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Trial of Ursodeoxycholic Acid (UDCA) for Parkinson's Disease: The "UP" Study

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ClinicalTrials.gov Identifier: NCT03840005
Recruitment Status : Recruiting
First Posted : February 15, 2019
Last Update Posted : February 27, 2019
Sponsor:
Collaborators:
JP Moulton Charitable Foundation
PRO.MED.CS Praha a.s.
Clinical Trials Research Unit, University of Sheffield
Information provided by (Responsible Party):
Sheffield Teaching Hospitals NHS Foundation Trust

Brief 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.


Condition or disease Intervention/treatment Phase
Parkinson's Disease Drug: Ursonorm Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
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)
Masking Description:

This is a double-blind trial. The investigators, clinical study team, participants and analysing statistician will be blind to treatment allocation. The active treatment will be over-encapsulated and a matched placebo manufactured to maintain the blind.

The Independent Data Monitoring Committee (IDMC) is the only oversight body that has access to unblinded accumulating comparative data.

Primary Purpose: Other
Official Title: A Phase II, Placebo Controlled, Double Blind, Randomised Clinical Trial To Assess The Safety And Tolerability Of 30mg/kg Daily Ursodeoxycholic Acid (UDCA) In Patients With Parkinson's Disease (PD)
Actual Study Start Date : December 18, 2018
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Ursodiol

Arm Intervention/treatment
Placebo Comparator: Placebo
2:1 in favour of UDCA
Drug: Ursonorm
Ursodeoxycholic acid
Other Name: UDCA

Experimental: Ursonorm (Ursodeoxycholic acid)
UDCA 30 mg/kg daily, tablet form taking orally , administered 3 monthly for 12 months, dose titration during the 1st month will occur.
Drug: Ursonorm
Ursodeoxycholic acid
Other Name: UDCA




Primary Outcome Measures :
  1. Number of Participants with Incidence of Treatment-Emergent Adverse Events [ Time Frame: Timepoint: start of treatment to 56 weeks (visit 6) ]
    Safety of a 56-week UDCA Intervention will be assessed by measuring the number of participants with adverse events that are related to treatment.

  2. Number of Participants with Incidence of Serious Adverse Events [ Time Frame: Timepoint: start of treatment to 56 weeks (visit 6) ]
    Safety of a 56-week UDCA Intervention will be assessed by measuring the number of participants with serious adverse events.

  3. Number of Participants that complete the study [ Time Frame: Timepoint: start of treatment to 56 weeks (visit 6) ]
    Safety of a 56-week UDCA Intervention will be assessed by measuring the number of participants that complete the study.


Secondary Outcome Measures :
  1. Mean change from baseline to week 48 in participant scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 motor subsection in the "OFF" medication state. [ Time Frame: Timepoint: 48 weeks (visit 5) ]

    Motor symptoms will be measured using the MDS-UPDRS part 3 motor subsection. Part III of the scale will be completed at baseline, visit 3 (24 weeks), visit 5 (48 weeks).

    The scale consists of four parts; Part I "Non-motor experiences of daily living" (13 questions), Part II "Motor Experiences of daily living" (13), Part III "Motor Examination" (33) and Part IV "Motor Complications" (6). Each question has five responses that are linked to common clinical terms: 0=Normal, 1=Slight, 2=Mild, 3=Moderate, 4=Severe. Whereas each response is tailored to the question, the progression of impairment is based on consistent infrastructure. "Slight" refers to symptoms with sufficiently low frequency/intensity to cause no impact on function; "Mild" refers to symptoms of frequency/intensity sufficient to cause modest impact on function; "Moderate" refers to symptoms sufficiently frequent/intense to impact considerably, but not prevent, function; "Severe" refers to symptoms that prevent function.


  2. Mean change from baseline to week 48 in in vivo parameter estimates of Adenosine Triphosphate (ATP) levels, derived from participant cranial 31P-Magnetic Resonance Spectroscopy (MRS) centered on the basal ganglia and related motor regions. [ Time Frame: Timepoint: 48 weeks (visit 5) ]
    Patients who consent to having the 31P-MR spectroscopy, data will be analysed for the change in energy metabolic levels at baseline and visit 5 (week 48).

  3. Mean change from baseline to week 48 in in vivo parameter estimates of Phosphocreatinine (PCr) levels, derived from participant cranial 31P-Magnetic Resonance Spectroscopy (MRS) centered on the basal ganglia and related motor regions. [ Time Frame: Timepoint: 48 weeks (visit 5) ]
    Patients who consent to having the 31P-MR spectroscopy, data will be analysed for the change in energy metabolic levels at baseline and visit 5 (week 48).

  4. Mean change from baseline to week 48 in in vivo parameter estimates of Inorganic Phosphate (Pi) levels , derived from participant cranial 31P-Magnetic Resonance Spectroscopy (MRS) centered on the basal ganglia and related motor regions. [ Time Frame: Timepoint: 48 weeks (visit 5) ]
    Patients who consent to having the 31P-MR spectroscopy, data will be analysed for the change in energy metabolic levels at baseline and visit 5 (week 48).

  5. Mean change from baseline to week 48 in objective quantification of participant motor impairment, using motion sensors. [ Time Frame: Timepoint: 48 weeks (visit 5) ]
    For the subset of patients who consent to having the Opticals sensor based gait assessment, the data will be analysed for changes in motor impairment at baseline and visit 5 (week 48).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03840005


Contacts
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Contact: Sarah Moll 0114 2712563 ext 12563 sarah.moll@sth.nhs.uk
Contact: Jodie Keyworth 0114 2265394 ext 65394 jodie.keyworth@sth.nhs.uk

Locations
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United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust Recruiting
Sheffield, South Yorkshire, United Kingdom, S10 JJF
Contact: Sarah Moll, MSc    0114 2712563    sarah.moll@sth.nhs.uk   
Principal Investigator: Oliver Bandmann, MBChBMPhD         
University College London Institute of Neurology Not yet recruiting
London, United Kingdom, WC1 3BG
Contact: Sarah Moll, MSc    01142713796    sarah.moll@sth.nhs.uk   
Principal Investigator: Thomas Foltynie, MBBMRCPPhD         
Sponsors and Collaborators
Sheffield Teaching Hospitals NHS Foundation Trust
JP Moulton Charitable Foundation
PRO.MED.CS Praha a.s.
Clinical Trials Research Unit, University of Sheffield
Investigators
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Principal Investigator: Oliver Bandmann Sheffield Teaching Hospitals NHS Foundation Trust

Publications:

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Responsible Party: Sheffield Teaching Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT03840005     History of Changes
Other Study ID Numbers: STH18493
2018-001887-46 ( EudraCT Number )
ISRCTN73371260 ( Registry Identifier: ISRCTN Registry )
First Posted: February 15, 2019    Key Record Dates
Last Update Posted: February 27, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The results of this trial will be submitted for publication in a peer reviewed journal, in addition to reports at appropriate specialist conferences. The results of the trial will be disseminated regardless of the direction of effect. No participants will be identified during this process.
Supporting Materials: Study Protocol
Time Frame: Requests for the supporting information will be considered on a case by case basis with the CI and sponsor in conjunction with contract agreements with collaborators
Access Criteria: As above

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Ursodeoxycholic Acid
Cholagogues and Choleretics
Gastrointestinal Agents