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MUSTARDD-PD Report - PD Med

VIEWS: 9 PAGES: 18

									      MUSTARDD-PD:
      Too Hot to Handle?


David J Burn
(d.j.burn@ncl.ac.uk)


        Institute for
        Ageing and
        Health
What is MUSTARDD-PD?

• Multi-centre UK Study of the
  Acetylcholinesterase Inhibitor
  Donepezil in Early Dementia
  Associated with PD
• HTA Application
   – 60 months
   – £2.4 million
• Objective to determine whether
  donepezil is clinically beneficial
  & cost effective in the long-term
  management of people with early
  dementia associated with PD
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                                       Ageing and
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MUSTARDD-PD: Applicants

•   David Burn (CI)       •   Andrew Lees
•   Roger Barker          •   Iracema Leroi
•   Belinda Braithwaite   •   Elaine McColl
•   Alistair Burns        •   Ian McKeith
•   Carl Clarke           •   John O’Brien
•   John Hindle           •   Nick Steen
•   Martin Knapp          •   Keith Wheatley


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Cholinesterase Inhibitors & PDD

• Profound loss of cholinergic
  neurotransmission in PDD
   – imaging
   – neurochemistry
   – pathology
• ChEIs reduce enzymatically                    Donepezil
  mediated breakdown of acetylcholine
   – rivastigmine inhibits both
     butyrylcholinesterase &
     acetycholinesterase
   – galantamine also an allosteric modulator
     of nicotinic receptors

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Cholinesterase Inhibitors in PDD: Summary

• Two large RCTs mild-moderate dementia severity
     – EXPRESS (rivastigmine) n = 541, duration 24 weeks
     – EDON (donepezil) n = 549, duration 24 weeks
• ADAS-cog primary outcome measure (range 0-70)
     – 2.8-3.4 points improvement in both studies
• Significant improvements in several secondary outcome
  measures
• EXPRESS study
     – 73% allocated to rivastigmine & 82% to placebo completed
       treatment
     – adverse events predictable & related to cholinergic effects

                                                              Institute for
Emre 2004; Dubois 2007
                                                              Ageing and
                                                              Health
Problems with Existing Studies

• Use of Alzheimer-based primary outcome
  measure & DSM-IV dementia classification
• Mild to moderate dementia with 6 month follow-
  up in main studies
• “Last observation carried forward” to impute
  missing data
• What is “clinically significant”?
• No measure of quality of life or carer strain
• No health economic measures
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                                          Ageing and
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MUSTARDD-PD: Trial Design

• Placebo-controlled, double-blind trial of 500
  people with PD & early dementia
   – randomised to either donepezil or matching placebo in a
     1:1 ratio
   – 21 sites in UK with good DeNDRoN coverage
• Patients allocated to donepezil will receive
  5mg/day for 8 weeks before their dose is increased
  to 10mg/day
• If participants remain in the study for the two year
  treatment period, they will therefore receive
  10mg/day of donepezil for a total of 96 weeks
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Inclusion Criteria


1.       A diagnosis of PD according to UK Parkinson's Disease Society
         Brain Bank Criteria
2.       Mild dementia associated with PD, where the patient and/or their
         family have become aware of cognitive ± behavioural symptoms that
         are causing functional impairment
     –      “dementia" defined according to recently published Movement Disorder
            Society Task Force criteria for dementia associated with PD &
            “operationalised” using the Addenbrooke's Cognitive Examination
     –      participants will have an ACE-R ≤ 88
     –      if this criterion is met, subjects will be further assessed using the Mattis
            Dementia Rating Scale (DRS-2)
     –      age- & education-corrected total DRS-2 score < 8 but > 6 (corresponding to
            between 6th & 28th percentile) will define "mild" dementia
3.       Community-living & spouse, close relative or well-established carer
         to accompany the subject


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MDS Task Force for Diagnosis of PD Dementia

I.        Core features
      –     diagnosis of PD according to QSBB criteria
      –     dementia syndrome with insidious onset & slow progression
            •   impairment in > 1 cognitive domain
            •   a decline from pre-morbid level
            •   deficits severe enough to impair daily life, independent of motor or
                autonomic symptoms
II.       Associated clinical features
      –     cognitive features
            •   attention, executive, visuospatial, memory, language
      –     behavioural features
            •   apathy, mood, hallucinations, delusions, EDS
III. Features making the diagnosis less certain
IV. Features suggesting other diseases as cause of mental
     impairment
                                                                        Institute for
Emre 2007                                                               Ageing and
                                                                        Health
MDS Task Force for Diagnosis of PD Dementia


• Probable PDD
    – both core features present
    – typical impairment in at least 2 of 4 core cognitive domains & ≥ 1
      behavioural symptom
    – none of group III or IV criteria present
• Possible PDD
    – both core features present
    – atypical cognitive profile in ≥ 1 domain; behavioural symptoms
      may or may not be present
                                      OR
    – ≥ 1 group III criteria present
    – none of group IV criteria present
                                                              Institute for
Emre 2007                                                     Ageing and
                                                              Health
Exclusion Criteria


1. Dementia within ≤ 1 year of onset of motor symptoms
2. Such severe motor disability, or so impaired in ADLs
   from other aspects of PD, that it would interfere with
   cognitive & global assessment
3. Severe current depressive episode
   –   Beck Depression Inventory & a cut-off score of 13/14
   –   recommended by recent Movement Disorder Society Task Force
       report
4. Unstable significant medical co-morbidity
5. Previous exposure to a cholinesterase inhibitor or
   contraindication to donepezil (incl. clinically significant
   cardiac conduction defect)
6. Previous neurosurgery for PD
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Outcomes

• Primary outcome measures
  – Mattis DRS-2
  – Neuropsychiatric Inventory (NPI-10)
  – Bristol Activities of Daily Living Scale (BADLS)
• Secondary outcome measures
  – EQ-5D, DEMQOL & DEMQOL-proxy
  – Scale of Quality of Life of Caregivers
• Health economics analysis
  – Client Service Receipt Inventory
• Adverse events
                                                 Institute for
                                                 Ageing and
                                                 Health
Recruitment

• 21 sites in UK
   – additional sites spontaneously expressing interest
• 24 months to recruit 500 patients from 21 centres
   – i.e. 24 patients recruited from each centre at a rate of 1
     per month
• Each centre will see approximately 400-500
  people with PD in their clinics
   – 20-30% will be demented to various levels of severity
• Of the 80-150 PDD patients per centre ~ 30-40
  will fulfil inclusion/exclusion criteria
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                                                       Ageing and
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MUSTARDD-PD: Study Timelines
   Time               Action
   Spring 2009        Contract signed with HTA
   June 2009          Advertise for Trial Manager, Secretary and Data Manager
   August 2009        Protocol finalised
                      NRES & MHRA applications submitted (via NCTU)
                      Stability testing of over-encapsulated drug and placebo (if required)
   November 2009      Trial officially commences
                      Trial staff commence employment on project
                      Standard operating procedures reviewed and finalised
   February 2009      NRES & MHRA approvals obtained
                      Applications for R & D approval submitted & contracts agreed with
                      trial sites
                      Investigator / collaborator meeting (#1)
   April-May 2010     All sites initiated and “active”
   February 2010      Investigator / collaborator meeting (#2)
   April 2011         Half of recruitment period completed
   February 2011      Investigator / collaborator meeting (#3)
   April 2012         Recruitment completed (n=500)
   May 2014           Last patient completes treatment allocation
   June - July 2014   Database queries resolved & “locking”
                      Data analysis commences
   October 2014       Results available
                      HTA report written & paper submitted for publication
                      Investigator / collaborator meeting (#4)
                      Feedback to study participants

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MUSTARDD-PD: Flow Diagram




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Research Governance

• Sponsor: Newcastle upon Tyne Hospitals NHS Foundation
  Trust
   – sponsor-level activities carried out by Newcastle Clinical Trials Unit
     (Professor Elaine McColl)
• Trial Steering Committee
   – Dr Carl Counsell (University of Aberdeen) chair
   – one geriatrician & an old age psychiatrist with an interest in PD who
     do not participate in the trial
   – 2 lay people
   – Professor Burn
   – observers from the HTA programme will be invited to all meetings
• Data Monitoring & Ethics Committee
   – Professor Bastian Bloem (University of Nijmegen, Netherlands) chair
   – experienced trial statistician & geriatrician with an interest in PD from
     the UK who are not participating in the trial

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                                                                  Ageing and
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Too Hot to Handle? Potential Obstacles

• Recruitment difficulties
   – inclusion/exclusion criteria
   – time & motivation
• Attrition
• End-points
   – sensitive?
   – appropriate?
• Clinical vs. cost effectiveness


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                                         Ageing and
                                         Health
Conclusion: Will MUSTARDD-PD Deliver?

• Timely trial given recent DoH
  Dementia Strategy document
• Trial geared to dementia
  associated with PD, using
  clinically relevant end-points
• Health economics analysis at
  three time horizons
• “Long-term” treatment planned
  for each case with intention to
  treat analysis


                                    Institute for
                                    Ageing and
                                    Health

								
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