Clinical trial NCT05635409: A Trial to Determine the Safety and Tolerability of Transplanted Stem Cell Derived Dopamine Neurons to the Brains of Individuals With Parkinson's Disease
Official title: STEM-PD Trial: A Multicentre, Single Arm, First in Human, Dose-escalation Trial, Investigating the Safety and Tolerability of Intraputamenal Transplantation of Human Embryonic Stem Cell Derived Dopaminergic Cells for Parkinson's Disease (STEM-PD Product)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Parkinson Disease
Lead sponsor: Region Skane
Sponsor class: OTHER
Collaborators: name: Lund University
name: Cambridge University Hospitals NHS Foundation Trust
name: University of Cambridge
First posted: 2022-12-02
Enrollment: 8
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is a multicentre, single arm, dose escalation, first in human advanced therapy investigational medicinal product (ATIMP) trial.
Primary purpose: TREATMENT

Brief summary: Parkinson's disease (PD) occurs when an area of the brain begins to lose nerve cells that produce a chemical called dopamine. Dopamine is an important chemical, and one of its functions is that it helps to regulate body movement. The loss of these nerve cells leads to a reduction of dopamine in the brain. Medications used to treat PD temporarily replace this lost dopamine, but they do not repair the underlying disease. One of the most promising PD therapies to date has been the transplantation of dopamine producing cells into the brain. Unlike current treatments, these therapies may be able to repair the damage caused in PD.

In this trial, the investigators will transplant a new stem cell therapy, called the STEM-PD product, into the area of the brain affected in people with PD. These stem cells can develop into many different cell types, including dopamine-producing nerve cells. The investigators will transplant the stem cells using a device that has been previously used for similar transplants in Lund. This is the first time that the STEM-PD product will be given to humans.

The trial aims to assess whether the STEM-PD product is safe to use in people with PD. The investigators will also be looking for preliminary signs of efficacy.

The trial will recruit participants with PD from the UK and Sweden. Eight participants will undergo the STEM-PD product transplant. Participants will receive a single dose of the STEM-PD product. Participants will attend for 25 visits primarily at their local recruiting hospital. For participants from the UK, some of the imaging will be performed at Invicro (London), and the surgery (including some visits before and after) and some imaging will be performed in Lund. All participants will be followed up for 36 months following surgery


Eligibility criteria: Inclusion Criteria:

* Have given written informed consent to participate in the trial
* Diagnosed with PD as defined using Queens Square Brain Bank criteria
* Moderate disease as defined by having Hoehn and Yahr stage 2-3 in OFF state
* Disease duration \> 10 years
* Male or female, aged between 50 and 75 years (inclusive)
* Have a significant response to dopamine therapies as judged by the PI or other delegated clinician
* Have symptoms that are not appropriately controlled by existing oral anti-PD medications, as judged by the PI or other delegated clinician
* Ability to travel to Lund for surgery
* Followed up for at least 12 months prior to inclusion in this trial in the TransEUro observational study
* Be fluent in English/Swedish to enable completion of questionnaires as assessed by the PI or other delegated clinician at Cambridge/Lund, respectively
* Be approved by the TMG clinical sub-group for trial participation

Exclusion Criteria:

* Tremor dominant disease, as assessed by the PI or other delegated clinician
* Significant drug induced dyskinesias as defined by a score of \> 2 in the Abnormal Involuntary Movement Scale (AIMS) dyskinesias rating scale, in any body part in the ON state
* Ongoing major medical or psychiatric disorders, including depression (MADRS \> 20) and psychosis, that make participation unsuitable, as judged by the PI or other delegated clinician
* Any contraindication to neurosurgery
* Unable to be imaged using MRI
* Extensive ventral striatal loss or normal findings on F-DOPA PET at screening
* Significant cognitive impairment indicative of an incipient dementia/established dementia or values consistent with MoCA score of ≤ 24
* Unable to perform normal copying of interlocking pentagons and/or a semantic fluency score for naming animals of less than 20 over 90 seconds
* Other concomitant treatment with neuroleptics (including atypical neuroleptics) and/or cholinesterase inhibitors
* Previous neurosurgery to the brain, or cell or organ transplantation, or recipient of repeated blood transfusions
* Any contraindication to immunosuppressive therapy, prophylactic antibiotics, and/or osteoporosis prophylaxis (refer to STEM-PD Trial Immunosuppressant Manual)
* High levels of pre-formed specific anti-HLA antibodies to the cell product
* Severely reduced TPMT activity (less than half of the lower normal TPMT activity level)
* History of documented severe/significant allergy requiring treatment
* Female who is pregnant or breastfeeding
* Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks of the screening visit, or is currently enrolled in an interventional investigational trial
* Female of childbearing potential or male unwilling to follow contraception requirements (see protocol section 12.15)
* Any other condition which, in the opinion of the investigator, makes the patient inappropriate for entry into the trial

Primary outcomes:
measure: The number and nature of adverse events and serious adverse events in the first 12 months following transplantation
timeFrame: 12 months following transplantation
measure: Absence of space occupying masses on cranial MRI in the first 12 months following transplantation
timeFrame: 12 months following transplantation
Secondary outcomes:
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; emergence of new neurological features,
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using the Montreal Cognitive Assessment (MoCA)
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using the Hopkins verbal learning task-revised (HVLT-R)
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using semantic (animal naming) fluency
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using the stroop test
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using the Digit Span test.
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using the Boston naming task.
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using the Wechsler Adult Intelligence Scale (WAIS) similarities test
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; global cognitive changes assessed using the pentagon copying test
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; changes in non-motor and QOL assessments using the Parkinson's Disease Questionnaire 39 (PDQ-39)
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; changes in non-motor and QOL assessments using the EuroQol five-dimension, 5 level scale (EQ-5D-5L)
timeFrame: 36 months following transplantation
measure: Changes in clinical effects at 36 months following transplantation compared to baseline; changes in non-motor and QOL assessments using the PD non motor symptom scale (NMSS).
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS)
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using the nine-hole peg test
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using the timed sit-stand-walk test
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using the Hauser patient diary card
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using Parkinson KinetiGraph® (PKG®)
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using the RUSH dyskinesia scale
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using the Abnormal Involuntary Movement Scale (AIMS)
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using the 30 second tap test
timeFrame: 36 months following transplantation
measure: Changes in motor features in the OFF state using a challenge test of levodopa
timeFrame: 36 months following transplantation
measure: Change in anti-Parkinson medication as measured by change L-dopa equivalent dose
timeFrame: 36 months following transplantation
measure: Changes in F-DOPA uptake and dopamine transporter (DAT) binding at 36 months on PET imaging with F-DOPA and PE2i compared to PET imaging performed pre-transplant
timeFrame: 36 months following transplantation
measure: The number and nature of SAEs and AEs in the 12 to 36 months period following transplantation
timeFrame: 12 to 36 months period following transplantation
Other outcomes:
measure: Exploratory outcome: changes in F-DOPA uptake and dopamine transporter (DAT) binding at 6 months post transplantation on PET imaging with F-DOPA and PE2i compared to PET imaging performed pre-transplant.
timeFrame: 6 months post transplant
measure: Exploratory outcome: changes in F-DOPA uptake and dopamine transporter (DAT) binding at 12 months post transplantation on PET imaging with F-DOPA and PE2i compared to PET imaging performed pre-transplant.
timeFrame: 12 months post transplant
measure: Exploratory outcome: changes in F-DOPA uptake and dopamine transporter (DAT) binding at 24 months post transplantation on PET imaging with F-DOPA and PE2i compared to PET imaging performed pre-transplant.
timeFrame: 24 months post transplant
measure: Exploratory outcome: change in Fluctuation Dyskinesia Score (FDS) compared to baseline as determined by measurement using wearable movement monitoring devices (Parkinson KinetiGraph™ [PKG])
timeFrame: 36 months post transplant
measure: Exploratory outcome: change in Dyskinesia score (DKS) compared to baseline as determined by measurement using wearable movement monitoring devices
timeFrame: 36 months post transplant
measure: Exploratory outcome: change in Bradykinesia score (BKS) features compared to baseline as determined by measurement using wearable movement monitoring devices
timeFrame: 36 months post transplant
measure: Levels of donor cell specific anti-human leukocyte antigen (HLA) class I antibodies post-transplant
timeFrame: 36 months post transplant
measure: Exploratory outcome: changes in markers of inflammation in the cerebrospinal fluid (CSF)
timeFrame: 18 months post transplant
measure: Exploratory outcome: change in response to a L-dopa challenge test including measuring the duration and profile of the L-dopa effects between baseline and 36 months: change in MDS-UPDRS Part III score
timeFrame: 36 months post transplant
measure: Exploratory outcome: change in response to a L-dopa challenge test including measuring the duration and profile of the L-dopa effects between baseline and 36 months; change in AIMS score
timeFrame: 36 months post transplant
Locations:
city: Lund
country: Sweden
facility: Region Skåne - Skåne University Hospital
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
Study officials:
affiliation: Cambridge University Hospitals NHS Foundation Trust & University of Cambridge
name: Roger Barker
role: PRINCIPAL_INVESTIGATOR
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