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

NCT03840005 | Completed Phase 2 DMC

• 2 other identifiers: STH184932018-001887-46
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 2

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.

Conditions

Parkinson's Disease

Outcome Measures

Primary Outcomes (3)

• Number of Participants with Incidence of Treatment-Emergent Adverse Events

  Safety of a 56-week UDCA Intervention will be assessed by measuring the number of participants with adverse events that are related to treatment.

  Timepoint: start of treatment to 56 weeks (visit 6)

• Number of Participants with Incidence of Serious Adverse Events

  Safety of a 56-week UDCA Intervention will be assessed by measuring the number of participants with serious adverse events.

  Timepoint: start of treatment to 56 weeks (visit 6)

• Number of Participants that complete the study

  Safety of a 56-week UDCA Intervention will be assessed by measuring the number of participants that complete the study.

  Timepoint: start of treatment to 56 weeks (visit 6)

Secondary Outcomes (5)

• 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.

  Timepoint: 48 weeks (visit 5)

• 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.

  Timepoint: 48 weeks (visit 5)

• 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.

  Timepoint: 48 weeks (visit 5)

• 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.

  Timepoint: 48 weeks (visit 5)

• Mean change from baseline to week 48 in objective quantification of participant motor impairment, using motion sensors.

  Timepoint: 48 weeks (visit 5)

Study Arms (2)

Placebo

PLACEBO COMPARATOR

2:1 in favour of UDCA

Drug: Ursonorm

Ursonorm (Ursodeoxycholic acid)

EXPERIMENTAL

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

Interventions

Ursonorm DRUG

Ursodeoxycholic acid

Also known as: UDCA

Placebo; Ursonorm (Ursodeoxycholic acid)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sheffield Teaching Hospitals NHS Foundation Trust: lead
• JP Moulton Charitable Foundation: collaborator
• PRO.MED.CS Praha a.s.: collaborator
• Clinical Trials Research Unit, University of Sheffield: collaborator

Study Sites (2)

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, South Yorkshire, S10 JJF, United Kingdom

Location

University College London Institute of Neurology

London, WC1 3BG, United Kingdom

Location

Related Publications (37)

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MeSH Terms

Conditions

Parkinson Disease

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• Oliver Bandmann

  Sheffield Teaching Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: February 11, 2019
• First Posted: February 15, 2019
• Study Start: December 18, 2018
• Primary Completion: May 13, 2021
• Study Completion: May 13, 2021
• Last Updated: November 8, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: 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

Locations

GB (2)