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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2018-001887-46
    Trial protocol
    		 GB  
    Global end of trial date
    09 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    STH18493
    Additional study identifiers
    ISRCTN number
    		 ISRCTN73371260
    US NCT number
    		 NCT03840005
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sheffield Teaching Hospitals NHS Foundation Trust
    Sponsor organisation address
    Trust Headquarters of 8 Beech Hill Road, Sheffield, United Kingdom, S10 2SB
    Public contact
    Dr Dipak Patel, Sheffield Teaching Hospitals NHS Foundation Trust, sth.ResearchAdministration@nhs.net
    Scientific contact
    Dr Dipak Patel, Sheffield Teaching Hospitals NHS Foundation Trust, sth.ResearchAdministration@nhs.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the safety and tolerability of UDCA at 30 mg/kg in PD compared to placebo as indicated by: • Number of serious adverse events (SAEs) • Number of adverse treatment-reactions • Number of patients completing the study
    Protection of trial subjects
    There are small risks associated with needle injections. For most people, needle injections do not cause serious problems, however some people experience a small amount of swelling, bleeding or pain at the needle site or some people may feel faint. On very rare occasions infection may occur. Only trained individuals were permitted to take blood samples. If the team detected any relevant genetic changes in blood they would discuss them with the patient and offer a referral to colleagues in Clinical Genetics so that the patient/family members may be formally tested if required. Any results from the genetic testing would first be received by the Chief Investigator at Sheffield and for participants recruited at UCLH the results would be passed onto Professor Foltynie. Sometimes people can feel claustrophobic, breathless or generally unwell in the MRI scanner, but patients had a buzzer which they could press at any time to be let out for any reason. There is a small chance that having a scan could result in finding an unexpected abnormality which was causing no major symptoms, for example, an aneurysm or small tumour. If this were to occur, deciding what to do about the abnormality could be difficult. In these circumstances, the patient would be informed of the abnormality and referred on to the relevant specialist for further assessment and discussion of treatment options. Patients asked to consider carefully this potential risk before they decided whether they wished to take part in this study. The gait analysis equipment is manufactured and CE marked to standards for a medical device. The study team were happy to discuss the results of the depression and memory questionnaires with patients and provide further support, if required.
    Background therapy
    		 NA
    Evidence for comparator
    		 NA, this is a placebo controlled trial
    Actual start date of recruitment
    07 Jan 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 30 participants with Parkinson's Disease to be recruited and receive either Ursodeoxycholic Acid (UCDA) or placebo for 12 months, across 2 UK sites (Sheffield and London).

    Pre-assignment
    Screening details
    		 Screening of potentially eligible participants was performed over the telephone, where diagnosis, medical history, medications and other relevant inclusion and exclusion criteria were checked (where possible over the telephone) by a member of the study team. If patient deemed eligible then invited for a full screening visit in person.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    To preserve blinding as far as possible, members of site research teams assigned to undertake the MoCA and UPDRS questionnaires should not be involved in monitoring adverse events or titration of study medication dose.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 UDCA
    Arm description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 20 patients will be randomised to UDCA at a dose of 30 mg /kg . This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ursodeoxycholic Acid
    Investigational medicinal product code
    PL 12762/0515
    Other name
    UDCA, Ursonorm
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Research participants will be asked to start taking a single capsule of trial medication (250 mg UDCA) the day after their baseline visit. The medication is to be taken with food. The dose will then be increased every three days by a further capsule of the trial medication until the patient reaches an initial final dose of 30 mg/kg of UDCA (rounded to the nearest possible dose). Once the target dose is reached patients advised to remain on the maximum dose if tolerated until their 12 week visit and subsequently throughout weeks 12-48.

    Arm title
    		 Placebo
    Arm description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 10 patients will be randomised to 30 mg /kg matched placebo. This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    NA
    Other name
    NA
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Research participants will be asked to start taking a single capsule of trial medication (placebo) the day after their baseline visit. The medication is to be taken with food. The dose will then be increased every three days by a further capsule of the trial medication until the patient reaches an initial final dose of 30 mg/kg of placebo. Once the target dose is reached patients advised to remain on the maximum dose if tolerated until their 12 week visit and subsequently throughout weeks 12-48.

    Number of subjects in period 1
    		UDCA Placebo
    Started
    20
    11
    Randomised
    20
    11
    Withdrawn from treatment
    2 [1]
    1 [2]
    Completed study
    18
    10
    Completed
    18
    10
    Not completed
    2
    1
         Consent withdrawn by subject
    2
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: In the UDCA arm there were 20 patients randomised, 20 patients with a full dataset, 18 that completed the study treatment and 2 withdrawn from treatment
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: In the Placebo arm there were 11 patients randomised, 11 patients with a full dataset, 10 that completed the study treatment and 1 withdrawn from treatment

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    UDCA
    Reporting group description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 20 patients will be randomised to UDCA at a dose of 30 mg /kg . This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 10 patients will be randomised to 30 mg /kg matched placebo. This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.

    Reporting group values
    		 UDCA Placebo Total
    Number of subjects
    		 20 11 31
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.3 ( 7.61 ) 61.9 ( 8.28 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6 12
        Male
    		 14 5 19

    End points

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    End points reporting groups
    Reporting group title
    UDCA
    Reporting group description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 20 patients will be randomised to UDCA at a dose of 30 mg /kg . This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 10 patients will be randomised to 30 mg /kg matched placebo. This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.

    Primary: The number of Serious Adverse Events (SAEs)

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    End point title
    		 The number of Serious Adverse Events (SAEs) [1]
    End point description
    The primary outcome of the study is safety and tolerability of UDCA which is a assessed using the number of observed SAEs.
    End point type
    Primary
    End point timeframe
    from randomisation to week 56.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: there is no appropriate statistical analysis for these primary endpoints.
    End point values
    		 UDCA Placebo
    Number of subjects analysed
    20
    11
    Units: number
    0
    1
    No statistical analyses for this end point

    Primary: The number of Adverse Treatment Reactions

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    End point title
    		 The number of Adverse Treatment Reactions [2]
    End point description
    The primary outcome of the study is safety and tolerability of UDCA which is a assessed using the number of observed ATRs.
    End point type
    Primary
    End point timeframe
    from randomisation to week 56.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: there is no appropriate statistical analysis for these primary endpoints.
    End point values
    		 UDCA Placebo
    Number of subjects analysed
    20
    11
    Units: number
    10
    4
    No statistical analyses for this end point

    Primary: Number of patients still taking the study treatment at any dose at the 48 week visit

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    End point title
    		 Number of patients still taking the study treatment at any dose at the 48 week visit [3]
    End point description
    The primary outcome of the study is safety and tolerability of UDCA which is a assessed using the number of patients till taking the study treatment at any dose at the 48 week visit
    End point type
    Primary
    End point timeframe
    from randomisation to week 48.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: there is no appropriate statistical analysis for these primary endpoints.
    End point values
    		 UDCA Placebo
    Number of subjects analysed
    20
    11
    Units: number
    18
    10
    No statistical analyses for this end point

    Secondary: The change from baseline to week 48 in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 motor subsection “OFF” medication score

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    End point title
    		 The change from baseline to week 48 in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 motor subsection “OFF” medication score
    End point description
    The change from baseline to week 48 (planned end of treatment) in MDS-UPDRS part 3 score to be compared between treatment groups
    End point type
    Secondary
    End point timeframe
    from randomisation to week 48.
    End point values
    		 UDCA Placebo
    Number of subjects analysed
    20
    11
    Units: score
        number (not applicable)
    -1.68
    -5.2
    Statistical analysis title
    		 comparison of change in MDS-UPDRS from baseline to
    Statistical analysis description
    Analysis specification is pre-specified with 19 in UDCA arm and 10 in placebo arm
    Comparison groups
    UDCA v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1844
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (net)
    Point estimate
    3.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.83
         upper limit
    		 8.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.55

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs recorded from the baseline visit until the date the participant completes follow-up or withdraws from the study. AEs may be identified during follow-up visits, telephone contacts or as a result of direct reporting by the participant or clinician.
    Adverse event reporting additional description
    Multiple symptoms should be recorded as separate events. The PI or authorised delegate is responsible for assessing the relationship between each adverse event and the trial treatment. Completed AE forms will be entered onto the Prospect database by a member of the research team and paper copies filed in the site file.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    UDCA
    Reporting group description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 20 patients will be randomised to UDCA at a dose of 30 mg /kg . This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients with PD who have been diagnosed ≤ 3 years ago. 10 patients will be randomised to 30 mg /kg matched placebo. This will include 48 week exposure period and a subsequent 8 week washout period. Detailed evaluations of all patients will take place at Screening, Baseline, 12, 24, 48 and 56 weeks. The trial medication will be taken at three equal doses per day, to be taken orally with food. The dose will be increased gradually by 250 mg (one capsule) every three days until patient reaches a dose of 30 mg/kg.

    Serious adverse events
    		 UDCA Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 UDCA Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 20 (80.00%)
    8 / 11 (72.73%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 11 (27.27%)
         occurrences all number
    1
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Insomnia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Stress
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Head injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Product use complaint
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Dyskinesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    Loss of consciousness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Parkinson's disease
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Syncope
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    2
    Dry mouth
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    4 / 20 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    5
    0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Ligament operation
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Periarthritis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2019
    The IDMC advised that it would be helpful for the protocol to contain further instructions in the event of raised LFTs and when these should be repeated. The re-start of the medication may be conducted via a telephone visit or clinic visit as appropriate. Stopping criteria for permanent discontinuation of trial treatment updated. Temporary Discontinuation of trial treatment updated. Include a further exclusion criterion as follows: 'participants with previous or current diagnosis of inflammatory bowel disease e.g. ulcerative colitis or Crohn's disease’. To ask participants who permanently stop their study medication to continue to attend for the remaining study visits as the data collected at these visits will inform decision to treat analysis. Prior to UCLH participants attending Sheffield, a member of the Sheffield Research team will phone the participant to complete the clinical screening form to ensure the participants are suitable for the MRSpectroscopy before travelling to Sheffield’. Protocol updated to remove the 'slow speed test' as this will no longer be undertaken. Participants to be advised not to eat too much protein prior to attending their OFF state visits. updated the participant information sheet To state that regular newsletters will be available at clinic visits so that participants are kept up to date with how the study progresses.
    06 Mar 2019
    To open Participant Identification Centres (PICs) at Doncaster and Bassetlaw Teaching Hospitals; Barnsley Hospital NHS Foundation Trust; The Rotherham NHS Foundation Trust; Chesterfield Royal Hospital. To provide a study specific flyer to the local teams at each PIC to hand to potentially eligible participants and again asking these participants to contact the central team at Sheffield Teaching Hospitals, so that the central team can send these participants an invite letter, PIS and reply slip. To amend study team details. Updated the flow chart on P16 to state that the 'wash-out' phase is between week 48 and week 56 and not before week 48. We have clarified that for any unscheduled clinic visits a tablet count will be undertaken to ensure compliance data is captured where there is a temporary stop to medication or after a re-start to medication. Unblinding has been updated to state that members of the local research team who undertake the MoCA and UPDRS questionnaires should not be involved in the monitoring of adverse events. The participant information sheet has been updated to ask participants to wear sensible shoes for the gait analysis tests.
    21 Jun 2019
    To ask participants attending UCLH to wear a physical activity monitor (Dynaport Movemonitor+, McRoberts, Netherlands) to undertake gait analysis tests at their clinic baseline visit and week 48. To add an additional exploratory outcome measure to the protocol to assess 'the change from baseline to week 56 between the randomised treatment groups' as this will enable the statistician to analyse this timeline taking into account 8 weeks off study treatment. The updated protocol includes reference to unscheduled visits for reasons other than raised LFTs or temporary stop of medication as participants may be invited to attend unscheduled visits for other reasons e.g. raised potassium levels to be repeated. To amend one of the inclusion criteria 'diagnosis of Parkinson's disease <3 years to <5 years. The Physical Activity diary has been amended to state that the physical activity monitor will be set to record the participant's movements from 12 am rather than 5 am and that participants can either chose to return the activity monitor at their next appointment or using the pre-paid envelope.
    15 Jan 2020
    Increased the telephone contact call windows that currently have a +/- 2 day limitation to +/-4 days to allow for weekends and bank holidays. Posting out Sensors prior to week 48 visit. Substantial amendment 03 for this study was submitted to MHRA/NRES/HRA in June 2019. SA03 included the amendment of one of the inclusion criteria ‘diagnosis of Parkinson's disease <3 years to <5 years”. To ensure the GP Notification Alert Letter is consistent with the above change, the study team have now updated the diagnosis period from “within the past 3 years” to “within the past 5 years”. To include: newsletter to be distributed via email, post and relevant websites by the local research team. To include data may be required from the UP study for use in future studies, where relevant. This data would help to develop future algorithms for data analysis. The recruitment end date for this study was 30/09/2019, however as per the protocol (version 4.1 22 Aug 2019) any participant withdrawing prior to Week 12 will be replaced. We therefore may replace participants between 30th September and 31st December 2019. The study team wish to thank participants upon completion of the study, to thank them for their time and participation. The study team will also inform the participants that the study team will update them with the progress of the study and inform them of the outcome of the study as soon as the study teams are able.
    20 May 2020
    To change from postal consent to verbal consent and do not intend to provide information to participants ahead of the phone call. Due to the impact of COVID-19 face to face appointments for the study have changed to virtual visits either by telephone or utilising video conferencing facilities. Due to these changes, participants are posted a sensor to wear for 7 days prior to visit 5 and are also posted questionnaires to complete for visit 5 and visit 6. Therefore to not overburden participants further with an additional cover letter and consent form relating to the gait data, we propose that during the telephone call visits we seek verbal consent from the participant that they are willing for their gait data to be used for future research. To telephone participants who are not due a virtual clinic visit to seek verbal consent from the participant that their gait data can be used for future research.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    NA

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32759251
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