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COmBining memantine And cholinesterase inhibitors in Lewy body dementia treatment Trial (COBALT)��John-Paul Taylor�Chief Investigator

COBALT

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The challenge

Dementia with Lewy bodies (DLB)

Parkinson’s disease dementia (PDD)

Lewy body dementia (LBD)

Time from diagnosis

Survival

LBD (≈ 3 years)

Alzheimer’s (≈ 7 years)

Yet often undiagnosed / misdiagnosed

2nd commonest cause of late life dementia

Poor quality of life, significant morbidity and mortality

LACK OF EVIDENCE BASED TREATMENTS

COBALT

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The challenge

Cognition

Psychiatric

Parkinsonism

Autonomic

Sleep

Cognitive baseline

time

Switched off

Lucid

Confused

COBALT

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Donepezil/rivastigmine: Clinical Global Impression of Change (CGIC) change from baseline (improvements)

Stinton et al. American Journal of Psychiatry 2015

Box plot: Clinical Global Impression of Change (CGIC) change from baseline (no deterioration)

TAKE HOME:

  • CHEIs offer small but significant global improvements
  • Even if there no improvement – there is less likely to be deterioration

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Box plot: MMSE

Stinton et al. American Journal of Psychiatry 2015

TAKE HOME: Typically 1-3 point improvement on MMSE with CHEI

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Benefits of cognitive enhancers long term and beyond cognition

Electronic records study a.k.a. “real-world” data found CHEIs with or without memantine associated:

  • With shorter duration of hospital admissions
  • Decreased risk of mortality

Chen et al. PLoS Medicine 2022

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Benefits of cognitive enhancers long term and beyond cognition

Swedish Registry study

  • N=1095 DLB
  • Initiation of CHEI or memantine or non-use within 90 days of diagnosis
  • 5-year follow-up

Xu et al. Alzheimer’s & Dementia 2024

CHEI associated with lower risk of death in the first year after DLB diagnosis (adjusted hazard ratio [HR] 0.66, 95% CI 0.46, 0.94)

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MMSE decline per year (95% CI)

CHEI

-0.39 (-0.96 to 0.18)

Memantine

-2.49 (-4.02 to -0.97)

Non-use

-2.50 (-4.28 to -0.73

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Outcome measure

Aarsland et al. (2009)

Emre et al. (2010)

Global outcomes (CGIC)

Not improved in DLB but improved in PDD vs. placebo

Improved in DLB but not PDD vs. placebo

Neuropsychiatric inventory

No improvements across whole group in active vs. placebo

Improved in DLB but not PDD vs. placebo

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Cognition

Improvements in MMSE and attention in active vs. placebo

No improvements in either DLB or PDD vs. placebo

Activities of daily living

Less worsening in active group

No differences in either DLB or PDD active vs. placebo

Drop outs

Dropouts active 20%; placebo 23%

Dropouts active 11%; placebo 12%

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199 patients with DLB or PDD

72 patients with DLB or PDD

Allowed CHEI use

Do not allow CHEI use

Memantine

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TAKE HOME: Evidence is inconsistent for memantine

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Outcome measure

Aarsland et al. (2009)

Emre et al. (2010)

Global outcomes (CGIC)

Not improved in DLB but improved in PDD vs. placebo

Improved in DLB but not PDD vs. placebo

Neuropsychiatric inventory

No improvements across whole group in active vs. placebo

Improved in DLB but not PDD vs. placebo

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Cognition

Improvements in MMSE and attention in active vs. placebo

No improvements in either DLB or PDD vs. placebo

Activities of daily living

Less worsening in active group

No differences in either DLB or PDD active vs. placebo

Drop outs

Dropouts active 20%; placebo 23%

Dropouts active 11%; placebo 12%

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199 patients with DLB or PDD

72 patients with DLB or PDD

Allowed CHEI use

Do not allow CHEI use

Memantine

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TAKE HOME: Evidence is inconsistent for memantine

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Need a trial to assess the benefits of memantine, particularly in the context of people with either DLB or PDD who are already taking CHEI

COBALT

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Study synopsis

  • Intervention: DLB/PDD patients on a stable dose of ChEI randomised (1:1) to either memantine or placebo for 52 weeks with an initial dose titration (titrated to maximum tolerated dose of 20 mg in 5 mg increments over 4 weeks)
  • Aim to recruit 372 participants (n=186 DLB and n=186 PDD)
  • Basket trial design (same intervention and procedures for both DLB and PDD)
  • International trial across UK (n=300, 30 sites) and Australia (n=72)

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COBALT

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Study synopsis

Population:

    • Patients with a diagnosis of probable PDD or DLB
    • Age >50; MMSE 8 or above
    • On stable dose of ChEI for ≥12 weeks before baseline and no medication changes 4 weeks before enrolment
    • Patients with or without capacity

Exclusions:

    • Atypical clinical features suggestive of an alternative dementia diagnosis
    • Any clinically relevant concomitant disease that will affect ability to participate in the study
    • Other condition which may contribute to cognitive impairment above and beyond that caused by the participant's DLB/PDD
    • Taking memantine, amantadine, ketamine or dextromethorphan; no caregiver/informant available.

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COBALT

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Baseline

24 weeks

52 weeks

Longer term F/U

COBALT

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Baseline

24 weeks

52 weeks

Longer term F/U

Randomisation (1:1)

COBALT

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Baseline

24 weeks

52 weeks

Longer term F/U

Primary Outcome

Adapted Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale

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Health economic data EQ-5D-5L, EQ-5D-5L-proxy; DEMQOL, DEMQOL-proxy, CSRI

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Randomisation (1:1)

Baseline clinical history

Secondary measures

Exploratory measures

COBALT

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Baseline

24 weeks

52 weeks

Longer term F/U

Secondary Outcomes

  • MoCA in PDD
  • MMSE in DLB
  • NPI+
  • DEMQOL and DEMQOL-proxy
  • EQ-5D and EQ-5D-5L proxy

Secondary Outcomes

  • Adapted ADCS-CGIC
  • MoCA in PDD
  • MMSE in DLB
  • NPI+
  • DEMQOL and DEMQOL-proxy
  • EQ-5D and EQ-5D-5L proxy

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Randomisation (1:1)

Baseline clinical history

Secondary measures

Exploratory measures

COBALT

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Baseline

24 weeks

52 weeks

Longer term F/U

Exploratory Outcomes

  • MoCA in DLB
  • MMSE in PDD
  • Hospital Anxiety and Depression Scale
  • Disability Assessment For Dementia
  • MDS UPDRS-III
  • Zarit burden scale
  • Carer HADS
  • Carer WHO Quality of Life-Brief
  • Epworth sleepiness scale (ESS)
  • Parkinson’s disease Sleep Scale (PDSS)

Exploratory Outcomes

  • MoCA in DLB
  • MMSE in PDD
  • Hospital Anxiety and Depression Scale
  • Disability Assessment For Dementia
  • MDS UPDRS-III
  • Zarit burden scale
  • Carer HADS
  • Carer WHO Quality of Life-Brief
  • Epworth sleepiness scale (ESS)
  • Parkinson’s disease Sleep Scale (PDSS)

Baseline clinical history

Secondary measures

Exploratory measures

Randomisation (1:1)

COBALT

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Baseline

24 weeks

52 weeks

Longer term F/U

  • Hospitalisation
  • Institutionalisation
  • Mortality

Randomisation (1:1)

COBALT

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Cobalt Sites

Newcastle upon Tyne Hospitals NHS Foundation Trust

PI; Prof Alison Yarnall

South London & Maudsley NHS Foundation Trust

PI: Prof Dag Aarsland

Cambridge and Peterborough NHS Foundation Trust

PI: Dr Vandana Menon

Essex Partnership University NHS Foundation Trust

PI: Prof Zuzana Walker

Norfolk & Suffolk NHS Foundation Trust

PI: Dr Chris Fox

Hampshire & Isle of Wight Healthcare NHS Foundation Trust

PI: Dr Jay Amin

Greater Glasgow Central NHS Foundation Trust

PI: Dr Eric Jackson

Sussex Partnership NHS Foundation Trust

PI: Prof Naji Tabet

Devon Partnership NHS Trust

PI: Prof Louise Allan

North Bristol NHS Trust

PI: Dr Elizabeth Coulthard

Sheffield Health and Social Care NHS Foundation Trust

PI: Dr Aparna Mordekar

Tees, Esk and Wear Valleys NHS Foundation Trust

PI: Dr Jenny Martin

Cornwall Partnership NHS Foundation Trust

PI: Dr Vandana Mate

NHS Fife

PI: Dr Nancy Attalla

Nottinghamshire Healthcare NHS Foundation Trust

PI: Dr Sarah Wilson

NHS Lothian

PI: Dr Gordan Duncan

Surrey & Borders Partnership NHS Foundation Trust

PI: Dr Ramin Nilforooshan

South West London and St George's Mental Health NHS Trust

PI: Dr Robert Lawrence

University College London Hospital NHS Foundation Trust

PI: Dr Rimona Weil

Kent & Medway NHS and Social Care Partnership Trust

PI: Dr Joanna Rodda

Oxford Health NHS Foundation Trust

PI: Dr Qi Pei

IN SET-UP

Imperial College Healthcare NHS Trust

PI: Dr Paul Edison

Bradford District Care Foundation Trust

PI: Dr Gregor Russell

Belfast Health and Social Care Trust

PI: Dr Joe Kane

Sherwood Forest Hospitals NHS Foundation Trust

PI: Dr Nishantha Silva

Northern Care Alliance NHS Foundation Trust

PI: Dr Jason Raw

IN SET-UP

Walton Centre NHS Foundation Trust

PI: Dr Rhys Davies

IN SET-UP

Lancashire and South Cumbria NHS Foundation Trust

PI: Dr Salman Karim

IN SET-UP

Derbyshire Healthcare NHS Foundation Trust

PI: Dr Kaanthan Jawahar

29 approved UK sites – 25 open to recruitment, 4 currently in set-up, 1 to be determined

COBALT

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Recruitment

  • 147 UK recruits (99 DLB, 48 PDD)
  • Projected 300 UK recruits by end of May 2026

COBALT

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Self referral

The COBALT trial is registered with Parkinson’s UK Take Part Hub and Join Dementia Research -

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Take part in research | Parkinson's UK

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Join dementia research - register your interest in dementia research : Home

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COBALT

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Timelines

Recruitment is open until May 2026

COBALT

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Any Questions?��Main contact:�Cobalt.study@ncl.ac.uk

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Website:

Key message: We need more PDD participants

COBALT

https://research.ncl.ac.uk/cobalttrial/