A Trial to Determine the Safety and Tolerability of Transplanted Stem Cell Derived Dopamine Neurons to the Brains of Individuals With Parkinson's Disease

A physical examination, to include a review of all body systems as per standard practice will be performed to identify any clinical changes. Specifically, any signs of graft-induced dyskinesias (GIDs) will be looked for.

The Montreal Cognitive Assessment (MoCA) is a 30-question test of global cognitive function, which evaluates different types of cognitive abilities, including: orientation, short-term memory, executive function, visuospatial ability, language ability, abstraction, animal naming, and attention. The maximum score is 30 and a score of >26 is considered normal. A higher score is considered a better outcome.

The HVLT-R consists of a 12-item word list, composed of four words each from one of three semantic categories to be learned over the course of three immediate recall learning trials. Participants are also required to undergo a delayed recall trial (requiring free recall of any of the words remembered) and a recognition trial (composed of 24 words, including the 12 target words plus 12 false-positives. A point is given for each correct word and a higher score is considered a better outcome.

Participants are asked to name as many animals as possible in 90 seconds. One point is scored for admissible response. A higher score considered a better outcome.

The Stroop test is a measure of verbal processing speed and response inhibition, consisting of three timed trials.

Participant is read a list of numbers and asked to repeat the numbers back to the assessor. The lists of numbers gradually gets longer until the participant is unable to remember all of the digits. A backwards span assessment is also completed where the participant is asked to repeat the numbers back in a reverse order.

One point is scores for each verbatim correct repetition. The total Digit Span total score is a sum of all the forwards and backward scores. A higher score is a better outcome.

In the Boston naming task participants are shown a number of images and are asked to say what the image is. This protocol uses a shortened 15-item version (Lansing et al., 1999) designed for use in patients with neurodegenerative disease. One point for every correct response.

The WAIS similarities assessment includes 14 pairs of words, where participants are asked to name how they are alike or similar. Tests are scored out of 28 and a higher score is considered a better outcome.

In the pentagon copying assessment, participants are asked to copy an intersecting double pentagon figure. Attempts are scored out of a maximum of two points and a higher score is considered a better outcome.

The PDQ-39 is a self-rated questionnaire designed to measure PD-related quality of life. It contains 39 questions, covering 8 aspects of quality of life: mobility, activities of daily living (ADL), emotions, stigma, social support, cognition, communication and bodily discomfort. It will be completed by the participant. The total score can be summarised as a percentage, with the score ranging between 0 and 100. A lower scores indicate better health related quality of life.

The EuroQol five-dimension, 5 level scale (EQ-5D-5L) is a standardised instrument for measuring generic health status in terms of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. It will be completed by the participant.

The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions, where higher scores indicate more severe or frequent problems. In addition, there is a visual analogue scale (VAS) to indicate the general health status with 100 indicating the best health status

The PD NMSS is a 30-point validated scale which is designed to quantify the extent and severity of non-motor symptoms of PD experienced by the patient. It will be completed by the delegated members of the local research team. Higher scores indicate higher severity and frequency of non-motor symptoms.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

This is a scale which has sections to be completed by the person with PD together with their carers (if appropriate), as well as sections to be completed by the clinician. Part I assesses the non-motor aspects of experiences of daily living in the week prior to the visit. Part II assesses the motor aspects of experiences of daily living in the week prior to the visit. Part III assesses the motor examination of a participant at the time of the visit (including the Hoehn and Yahr stage), and part IV assesses motor complications in the week prior to the visit. Each item will receive a score ranging from 0 to 4, where 0 represents the absence of impairment and 4 represents the highest degree of impairment.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

The nine-hole peg test is used to measure finger dexterity in participants with neurological diagnoses. It is administered by asking the participant to take the pegs from a container, one by one, and placing them into the holes on the board as quickly as possible. Participants must then remove the pegs, one by one, and replace them into the container. Scores are based on the time taken to complete the test activity.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

The timed sit-stand-walk test is used as a measure of lower extremity strength and speed of walking. Participants begin the test sitting in a chair and told to come to a full stand, then walk 6 metres to a defined point, return to the chair and sit down. The time taken to complete this is measured.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

The Hauser patient diary card is a 24-hour diary, divided into 30-minute sections. This is used to record PD symptoms and how much time is spent in the different motor states (ON without dyskinesia, ON with non-troublesome dyskinesias, ON with troublesome dyskinesias, OFF, or asleep). Participants will be provided with the diary cards prior to attending the visits and asked to complete this for 3 consecutive days. The completed diary cards will then be collected at the relevant visits.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

The PKG® is a wrist worn accelerometer from Global Kinetics Pty Ltd. The PKG® watch is worn on the most affected side of the body. Registration will be done for 7 consecutive days just before a visit. For the purposes of this trial, the following data will be collected: bradykinesia and dyskinesia index, OFF time (to correlate with the Hauser patient diary card), and registration of intake of anti-PD medications. Participants will be provided with the PKG® prior to attending the visits to complete data collection and will be asked to return the PKG® at the relevant visit.

Once the electronic data is transferred from the device to a computer platform, it is processed to generate data.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

The RUSH dyskinesia scale is a scale to assess the severity of overall dyskinesias based on interference in activities in daily living, to distinguish chorea from dystonia (the two major types of dyskinesias in PD), and to identify the single most disabling form of dyskinesia. A higher score is considered a worse outcome.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

The AIMS is used to quantify dyskinesias in the arms, legs or head, and trunk, which includes items such as facial behaviours (jaw, facial muscles, tongue and lips), full-body behaviours (upper, lower, and trunk), and incapacitation due to these movements. The items are scored from 0 to 4, where 0 is normal/healthy and 4 is severely affected.

Specified motor tasks will be performed in both ON and OFF states. For the OFF state, participants will be asked to stop medication at least 12 hours prior to the visit (for L-dopa/COMT inhibitors) or at least 24 hours (for long-acting dopamine agonists/MAO-B inhibitors).

The 30 second tap test is a dexterity assessment where the participant is asked to finger tap for 30 seconds. It is tested on both sides, as quickly as possible with the fingers fully open. The number of taps over 30 seconds is registered and the test is performed twice on each hand.

A challenge dose of L-dopa is given, calculated as the participant's average dose (total 24 hours LED/number of dosages per 24 hour period - up to a maximum of 250 mg of L-dopa).

The challenge dose is given after being off standard L-dopa/COMT inhibitors medications for at least 12 hours or at least 24 hours for long-acting dopamine agonists or L-Dopa preparations and for MAO-B inhibitors, i.e. "practically defined OFF phase". Participants are tested after a low protein breakfast, examples of which will be provided to the participants. After taking the challenge dose, participants will wait for 30 minutes and then perform the MDS-UPDRS part III and the AIMS. These two assessments will then be repeated every 30 minutes up to 120 minutes after taking the challenge dose (or longer if needed, until the L-dopa effect has worn off).

At every visit during the trial, a review of concomitant medication (including anti-PD medication) will be performed and any changes recorded. Anti-PD medication will be recorded as a LED, and the change in LED will be monitored throughout the trial.

The screening F-DOPA PET scans will act as the 'baseline' measurement for changes in F-DOPA uptake. The baseline PE2i will act as the 'baseline' measurement for DAT binding. Changes from this baseline measurement up to and including the 36 months post-transplant time point will be recorded.

Adverse events are recorded from the point of participant informed consent and at every trial visit. The difference between this and the primary outcome is that this specifically relates to any safety events reported after the 12 months posttransplant time point.