Trial of Ursodeoxycholic Acid (UDCA) for Parkinson's Disease: The "UP" Study
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Ursonorm
Intervention type(s): Drug
Intervention description(s): Ursodeoxycholic acid
Other intervention name(s): UDCA
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A randomised double-blind, placebo controlled 48 week trial of UDCA at a daily dose of 30 mg/kg in patients with early Parkinson's disease <3 years post diagnosis.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Other