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MUSTARDD-PD: Too Hot to Handle? David J Burn (firstname.lastname@example.org) 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 Institute for Ageing and Health 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 Institute for Ageing and Health 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 Institute for Ageing and Health 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 Institute for Ageing and Health 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 Institute for Ageing and Health 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 Institute for Ageing and Health 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 Institute for Ageing and Health 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 Institute for Ageing and Health 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 Institute for Ageing and Health MUSTARDD-PD: Flow Diagram Institute for Ageing and Health 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 Institute for Ageing and Health Too Hot to Handle? Potential Obstacles • Recruitment difficulties – inclusion/exclusion criteria – time & motivation • Attrition • End-points – sensitive? – appropriate? • Clinical vs. cost effectiveness Institute for 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
"MUSTARDD-PD Report - PD Med"