European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study (LCS)

Alzheimer's Dementia Clinical Trial

— EPAD-LCS  

Official title:

European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study (LCS)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02804789
• Other study ID #: EPAD-UoE-001
• Status: Terminated
• Start date: May 2016
• Est. completion date: March 13, 2020

Study information

• Verified date: March 2020
• Source: University of Edinburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Brain changes associated with Alzheimer's disease may precede symptoms of Alzheimer's Dementia by over 20 years. The Investigators hope to be able to identify Alzheimer's disease at its very earliest stages when in theory treatments are most likely to be successful in preventing further spread of the disease in the brain and causing dementia. The aim of EPAD programme is to develop new treatments more quickly to prevent Alzheimer's dementia. A major component of the EPAD programme is the EPAD Longitudinal Cohort Study which can provide subjects for the EPAD trial as well as data to improve understanding of disease before dementia develops.

The Investigators will approach a broad range of people over the age of 50 who have previously taken part in various research studies and consented to being recontacted for further research. Participants will be asked questions to assess their memory and other cognitive function. The participants will also undertake a brain scan, provide a sample of spinal fluid, blood, urine and saliva to look at markers in these bodily fluids that may change in Alzheimer's disease. The Investigators will then follow these participants until December 2019 repeating these tests annually. This will be called the EPAD Longitudinal Cohort Study (EPAD LCS). The main reasons for EPAD developing a cohort are to help the Investigators understand more about what happens to people before dementia develops, and to help recruit people more quickly into the EPAD trials of new medications or other interventions expected to prevent dementia.

People in the EPAD LCS may be invited to take part in the EPAD Proof of Concept prevention studies to see if interventions can modify the probability of developing dementia or cognitive problems (this will be subject to separate ethics approval and consent). Together EPAD LCS and EPAD PoC make up the full EPAD Programme.

Description:

The EPAD project has been established to overcome the major hurdles hampering drug development for secondary prevention of AD dementia, by conducting the EPAD LCS (fed mainly from existing Parent Cohorts (PC) across Europe) in alignment with the adaptive design EPAD PoC trial. Both EPAD LCS and EPAD PoC trial will be run in an exclusive network of highly selected, expert Trial Delivery Centres (TDC) that will be selected on the basis of strictly applied criteria to ensure the highest possible data quality, successful recruitment and adherence to the EPAD principles.

While interventions must start early in the course of AD, accurate disease models covering the entire course of AD before dementia onset are lacking. Estimating with reasonable confidence an individual's overall probability of developing AD dementia over a defined time period must take into account multiple dimensions simultaneously (e.g. cognition, biomarkers, traditional risk factors - genetic and environmental). This will allow any given individual to be placed somewhere on a probability spectrum from negligible probability to high probability. Because individuals with similar overall probability may have very different contributions from various components in each dimension, flexible algorithms are needed instead of simple cut-offs to identify a probability-spectrum population adequate for both disease modelling and for providing a sufficient number of potential trial participants (especially in adaptive trials with multiple arms testing drugs with different mechanisms of action).

EPAD LCS is designed to address the dual need for development of accurate longitudinal models for AD covering the entire disease course, and development of adequate infrastructure for facilitating identification of research participants and clinical trial recruitment. EPAD LCS will have a probability-spectrum population selected mostly from already existing PCs across Europe to facilitate fast recruitment. Different types of PCs will be considered (e.g. memory clinic-based, population-based). Due to the variety of PCs, some EPAD LCS research participants will be e.g. memory clinic patients without dementia, while others will be e.g. participants without dementia from the general population. The variety of PC settings will ensure that the EPAD LCS probability-spectrum population can cover the entire continuum of probability for AD dementia development. Regular EPAD LCS follow-up with clinical, cognitive and biomarker assessments will provide a well-phenotyped probability-spectrum population, generating high-quality data for updating disease models, for easier identification of individuals suitable for trial inclusion, and for use as trial run-in data and reference for evaluating intervention efficacy.

The flow of research participants from the population at large to the trial is divided into the following stages: firstly, EPAD will engage existing PCs from across Europe who may have eligible research participants for the EPAD LCS. The next step is drawing research participants from the PCs into the EPAD LCS to maintain a suitable population of approximately 6,000 research participants. Recruitment will be complemented with research participants who are recruited from a clinical setting by their referring clinician. To enable access to the EPAD LCS for these potential participants, the referring clinician will check if they match the flexible algorithm. Finally, research participants in the EPAD LCS who fulfil trial inclusion criteria (approximately 1,500 research participants), will be invited to enter the EPAD PoC (PoC) trial for evaluation of treatment for secondary prevention of AD dementia. This trial is a standing, adaptive, PoC trial that could involve multiple arms running concurrently. Successful graduation through PoC into phase 3 confirmatory trials of single or combinatorial interventions will be based on success against an intermediary, target specific biomarker and then success against a cognitive measure.

Once recruitment is completed, at any given time there should be approx. 6,000 research participants in the EPAD LCS and approx. 1,500 in the EPAD PoC, hence the need to replenish each from PCs as participants are lost through attrition. EPAD LCS will initially run until the end of December 2019, and extension of consent will be sought after 4 years.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2095
• Est. completion date: March 13, 2020
• Est. primary completion date: March 13, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

1. At least 50 Years of Age

2. Characterisation of cognitive, biomarker and risk factors (genetic, environmental) status of research participants based on data collected at the EPAD screening/baseline visit, so that decisions on selection/deselection can be made with reference to the dual needs of having sufficient heterogeneity across the entire probability-spectrum population for disease-modelling work, and suitable research participants for the EPAD PoC trial (Balancing Committee decision)

3. Able to read and write with a minimum of 7 years of formal education.

4. Willing in principle to participate in the EPAD Proof of Concept Trials (with additional consent).

5. Have a study partner or can identify someone willing to be a study partner. The primary role of the study partner will be as informant. They will also receive oral and written information about the EPAD LCS, and will sign an Informed Consent Form (ICF).

Exclusion Criteria:

1. Individuals who fulfill diagnostic criteria for any type of dementia.

2. Clinical Dementia Rating >=1

3. Known carriers of a Presenilin (PSEN) 1, PSEN 2 or Amyloid Precursor Protein (APP) mutation associated with Autosomal Dominant Alzheimer's dementia or any other neurodegenerative disease.

4. Presence of any neurological, psychiatric or medical conditions associated with a long-term risk of significant cognitive impairment or dementia including but not limited to pre- manifest Huntington's disease, multiple sclerosis, Parkinson's disease, Down syndrome, active alcohol/drug abuse; or major psychiatric disorders including current major depressive disorder, schizophrenia, schizoaffective or bipolar disorder.

5. Cancer or history of cancer in the last 5 years (excluding cutaneous basal or squamous cell cancer resolved by excision).

6. Any current medical conditions that are clinically significant and might make participation in an investigational trial unsafe, e.g., uncontrolled or unstable disease of any major organ system; history within the last 6 months of any acute illness of a major organ system requiring emergency care or hospitalization, including revascularization procedures; severe renal or hepatic failure; unstable or poorly controlled DM, hypertension, or heart failure; malignant neoplasms within the last 3 years (expect for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participants); any clinically relevant abnormalities in blood parameters included in local TDC routine assessments; severe loss of vision, hearing or communicative ability; or any conditions preventing co-operation or completion of the required assessments in the trial, as judged by the investigator.

7. Contraindications for MRI/Positron emission tomography (PET) Scan.

8. Contraindications for Lumbar Puncture.

9. Any evidence of intracranial pathology which, in the opinion of the Investigator, may affect cognition including but not limited to brain tumours (benign or malignant), aneurysm or arteriovenous malformations, territorial stroke (excluding smaller watershed strokes), recent haemorrhage (parenchymal or subdural), or obstructive hydrocephalus. Research participants with a MRI scan demonstrating markers of small vessel disease (e.g. white matter changes or lacunar infarcts) judged to be clinically insignificant, or microbleeds are allowed.

10. Participation in a clinical trial of an Investigational Product (CTIMP) in the last 30 days (continued participation in the parent cohort is expected). Participation in a non-CTIMP is not an exclusion criterion.

Diminished decision-making capacity/ not capable of consenting at Visit 1 or Visit 2. If at a subsequent annual EPAD LCS visit health professionals suspect diminished consent capacity according to local TDC routine procedures, a formal assessment of the research participant's capacity to consent will be conducted. The participant will be offered the opportunity to continue in the EPAD LCS under suitable local regulations regarding capacitous participants who have consented to enter a longitudinal study who subsequently loose capacity. Capacity will be assessed at each study visit using the correct legal framework.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Dementia
• Dementia

Locations

Country	Name	City	State
Belgium	Cliniques Universitaires Saint-Luc ASBL, Neurology Department	Brussels
Belgium	UZ Leuven, Campus Gasthuisberg	Leuven
France	CMRR du CHRU de Lille Hôpital Roger Salengro	Lille
France	CHU Gui de Chauliac Département de Neurologie	Montpellier
France	Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal	Paris
France	Hôpital Universitaire de la Pitié Salpêtrière	Paris
France	CMRR- Hôpital Laënnec Nord - CIC Neurologie / CHU de Nantes	Saint-Herblain
France	Toulouse University Hospital / Gérontopôle-Research Clinical Center	Toulouse
Greece	National and Kapodistran, University of Athens, 1st Department of Neurology, Aeginition Hospital	Athens
Italy	IRCCS San Giovanni di Dio - Fatebenefratelli	Brescia
Italy	Univerita di Perugia, Centro Disturbi della Memoria, Clinica Neurologica	Perugia	Loc. S Andrea Delle Fratte
Netherlands	VUmc Alzheimer Center and Alzheimer Research Center	Amsterdam	Noord Holland
Spain	BarcelonaBeta Brain Research Centre	Barcelona
Spain	Fundacion ACE, Institut Catala de Neurocienies Aplicades	Barcelona
Spain	Fundacion CITA-alzheimer Fundazioa, Center for Research and Advanced Therapies	San Sebastián
Spain	Unidade Deterioro Cognitivo, Servicio de Neurologia, Hospital Universitario	Santander	Cantabria
Sweden	Neuropsychiatric Research Unit, Sahlgrenska University Hoospital	Gothenburg	Vastra Gotaland
Sweden	Karolinska Institutet	Stockholm
Switzerland	Hôpitaux Universitaires de Genève - HUG	Geneva
Switzerland	Centre Leenaards de la memoire- CHUV, Department of Neurosciences cliniques	Lausanne
United Kingdom	NHS Grampian	Aberdeen
United Kingdom	North Bristol NHS Trust	Bristol
United Kingdom	University of Cambridge; Department of Clinical Neurosciences	Cambridge
United Kingdom	Monklands University Hospital	Cumbernauld	Lanarkshire
United Kingdom	NHS Tayside	Dundee
United Kingdom	University of Edinburgh, Centre for Dementia Prevention	Edinburgh	Midlothian
United Kingdom	Glasgow Clinical Research Facility; NHS Greater Glasgow and Clyde	Glasgow
United Kingdom	West London Mental Health NHS Trust	London
United Kingdom	Greater Manchester Clinical Research Network	Manchester
United Kingdom	University of Oxford, Department of Psychiatry	Oxford

Sponsors (2)

Lead Sponsor	Collaborator
University of Edinburgh	Innovative Medicines Initiative

Countries where clinical trial is conducted

Belgium,  France,  Greece,  Italy,  Netherlands,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in exploratory Cognitive Tests score: Allocentric space, over time, units on a scale.	Four Mountains Test	Measured at Baseline, 6 months, year 1, year 2, year 3
Other	Change in exploratory Cognitive Tests score: Egocentric space, over time, units on a scale.	Supermarket Trolley Virtual Reality Test	Measured at Baseline, 6 months, year 1, year 2, year 3
Other	Change in other secondary clinical outcome scale: Everyday functioning, total over time, units on a scale	Everyday functioning: Amsterdam Instrumental Activities of Daily Living Questionnaire.	Measured at Baseline, 6 months, year 1, year 2, year 3
Other	Changes in neuro-imaging assessments over time, Multi-regional Structural and Functional MRI & Functional regional and network measures, units on a scale	Cortical thickness, deep grey matter (GM) volumes, Fractional anisotropy (FA) of temporal lobe, diffusion kurtosis (multi b-value DTI), network alterations, Global & parietal Cerebral Blood Flow (CBF), Changes within the default-mode network (DMN) & relation with hippocampal activity (rsfMRI), Bolus arrival time (multi-delay ASL), Network analysis (rsfMRI)	Measured at Baseline, year 1, year 2, year 3
Other	Changes in Lifestyle factors over time: Smoking	Smoking: never/past/current	Measured at Baseline, year 1, year 2, year 3
Other	Changes in Lifestyle factors over time: Alcohol Consumption	Alcohol: units/week	Measured at Baseline, year 1, year 2, year 3
Other	Changes in Lifestyle factors over time: drug abuse/misuse	Drug abuse/misuse: never/past/current	Measured at Baseline, year 1, year 2, year 3
Other	Changes in Lifestyle factors over time: diet HATICE (Healthy Aging through Internet Counselling in the Elderly), units on a scale	Diet questionnaire: HATICE (Healthy Aging through Internet Counselling in the Elderly), physical activity.	Measured at Baseline, year 1, year 2, year 3
Other	Changes in Lifestyle factors over time: physical activity frequency	Physical activity: daily, 2-3 times/week, 2-3 times/month, a few times a year, not at all	Measured at Baseline, year 1, year 2, year 3
Other	Changes in Lifestyle factors over time: Life events over time	Life events: SNAC (Swedish National study on Ageing and Care).	Measured at Baseline, year 1, year 2, year 3
Other	Changes in Lifestyle factors over time: Self-rated health and fitness	Self-rated health and fitness: Very good/good/satisfactory/relatively poor/poor	Measured at Baseline, year 1, year 2, year 3
Other	Change in Mini-Mental Satus Exam (MMSE) over time	Measure of clinical state	Measured at Baseline, year 1, year 2, year 3
Other	Change in Clinical Dementia Rating Scale (CDR) over time	Assessment of six domains, (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care), from which the global CDR score, CDR sum of notes and a CDR rating for each domain are calculated.	Measured at Baseline, year 1, year 2, year 3
Other	Change in other clinical outcome scale: Depression, total over time, units on a scale	Depression: Geriatric Depression Scale	Measured at Baseline, year 1, year 2, year 3
Other	Change in other clinical outcome scale: Anxiety, total over time, units on a scale	Anxiety: State-Trait Anxiety Inventory	Measured at Baseline, year 1, year 2, year 3
Other	Change in other clinical outcome scale: Sleep, total over time, units on a scale	Sleep: Pittsburgh Sleep Quality Index	Measured at Baseline, year 1, year 2, year 3
Other	Other neuro-imaging measure: Vascular Burden, over time, units on a scale	Vascular Burden: Counts of White Matter Lesions, infarcts, laciness, micro bleeds and superficial siderosis.	Measured at Baseline, year 1, year 2, year 3
Other	Other clinical outcome: Dementia Diagnosed by a Participant's Physician	Type of Dementia and Date of Diagnosis	Measured at Baseline, year 1, year 2, year 3
Other	Genetic Assessment of apolipoprotein E (ApoE) genotype	APOE genotype determined by allele combination of e2, e3 and e4	Measured at Baseline
Other	Sociodemographic Factors (subject to local regulations	Date of Birth, Age, Ethnicity, Education, Marital Status, Handedness	Measured at Baseline
Other	Other clinical measure: Family History of AD	Family history of AD in number of family members of first degree with history compatible with AD	Measured at Baseline
Other	Other clinical measure: Medical History	Medical History: Yes/No for: Stroke, Diabetes (type 1 or 2), Hypertension, Hypercholesterolemia, Myocardial Infarction, Chronic Ischemic Heart Disease, Chronic Obstructive Pulmonary Disease, Asthma, Depression, Rheumatoid Arthritis, Any Cancer, General Anaesthesia after the age of 50 years, Head Injury assessed with the Brain Injury Screening Questionnaire (BISQ), Mild Cognitive Impairment, Other Conditions (Listed as free text)	Measured at Baseline, year 1, year 2, year 3
Other	Other clinical measure: Current Medication	Drug, treatment duration (<1year / 1-5years / >5years)	Measured at Baseline, year 1, year 2, year 3
Other	Other clinical measure: Body Height	Body Height: without shoes, measured to the nearest cm	Measured at Baseline
Other	Other clinical measure: Body Weight	Body Weight: measured to the nearest 0.1kg	Measured at Baseline, year 1, year 2, year 3
Other	Other clinical measure: Hip-waist Circumference	Hip-waist Circumference: measured to nearest 0.1cm	Measured at Baseline, year 1, year 2, year 3
Primary	Change in RBANS Composite score over time, units on a scale.	Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Composite score combining: List Learning & Story Memory; Figure Recall; Figure Copy & Line Orientation; Picture Naming; Semantic Fluency, Digit Span, Coding.	Measured at Baseline, 6 months, year 1, year 2, year 3.
Secondary	Change in other Secondary Cognitive Tests score: Working Memory, over time, units on a scale.	Dot Counting test	Measured at Baseline, 6 months, year 1, year 2, year 3
Secondary	Change in other Secondary Cognitive Tests score: Choice Reaction Time and Set Shifting, over time, units on a scale.	Flanker test	Measured at Baseline, 6 months, year 1, year 2, year 3
Secondary	Change in other Secondary Cognitive Tests score: Paired Associate Learning, over time, units on a scale.	Favourites	Measured at Baseline, 6 months, year 1, year 2, year 3
Secondary	Change in cerebrospinal fluid (CSF) AD biomarkers over time	Aß, t-tau and p-tau levels in pg/ml	Measured at Baseline, year 1, year 2, year 3
Secondary	Changes in neuro-imaging assessment of hippocampal and whole brain volume, over time	Hippocampal and whole brain volume, cm3	Measured at Baseline, year 1, year 2, year 3