Title: COmBining memantine And cholinesterase inhibitors in Lewy body dementia treatment Trial (COBALT)
Funder: Department of Health and Social Care

Abstract: AIM_x000D_ To find out if adding Memantine to existing medications (acetylcholinesterase inhibitors; AChEIs) improves overall health and function for people with dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD)._x000D_ _x000D_ BACKGROUND_x000D_ DLB and PDD are related illnesses with a wide range of distressing symptoms. People with DLB/PDD have worse quality of life, more complex symptoms, higher care costs, and are more sensitive to medications than people with Alzheimer’s disease. AChEIs are commonly used medicines that can help people with DLB/PDD by improving day to day functioning and thinking abilities. Another drug which might help is Memantine, but it is not clear if adding Memantine to AChEI is beneficial. We will test if combining these two medications will have a better outcome than only taking an AChEI by itself._x000D_ _x000D_ METHODS_x000D_ We will recruit 372 people with DLB/PDD who are on a stable dose of an AChEI from across the NHS, as well as in Australia. Participants will be randomized to receive either Memantine or an inactive drug (placebo). Neither participants nor study investigators will be aware of the drug allocation until the study is completed._x000D_ _x000D_ Participants will be 50 years of age or older and have mild to moderate dementia of DLB or PDD type. They will not be eligible to take part if they have physical illness that would prevent them from taking Memantine. All participants must have a reliable family member/caregiver. People who lack the ability to give consent can still take part if their legal representative (proxy decision maker in Scotland) consents. We will not include people who have other types of dementia or brain diseases._x000D_ _x000D_ We will use a test called the Alzheimer's disease cooperative study-clinical global impression of change (ADCS-CGIC) scale which provides a measure of whether someone is getting better, staying the same or getting worse. We will record this at 26 weeks. We will also test thinking abilities, look for changes in other symptoms (e.g. hallucinations, depression, and movement function) and monitor any significant side effects due to the combined treatment. We will assess any effects on quality of life for participants and their family/caregivers. We will also calculate any extra costs or savings that are made from taking the Memantine in addition to the AChEI. We will monitor the participants for 52 weeks and aim to follow-up participants longer term after the trial has finished._x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ Patient and Public Involvement (PPI) has informed the proposed study at stages 1 and 2, using workshops with DLB/PDD patients and carers brought together by our PPI panel. Ongoing PPI will consist of regular meetings to advise on the trial. The PPI panel will also collect participant feedback and organise events to publicise the findings._x000D_ _x000D_ DISSEMINATION_x000D_ We will use traditional methods of publications and conference presentations to share the results with other researchers, clinicians and people living with DLB/PDD and their families. We will also setup a website and social media platform to inform the general public. We will ensure that the clinical and economic value of adding Memantine to an AChEI is reported to government and is considered for inclusion in NICE guidelines.

Lay abstract: RESEARCH QUESTION_x000D_ 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)?_x000D_ _x000D_ BACKGROUND_x000D_ 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. _x000D_ _x000D_ AIMS_x000D_ To determine the effectiveness of augmenting AChEI with memantine in patients with DLB and in patients with PDD._x000D_ _x000D_ OBJECTIVES_x000D_ 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._x000D_ _x000D_ METHODS_x000D_ 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._x000D_ 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)._x000D_ _x000D_ ANALYSIS_x000D_ 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. _x000D_ 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. _x000D_ _x000D_ TIMELINES FOR DELIVERY_x000D_ 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._x000D_ _x000D_ IMPACT AND DISSEMINATION_x000D_ 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.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL