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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 2
- 主要终点
- Number of Participants with Incidence of Treatment-Emergent Adverse Events
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Placebo
2:1 in favour of UDCA
干预措施: Ursonorm (Drug)
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.
干预措施: Ursonorm (Drug)
结局指标
主要结局
Number of Participants with Incidence of Treatment-Emergent Adverse Events
时间窗: 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.
Number of Participants with Incidence of Serious Adverse Events
时间窗: 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.
Number of Participants that complete the study
时间窗: 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.
次要结局
- 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))