Trial of Ursodeoxycholic Acid (UDCA) for Parkinson's Disease: The "UP" Study
Trial of Ursodeoxycholic Acid (UDCA) for Parkinson's Disease: The "UP" Study
The aim of this study is to explore the potential of Ursodeoxycholic acid (UDCA) to slow down
 the progression of Parkinson's Disease (PD) in a randomised, double-blind,
 placebo-controlled, "proof of concept" study. The primary objective of the study will be to
 determine the safety and tolerability of this drug in patients with PD. Participants will be
 recruited form a cohort of patients who have been diagnosed with PD within the last 3 years
 and are potentially suitable for this study.

 There is strong evidence from previous research and the work carried out by other groups that
 UDCA rescues the function of the mitochondria (mitochondria are the "powerhouse" of the cell)
 in PD patient tissue and other models of PD. This suggests that UDCA may slow down the
 worsening of PD.

 UDCA has been in clinical use for the treatment of liver disease (primary biliary
 cholangitis) for over 30 years. The investigators therefore know that it is safe and well
 tolerated in patients with liver disease but the investigators don't know yet whether this is
 also the case in patients with PD. Furthermore, the dose used for patients with liver disease
 (15 mg/kg) is not high enough for UDCA to get into the brain. The investigators therefore
 need to double the dose to 30 mg/kg. This higher dose was also safe in clinical trials for
 liver disease, but is currently not used routinely in clinical practice.
The primary aim of this study is to generate clinical data to examine the safety,
 tolerability & potential effectiveness of 48 weeks exposure to UDCA compared to placebo.
 Furthermore, it will determine the usefulness of novel objective readouts (namely the
 objective sensor based quantification of motor progression & 31P-MRS/imaging-based in vivo
 quantification of ATP) which may allow a reduction of the sample size (& thus cost) of future
 trials.

 This is double-blind, randomised, placebo-controlled multi-centre parallel group trial in
 patients with PD who have been diagnosed ≤ 3 years ago. 30 patients will be randomised to
 UDCA at a dose of 30 mg/kg or matched placebo using a 2:1 split (20 patients on UDCA, 10 on
 placebo). This will include 48 week exposure period & a subsequent 8 week washout period.
 Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 36, 48 &
 56 weeks. The trial medication will be taken at 3 equal doses per day, to be taken orally
 with food. The dose will be increased gradually by 250 mg (1 capsule) every 3 days until
 patient reaches a dose of 30 mg/kg.

 Visit Schedule

 Telephone Contact 1 (Telephone Screening)

 Subsequent to the site staff having received a reply slip from the patient indicating their
 interest to participate in the study, a suitable time & date will be arranged with the
 respective patient to undergo telephone screening by a member of the research team to check
 potential eligibility, including a brief review of relevant medical history. The Chief
 Investigator (CI)/ Principal Investigator (PI) will check the screening record made after the
 telephone screening call. Any patients not deemed eligible to be invited for their screening
 visit will be contacted by a member of the research team to inform them of this outcome.
 Patients deemed eligible will be invited to a screening visit. The date of diagnosis &
 confirmation of the PD diagnosis & any other uncertainties relating to the
 inclusion/exclusion criteria will be confirmed subsequent to this telephone screening
 assessment for those patients who seem eligible but are outside the Sheffield Teaching
 Hospitals (STH)/ University College London Hospitals (UCLH) geographical area by requesting
 copies of relevant clinic letters or contacting their PD Clinical Consultants directly. The
 telephone screening call will be repeated if the patient cannot attend visit 0 (screening
 visit) within 1-8 weeks to ensure that s/he would still fulfil the telephone screening
 eligibility criteria.

 The telephone screening call will not be undertaken for study patients who are already
 patients of either site.

 Visit 0: Screening (Time -1 - 8 weeks prior to baseline visit)

 At this visit the research team will answer any further questions, check the patient's
 eligibility for the study as far as possible and, if the patient wishes to participate in the
 study, obtain written consent. A clinical diagnosis of PD is based on the opinion of the
 Principal Investigator (PI) after review of the patient's clinical history, examination
 findings & response to PD medication.

 The written informed consent process will be undertaken by the PI or by an appropriately
 trained member of the research team as delegated by the PI/ CI. This study will not include
 vulnerable patients or patients who lack capacity.

 Screening procedures

 The PI (or authorised delegate) will complete the following screening assessments/procedures
 with the patient:

 -  Obtaining consent

 -  Inclusion/Exclusion Review

 -  Demographic information & medical history

 -  Demographic data regarding PD

 -  Past medical history

 -  Medication History

 -  Family history

 -  Previous imaging

 -  Previous genetic tests

 -  Confirmation of eligibility

 -  Confirmation of date for diagnosis of Parkinson's disease by PIs or other experts in
 movement disorders (this may include review of medical records)

 -  Concomitant medication

 -  Physical examination (including assessment of modified Hoehn & Yahr stage), including
 weight, height &vital signs

 -  Montreal Cognitive Assessment (MoCA)

 -  Montgomery-Asberg Depression rating scale (MADRS)

 -  Confirmation of post-menopausal state

 -  Safety bloods (full blood count, urea & electrolytes, liver function tests, blood
 glucose, HbA1C, lipid profile)

 -  Serum sample (approach. 20 ml stored at -80 degrees Celsius)

 -  ECG

 -  Provision of physical activity monitor & activity diary

 Assuming that the patient fulfils the immediate eligibility criteria, arrangements will be
 made for the patient to attend a baseline appointment approximately 2 to 4 weeks after the
 screening visit. This interval enables review of the patient's blood results to confirm final
 eligibility. If more than 8 weeks have elapsed since the screening visit, the screening visit
 & screening assessments should be repeated before proceeding to the baseline visit.

 Patients who consent to the study but who are subsequently found not to meet the study
 eligibility criteria will be contacted by the research nurse or other member of the research
 team to inform them that they are not eligible to join the study. If any concerns about the
 patient's health or well-being are identified from out-of-range blood results or abnormal
 assessment scores, a member of the research team will inform the patient's General
 Practitioner (GP).

 Following written consent, randomisation will take place at the baseline visit. All patients
 will be assigned a unique patient ID number at screening that will link all of the clinical
 information collected for them on the study database, these will be in the format Sxx/nnnn;
 where xx is a unique number assigned to the site by the Trial Manager & nnnn is a unique
 number starting at 0001 &incrementing by 1. Once the patient ID number has been entered, the
 system will supply a randomisation number which will identify the treatment pack to be
 dispensed. The randomisation will be 2:1 in favour of UDCA. The randomization system will
 stratify by site.

 Site Study Teams

 The local PI, supported by an appropriate member of the research team will monitor patient
 well-being, record adverse events, titrate &prescribe study medication. Since the 'treating'
 nurse or doctor will review all blood results & be aware of any reported side effects, a
 separate member of the research team will act as a blinded assessor, undertaking the
 MDS-UPDRS & other outcome measures after appropriate training. Ideally the blinded assessor
 will undertake the MDS-UPDRS Part 3 with the patient in the "OFF" state, followed by the
 complete MDS-UPDRS, Non-Motor Symptom assessment Scale (NMS-Quest) & MADRS once the patient
 is in the "ON" state. The practically defined "OFF" medication state refers to the patient
 assessment conducted in the absence of their regular medication with the aim of exposing the
 severity of the underlying PD. Efforts should be made to ensure that the same outcome
 assessor is present at all visits but sites should identify back-up personnel to cover staff
 absences & avoid cross-over of 'assessing' &'treating' team members.

 Baseline (Visit 1)

 Eligible patients will attend a further clinic visit where baseline assessments will be
 performed. Results of blood tests & ECG will be reviewed prior to baseline evaluation to
 ensure patient eligibility. They will be asked to attend in the "practically defined OFF"
 state. The following assessment will be undertaken in the "practically defined OFF" state:

 -  Confirmation of eligibility/inclusion/exclusion review

 -  Medication review

 -  Physical examination

 -  Recording of any Adverse Events (AEs)

 -  MDS-UPDRS part 3 (motor examination)

 -  Optogait &Opals sensor-based objective quantification of motor impairment (Sheffield
 Patients only)

 They will be invited to take their PD medication following the assessment. The PI or
 authorised delegate will record any reported serious adverse events & changes to concomitant
 medications, including PD medication. In addition, the predicted progression will be
 calculated, following the model developed by Williams-Gray & co-workers. The Prognostic Model
 developed by Williams-Gray &co-workers identified the following three parameters as
 associated with more rapid PD progression: 1. Higher age, 2. Higher UPDRS motor examination
 axial score (items 27-30), 3. Lower animal naming fluency (patients will be asked to name as
 many animals as possible in a 1-minute time frame). The assessor will then complete the
 following procedures with the patient in the "practically defined ON" stage (typically 30-60
 min after patient has taken PD symptomatic medication):

 -  MDS-UPDRS

 -  NMS-Quest

 -  PDQ-39

 -  31P- MRS

 -  Blood sample for genetic analysis

 -  Safety bloods

 -  Serum sample

 -  Provision of patient diary

 -  Return of physical activity monitor &activity diary

 Patients will be randomised at this visit to receive either active of placebo medication (2:1
 ratio). The PI or appropriately delegated medically qualified member of the study team will
 complete &sign a study-specific prescription form for presentation to pharmacy by the
 patient. The prescription form will details the baseline medication allocation print-out from
 the randomisation computer system.

 All patients will be provided with a study-specific diary by their local research team at the
 baseline visit, in which to record any alterations in the dose of trial medication or
 concomitant medications taken. Patients should be advised to contact the study team promptly
 should they develop loose stools rather than waiting for the next study visit or scheduled
 telephone call.

 Visit 2: 12 week follow-up clinic

 Patients will attend a clinic visit twelve weeks after the baseline visit, having taken all
 medications as usual. The PI or authorised delegate will complete the following procedures
 with the patient in conjunction with study diary review:

 -  Record any AEs & changes to concomitant medications

 -  Assess compliance with study treatment & collect any unused medication

 -  Return of unused medication

 -  Safety bloods

 -  Serum sample

 -  Diary Review

 Provided that there are no immediate clinical contra-indications, the patient will be
 provided with a further 3 months prescription for the trial medication.

 Visit 3: 24 week follow-up clinic

 Patients will attend a clinic visit six months after the baseline visit, having taken all
 medications as usual. The PI or authorised delegate will complete the following procedures
 with the patient in conjunction with study diary review:

 -  Record any AEs & changes to concomitant medications

 -  ECG

 -  Safety bloods

 -  Serum sample

 -  Assess compliance with study treatment & collect any unused medication

 -  Return of unused medication

 -  MDS-UPDRS/part 3 motor assessment in the practically defined "ON" stage

 -  Diary Review

 Provided that there are no immediate clinical contra-indications, the patient will be
 provided with a further 3 months prescription for the trial medication.

 Visit 4: 36 week follow-up clinic

 Patients will attend a clinic visit thirty six weeks after the baseline visit, having taken
 all medications as usual. The PI or authorised delegate will complete the following
 procedures with the patient in conjunction with study diary review:

 -  Record any AEs & changes to concomitant medications

 -  Assess compliance with study treatment & collect any unused medication

 -  Return of unused medication

 -  Safety bloods

 -  Serum sample

 -  Diary Review

 Provided that there are no immediate clinical contra-indications, the patient will be
 provided with a further 3 months prescription for the trial medication.

 Visit 5: 48 week follow-up clinic

 Patients will attend a clinic visit 48 weeks after the baseline visit. For this visit,
 patients will be asked to attend on the day of assessment in the 'practically-defined OFF'
 state.

 The assessor will complete the following procedures with the patients in conjunction with
 study diary review:

 -  Record any AEs & changes to concomitant medications

 -  Assess compliance with study treatment & collect any unused medication

 -  MDS-UPDRS part 3 in the "practically defined OFF" state

 -  Opticals/Sensor based gait assessment (Sheffield patients only)

 -  Height & Weight

 Patients will then be invited to take their routine PD medication. The assessor will then
 complete the following procedures with the patient in the "practically-defined ON" state
 (typically 30 - 60 min later):

 -  MDS-UPDRS

 -  NMS-Quest

 -  MoCA

 -  MADRS

 -  PDQ-39

 -  Safety bloods

 -  Serum sample stored

 -  31P- MRS

 -  Diary review

 -  Return of the physical activity monitor &activity diary

 Visit 6: 56 week follow-up clinic

 Patients will attend a clinic visit 56 weeks after the baseline visit. For this visit,
 patients will be asked to attend on the day of assessment in the 'practically-defined OFF'
 state. The PI or authorised delegate will complete the following procedures with the patient:

 -  Record any AEs & changes to concomitant medications

 -  Safety bloods

 -  Serum sample

 -  MDS-UPDRS part 3 motor subscale in the "practically defined OFF medication state"

 Patients will then be invited to take their routine PD medication. The assessor will then
 complete the following procedures with the patient in the "practically-defined ON" state"
 (typically 30 - 60 min later):

 -  MDS-UPDRS

 -  NMS-Quest

 -  MoCA

 -  MADRS

 -  PDQ-39

 -  Diary review

 -  Diary collection

 For all visits, each procedure is undertaken as part of the study & not part of the patient's
 standard care.

 Telephone contacts There will be 12 telephone contacts throughout the study, weekly after the
 baseline visit during the dose escalation period &week 8, week 18, week 30, week 42 & week
 52. Patients will also be contacted via the telephone 2 days prior to their baseline visit,
 visit 5 & visit 6 to remind patients to attend their next visit in the "practically defined
 OFF medication state" for their next visit.

 Sensors At the screening visit, eligible patients will be given the DynaPort Movemonitor to
 wear for 7 days. A text message will be sent to the patients every morning to remind them to
 wear the device. A 2nd DynaPort Movemonitor will be posted to patients 2 weeks prior to their
 48 week visit with instructions to wear the sensor for 7 days prior to their next visit.
 Patients will then be asked to return this at their 48 week visit.
Inclusion Criteria:

 • Diagnosis of Parkinson's disease: PD is a clinical diagnosis as defined by the Queen
 Square Brain Bank criteria (bradykinesia defined as slowness of initiation of voluntary
 movement with progressive reduction in speed and amplitude on repetitive actions and at
 least one of the following: Rigidity, 4-6 Hz rest tremor). The diagnosis will have been
 made by the treating clinician and confirmed by the PI on site after review of the clinical
 history, examination findings and response to PD medication.

 The Queen Square brain bank criteria MAY be used to help assist in the diagnosis although
 this need not be a formal inclusion criteria, and the relevance of a positive family
 history of PD, or a confirmed genetic basis for an individual's symptoms will be evaluated
 in the context of other clinical features in determining diagnosis and eligibility.

 -  Diagnosis of Parkinson's disease ≤ 3 years ago by a clinician with particular
 expertise in the diagnosis and treatment of movement disorders (typically one of the
 PIs or their consultant colleagues). The date of diagnosis will be verified by a
 review of the medical records.

 -  Subjective improvement of motor impairment on dopaminergic medication, confirmed by PI
 through personal examination and/or review of medical records

 -  Hoehn and Yahr stage ≤ 2.5 in the practically defined "ON" medication state. This
 implies that all patients will be mobile without assistance during their best "ON"
 medication periods.

 -  Ability to take study drug

 -  Ability to communicate in English

 -  Age 18 - 75 yr of any gender

 -  Documented informed consent to participate

 -  Able to comply with study protocol and willing to attend necessary study visits

 Exclusion Criteria:

 -  Diagnosis or suspicion of other cause of parkinsonism such as Multiple system atrophy
 (MSA) or progressive supranuclear palsy (PSP), drug induced parkinsonism, dystonic
 tremor or essential tremor will not be recruited.

 -  Known abnormality on CT or MRI brain imaging considered likely to compromise
 compliance with trial/protocol/31P-MRS acquisition.

 -  Known claustrophobia or other reasons why patient could not tolerate or be suitable
 for 31P-MR Spectroscopy (31P-MRS)

 -  Current or previous exposure to UDCA

 -  Current or previous diagnosis of liver disease judged to be significant by the
 clinical investigator, in particular Primary Biliary Cholangitis (previously referred
 to as Primary Biliary Cirrhosis, PBC)

 -  Prior intracerebral surgical intervention for PD (including deep-brain stimulation).
 Patients who have previously undergone deep brain stimulation, intracerebral
 administration of growth factors, gene therapies or cell therapies will not be
 eligible.

 -  Already actively participating in a trial of a device, drug or surgical treatment for
 PD

 -  History of alcoholism

 -  Women of child - bearing potential (WOCBP)

 -  Participants who lack the capacity to give informed consent

 -  Any medical or psychiatric condition which in the investigator's opinion compromises
 the potential participant's ability to participate

 -  Concurrent dementia defined by Montreal Cognitive assessment (MoCA) score <25

 -  Concurrent severe depression defined by a score >16 on the Montgomery- Asberg
 Depression Rating Scale (MADRS)

 -  Serum transaminases (such as aspartate transaminase (AST) more than 2 times upper
 limit of normal.

 -  Patients on ciclosporin, nitrendipine or dapsone for the treatment of concomitant,
 general medical conditions.

 -  Participants with previous or current diagnosis of inflammatory bowel disease (i.e.
 ulcerative colitis or Crohn's disease)