title: TOOTH (The Open study Of dental pulp stem cell Therapy in Humans): Study protocol for evaluating safety and feasibility of autologous human adult dental pulp stem cell therapy in patients with chronic disability after stroke.
abstract: Stroke represents a significant global disease burden. As of 2015, there is no chemical or biological therapy proven to actively enhance neurological recovery during the chronic phase post-stroke. Globally, cell-based therapy in stroke is at the stage of clinical translation and may improve neurological function through various mechanisms such as neural replacement, neuroprotection, angiogenesis, immuno-modulation, and neuroplasticity. Preclinical evidence in a rodent model of middle cerebral artery ischemic stroke as reported in four independent studies indicates improvement in neurobehavioral function with adult human dental pulp stem cell therapy. Human adult dental pulp stem cells present an exciting potential therapeutic option for improving post-stroke disability.
  
  
  
  TOOTH (The Open study Of dental pulp stem cell Therapy in Humans) will investigate the use of autologous stem cell therapy for stroke survivors with chronic disability, with the following objectives: (a) determine the maximum tolerable dose of autologous dental pulp stem cell therapy; (b) define that dental pulp stem cell therapy at the maximum tolerable dose is safe and feasible in chronic stroke; and (c) estimate the parameters of efficacy required to design a future Phase 2/3 clinical trial.
  
  
  
  TOOTH is a Phase 1, open-label, single-blinded clinical trial with a pragmatic design that comprises three stages: Stage 1 will involve the selection of 27 participants with middle cerebral artery ischemic stroke and the commencement of autologous dental pulp stem cell isolation, growth, and testing in sequential cohorts (n = 3). Stage 2 will involve the transplantation of dental pulp stem cell in each cohort of participants with an ascending dose and subsequent observation for a 6-month period for any dental pulp stem cell-related adverse events. Stage 3 will investigate the neurosurgical intervention of the maximum tolerable dose of autologous dental pulp stem cell followed by 9 weeks of intensive task-specific rehabilitation. Advanced magnetic resonance and positron emission tomography neuro-imaging, and clinical assessment will be employed to probe any change afforded by stem cell therapy in combination with rehabilitation.
  
  
  
  Nine participants will step-wise progress in Stage 2 to a dose of up to 10 million dental pulp stem cell, employing a cumulative 3 + 3 statistical design with low starting stem cell dose and subsequent dose escalation, assuming that an acceptable probability of dose-limiting complications is between 1 in 6 (17%) and 1 in 3 (33%) of patients. In Stage 3, another 18 participants will receive an intracranial injection with the maximum tolerable dose of dental pulp stem cell.
  
  
  
  The primary outcomes to be measured are safety and feasibility of intracranial administration of autologous human adult DPSC in patients with chronic stroke and determination of the maximum tolerable dose in human subjects. Secondary outcomes include estimation of the measures of effectiveness required to design a future Phase 2/3 clinical trial.
authors.affiliation: School of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.
authors.forename: Anjali
authors.initials: A
authors.lastname: Nagpal
authors.affiliation: School of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.
authors.forename: Karlea L
authors.initials: KL
authors.lastname: Kremer
authors.affiliation: Neurology Department, The Queen Elizabeth Hospital, Woodville, South Australia School of Medicine, University of Adelaide, Adelaide, South Australia.
authors.forename: Monica A
authors.initials: MA
authors.lastname: Hamilton-Bruce
authors.affiliation: School of Medicine, The University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia.
authors.forename: Xenia
authors.initials: X
authors.lastname: Kaidonis
authors.affiliation: Neurology Department, The Queen Elizabeth Hospital, Woodville, South Australia.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Milton
authors.affiliation: Hunter Medical Research Institute, University of Newcastle, New South Wales, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Levi
authors.affiliation: School of Dental Medicine, University of Pennsylvania, Philadelphia, USA.
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.affiliation: Neurorehabilitation and Recovery research group, Stroke Division, Florey Institute of Neuroscience and Mental Health La Trobe University, Melbourne, Victoria, Australia School of Allied Health, La Trobe University, Melbourne, Australia.
authors.forename: Leeanne
authors.initials: L
authors.lastname: Carey
authors.affiliation: Health Sciences Divisional Office School of Health Sciences, University of South Australia, Adelaide, South Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Hillier
authors.affiliation: School of Allied Health, La Trobe University, Melbourne, Australia.
authors.forename: Miranda
authors.initials: M
authors.lastname: Rose
authors.affiliation: Department of Neurosurgery, Royal Adelaide Hospital, Adelaide, South Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zacest
authors.affiliation: Molecular Imaging and Therapy Research Unit, South Australian Health and Medical Research Institute, Adelaide, South Australia.
authors.forename: Parabjit
authors.initials: P
authors.lastname: Takhar
authors.affiliation: School of Medicine, University of Adelaide, Adelaide, South Australia SAHMRI & Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville, South Australia simon.koblar@adelaide.edu.au.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Koblar
mesh_terms: D064592:Autografts; D002908:Chronic Disease; D003782:Dental Pulp / Q000166:cytology* / Q000637:transplantation; D004185:Disability Evaluation; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000628:therapy*; D008297:Male; D019635:Neurosurgical Procedures; D016037:Single-Blind Method; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods
keywords: Ischemic stroke; adult human dental pulp stem cells; neurobehavioral outcomes; post stroke disability