Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT06379594 |
| Other study ID # |
294633 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 20, 2022 |
| Est. completion date |
June 2028 |
Study information
| Verified date |
April 2024 |
| Source |
South London and Maudsley NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
This project aims to understand the feasibility, acceptability and real-world evidence of a
novel UK-based remote brain health clinic for patients with mild cognitive impairment (MCI).
A timely and accurate diagnosis of dementia is a priority in the UK and MCI is indicative of
future risk of cognitive decline. An accurate etiological diagnosis of MCI (MCI-subtyping -
distinguishing those who are likely to go on to develop dementia and those who are not) is
vital for treatment planning. Whilst the assessment of molecular biological markers
(biomarkers) for etiological diagnosis of MCI and Alzheimer's disease (AD) is increasingly
recommended and employed internationally, the uptake is low in UK memory clinics. The Brain
Health Clinic (BHC) has been specifically designed as a state-of-the-art diagnostic centre
for those with MCI. Procedures will include a range of clinical and biomarker assessments,
with molecular biomarkers based on lumbar puncture and cerebrospinal fluid (CSF) analysis.
Additionally, the clinic will employ remote neuropsychiatric assessments using digital and
telephonic methods. This allows for regular contact, whilst adhering to changes in clinical
practice and national guidance due to the COVID-19 pandemic. Our overarching objectives are
to first establish the acceptability and feasibility of the remote Brain Health Clinic and
its novel clinical and biomarker assessment programme. Then secondly establish the impact of
care under the Brain Health Clinic on i) care management decisions (e.g. follow-up and
treatment planning); ii) time to etiological diagnosis of MCI (MCI-subtyping); and iii) time
to diagnosis of dementia and severity of dementia at the time of diagnosis.
Description:
The Brain Health Clinic is designed to complement the existing memory clinic pathway and will
complete the patient journey of patients with mild cognitive impairment (MCI). All patients
referred to the new brain health clinic will be assessed using a standardized battery of
clinical instruments by qualified clinicians, as per South London and Maudsley (SlaM) memory
clinic pathway. In line with clinical practice changes and national guidance due to the
COVID-19 pandemic, these assessments will be completed remotely via telephone and/or video
conferencing and online.
Consenting participants will be invited to complete the Brain health Clinic's initial
assessments. All assessments will be completed remotely. Assessments will include cognitive
assessments such as Telephone Interview for Cognitive Status Modified version 39 (TICS-M
v39), the Clinical Dementia Rating Scale Sum of Boxes (CDR-SoB) for telephone consultations,
Computerised Integrated Cognitive Assessment (ICA-comp). The Hospital Anxiety and Depression
(HADS) will be used to assess the symptoms of anxiety and depression. For the information
from participants' carers/study partners, the following questionnaires will used: Amsterdam
Instrumental Activities of Daily Living Questionnaire (A-IADL-Q), Informant Questionnaire on
Cognitive Decline in the Elderly (IQCODE); Adult Carer Quality of Life Questionnaire (AC-QoL)
and Neuropsychiatric Inventory-Questionnaire (NPI-Q). Assessment battery can be completed in
more than one session as required. Participants will be given the opportunity to complete
self-assessments such as HADS in their own time, prior to the first assessment session.
Participants will be reviewed in the clinic at baseline, 6 and 12 months. A biomarker program
consisting of lumbar puncture with cerebral spinal fluid (CSF) analysis following
international guidelines (Engelborghs et al., 2017) saliva sampling, and electroencephalogram
EEG will be applied to every consenting participant. This will be completed within two months
of baseline assessment. A safety questionnaire for lumbar puncture will be administered to
ensure eligibility for the procedure. The lumbar puncture facilities will be located in the
BRC Clinical Research Facility. The CSF samples collected from the lumbar puncture will be
shipped to Affinity Biomarker Labs where the analysis will be conducted using a Cobas® 6000
analyser for three assays: Elecsys® β-Amyloid(1-42) CSF, Elecsys® Phospho-Tau (181P) CSF,
Elecsys® Total -Tau CSF. Consented samples for future studies will undergo centrifugation,
transfer to new tubes, aliquoting into cryovials, and storage at -80 degrees Fahrenheit.
Saliva samples will be analysed by Cytox Group Limited, who will employ a polygenic risk
scoring algorithm, genoSCORE™-LAB, to identify those at the highest genetic risk of cognitive
decline and Alzheimer's disease using genetic data from the saliva sample (Daunt P et al.
2020). EEG will also be offered as an optional investigation to help support the diagnostic
process. The EEG will be acquired by a trained researcher or neurophysiologist.
The consented participants will also be seen by a phlebotomy trained study researcher who
will take blood plasma samples and store them at -80 degrees Fahrenheit.
As per clinic guidance, participants with negative CSF biomarker results (indicating that
their MCI is unlikely to progress to dementia) will be discharged from the brain health
clinic back to their General Practitioners (GP) and so will not complete the 6- and 12-month
assessments. They will however complete all appropriate feedback questionnaires and a
sub-sample will be invited to participate in a semi-structured interview to further explore
their experiences of the remote brain health clinic. The interview will be conducted remotely
(by telephone/video conferencing). Questionnaires will be administered to participants
concerning the feasibility and acceptability of i) the brain health clinic itself and; ii)
the following brain health clinic procedures: lumbar puncture, saliva sampling, EEG ICA-comp
assessment and CDR-SoB assessment. Additionally, carers/study partners will be asked to
complete a questionnaire concerning their views on the acceptability and feasibility of the
brain health clinic. The time from the first assessment until the final diagnosis will be
recorded, as well as diagnostic confidence and the plan for future monitoring, outlining the
determinants for continued monitoring vs discharge to GP. A subsample of 12 participants will
be invited to participate in a semi-structured interview to further explore their experiences
of the remote brain health clinic. The interview will be conducted remotely (by
telephone/video conferencing). The interviews will be audio recorded with participants'
consent and will be transcribed. Thematic analysis will be completed, supported by Nvivo
software (Qsr International, 2012). Magnetic resonance imaging (MRI)data obtained as part of
the memory service or Brain Health Clinic pathway will be analysed in order to establish the
predictive validity of BrainageR software and automated volumetric measures in reference to a
normative population. Novel AI and machine learning tools will also be applied to MRI scans
alongside existing biomarkers. No MRI scans will be carried out as part of this study.
Historical MRI scans will be retrospectively analysed. Historical data on patients receiving
MCI and dementia diagnoses will be obtained from the South London and Maudsley NHS Foundation
Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS)
resource. The CRIS system allows research access to the anonymized electronic health record
of one of Europe's specialist dementia care provider and currently data are available for
20,000 patients with dementia and more than 3,000 patients with MCI.
The data source has been enhanced through more than 100 natural language processing
algorithms, facilitating the extraction of in-depth data from free text, including the degree
of cognitive impairment at MCI and dementia diagnosis (Couch et al., 2021). This source will
be utilized to identify patients referred to SLAM memory clinics who have been diagnosed with
MCI (approximately 10%). The objectives are to determine 1) the time from discharge from the
memory clinic with MCI diagnosis to a new referral and dementia diagnosis, and 2) the
severity of dementia at the time of diagnosis.
A sub-study involving a programme of cognitive training games will be offered to a maximum
subset of 30 participants. The games target episodic memory, semantic and spatial abilities,
and working memory. Participants will train 5 days per week for 10 weeks. Each training
session lasts 24 min, i.e., participants will play 3 games per session each for 8 min.
The Quality assurance The monitoring of this trial to ensure compliance with Good Clinical
Practice and scientific integrity will be managed by the study team. The research team will
have quarterly meetings to monitor the conduct of the trail. A proportion of research
projects undertaken within the Institute of Psychiatry, Psychology and Neuroscience, King's
College London are selected at random and subjected to internal audit each year. It is
anticipated that no further monitoring or auditing will be necessary; however, the Chief
Investigator will be available to provide support with any situations that arise which have
not been accounted for.
Data Management and Monitoring
An electronic Case Report Form (CRF) will be used which will be stored in a password
protected database which is stored on a password protected encrypted secure network. Access
to this document will be restricted to the Chief Investigator and clinical researchers. Study
progress and all other aspects of data monitoring will be completed by the Chief Investigator
and research team. Quarterly meetings will be held to facilitate this.
Statistical analysis:
The statistical analysis will mainly consist of descriptive analyses such as mean or median
of scale scores with diversity measures (Standard Deviation or Interquartile Range) as
appropriate) or proportions with Confidence Interval. Given the cross-sectional nature of the
study, significant drop-out is not anticipated; however, a 10% drop-out rate will be factored
into the analysis. An interim analysis is scheduled for completion at 12 months.
Feedback questionnaires: Acceptability of the brain health clinic and its procedures will be
assessed from the perspective of participants via a series of short questionnaires that
include both 5-point Likert scales and open-ended questions. The likert scales will contain
ordinal variables therefore nonparametric methods will be used to analyse the data collected;
the central tendency will be summarised by median or the mode calculations and dispersion
summarised by the range across quartiles. The qualitative information obtained by the
open-ended questions will be manually coded and analysed by thematic analysis; the software
package NVivo will be utilised to support with this. All coding and themes will be checked by
a second researcher to ensure that no aspect of the data has been overrepresented. Brain
health clinic procedures will be considered acceptable if 70% of participants rate each
aspect of acceptability explored as satisfactory or above. Study partners will also complete
a questionnaire concerning acceptability, feasibility and clinical value of the brain health
clinic. The questionnaire will be analysed utilising the same methods as the participant's
questionnaires. Participant semi-structured interviews: Interviews will be audio recorded
with participants consent and the results transcribed. An inductive thematic analysis will be
completed, supported by Nvivo software (Qsr International, 2012). Braun and Clarke's six
phase method for conducting a thematic analysis will be followed (Braun & Clarke,
2006). Themes across the dataset will be checked by a researcher with qualitative experience
who is independent of the initial analysis to ensure that no aspect of the data has been
under or overrepresented. Themes will be reported to inform any amendments or improvements to
the brain health clinic.
Lab analysis: CSF - The following Assay system will be used to analyse CSF:
ElectroChemiLuminescence Immunoassay Instrument: Cobas® 6000 analyzer series. The Assays are:
Elecsys® β-Amyloid(1-42) CSF, Elecsys® Phospho-Tau (181P) CSF &
Elecsys® Total -Tau CSF. Saliva - Samples will be analysed by Cytox Group Limited, who will
employ a polygenic risk score algorithm, genoSCORE™-LAB, to identify those at highest genetic
risk of cognitive decline and Alzheimer's disease using genetic data from the saliva sample.
genoSCORE-LAB is a genetic test, that analyses patient genotypes generated from an array of
114,000 single nucleotide polymorphisms - common genetic variations - that are associated
with, or protective against, the risk of developing Alzheimer's disease. Blood plasma - Blood
samples will be immediately centrifuged. Plasma will be extracted from this sample and stored
for future diagnostic dementia research studies (subject to ethical review). Sub-study data
analysis: Data will be analysed using frequentist and Bayesian analysis methods. Variables of
interest are the maximum level reached and learning slope in each game, reaction times,
number of correct answers, and omission/commission errors.
