring surgery or increasing the risk of stereotaxic implantation
* Unstable medical conditions with expected survival \<12 months
* Any medical condition that would impair participation (eg progressive neurological disorders, mental illness)
* Major surgery within 30 days
* Previous allogeneic tissue transplant
* MMSE \< 24
* Epilepsy
* Coagulation disorders or anticoagulant treatment that cannot be interrupted
* Stimulants, botox, tamoxifen
* Contraindications to MRI

Primary outcomes:
measure: Incidence of adverse events
timeFrame: 1 year
Secondary outcomes:
measure: Barthel Index
timeFrame: 1 year
measure: Mini-Mental State Examination
timeFrame: 1 year
measure: modified Rankin Score
timeFrame: 1 year
measure: EQ-5D
timeFrame: 1 year
Other outcomes:
Locations:
city: Glasgow
country: United Kingdom
facility: Division of Clinical Neurosciences, Glasgow Southern General Hospital
Study officials:
References:
citation: Kalladka D, Sinden J, Pollock K, Haig C, McLean J, Smith W, McConnachie A, Santosh C, Bath PM, Dunn L, Muir KW. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet. 2016 Aug 20;388(10046):787-96. doi: 10.1016/S0140-6736(16)30513-X. Epub 2016 Aug 3.
citation: Stevanato L, Thanabalasundaram L, Vysokov N, Sinden JD. Investigation of Content, Stoichiometry and Transfer of miRNA from Human Neural Stem Cell Line Derived Exosomes. PLoS One. 2016 Jan 11;11(1):e0146353. doi: 10.1371/journal.pone.0146353. eCollection 2016.
citation: Stevanato L, Hicks C, Sinden JD. Differentiation of a Human Neural Stem Cell Line on Three Dimensional Cultures, Analysis of MicroRNA and Putative Target Genes. J Vis Exp. 2015 Apr 12;(98):52410. doi: 10.3791/52410.
citation: Stevanato L, Sinden JD. The effects of microRNAs on human neural stem cell differentiation in two- and three-dimensional cultures. Stem Cell Res Ther. 2014 Apr 11;5(2):49. doi: 10.1186/scrt437.