COmBining memantine And cholinesterase inhibitors in Lewy body dementia treatment Trial (COBALT)

RESEARCH QUESTION

What is the clinical and cost effectiveness of memantine compared to placebo in patients 1) with Dementia with Lewy bodies (DLB) and 2) Parkinson’s disease dementia (PDD) on a stable dose of an acetylcholinesterase inhibitor (AChEI)? BACKGROUND

DLB and PDD are related complex disorders with a wide spectrum of cognitive, neuropsychiatric, sleep, motor, and autonomic features. This application is in response to the Health Technology Assessment Board’s commissioned call 18/189. AIMS To determine the effectiveness of augmenting AChEI with memantine in patients with DLB and in patients with PDD.

OBJECTIVES

To conduct two separate trials in DLB and PDD respectively (COBALT-DLB and COBALT-PDD) to the same protocol. Both trials will be multi-centre, parallel arm, double blind, randomised, and placebo-controlled examining the clinical and cost-effectiveness of memantine augmentation in patients on an AChEI for 52 weeks with primary outcome assessed at 26 weeks.

METHODS

COBALT-DLB and COBALT-PDD trials will be conducted in 25 NHS centres in England and Scotland and 5 centres in Australia. Population: Patients with a diagnosis of DLB or PDD in accordance with established consensus criteria with or without capacity. Intervention: DLB/PDD patients on a stable dose of AChEI randomised (1:1) to either memantine or placebo for 52 weeks.

Primary outcome: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale at 26 weeks. Secondary and exploratory: Cognitive, neuropsychiatry, sleep, quality of life (QOL) measures at 26 weeks and 52 weeks as well as repeat assessment of ADCS-CGIC at 52 weeks. Health economic measures: Several measures including QOL and an adapted version of the Client Service Receipt Inventory for use in dementia.

Sample size: Separate power analyses for COBALT-DLB and COBALT-PDD. Specifying an alpha criterion of 5% and power of 90%, to detect an ADCS-CGIC score difference of 0.7 between groups, the required sample size, per study arm (active and placebo), is 74 participants. Inflating this for 20% loss to follow up at 26 weeks would give 93 per study arm or 186 in each trial (total 372).

ANALYSIS

Primary outcome: For each trial, intention to treat analysis of ADCS-CGIC score at 26 weeks. Separate individual generalised linear models will be fitted for PDD and DLB. Secondary and Exploratory outcomes: Evaluated at 26 weeks and on ADCS-CGIC and secondary/exploratory outcomes at 52 weeks using analogous methods.

Health economic outcomes: Cost-effectiveness will be determined over one year including mean incremental cost per quality adjusted life year and costs from an NHS and Personal Social Services perspective. TIMELINES FOR DELIVERY

Protocol development -4-0 months; Trial approvals/set-up 0-6 months; Recruitment 6-36 months; Follow-up period up to 48 months (for last participant to reach 12 months); analysis and reporting 48-54 months. Initial 12 month internal pilot during the recruitment phase with progression criteria and contingency strategies including, for example, expansion of recruitment sites.

IMPACT AND DISSEMINATION

If positive the results will have a major impact on clinical practice and will influence NICE guidelines and clinical practice. If negative, it would give a clear message that adding memantine to an AChEI in DLB/PDD cases should not be part of clinical care.