Clinical trial NCT02804789: European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study (LCS)
Official title: European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study (LCS)
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: Alzheimer's Dementia
Keywords: Prevention
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: Innovative Medicines Initiative
First posted: 2016-06-17
Enrollment: 2095
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Research participants will mainly be recruited from existing Parent Cohorts (PC) across Europe. PCs considered for EPAD are: active cohorts without dementia aged at least 50 years; the PC PI is willing to provide research participants for EPAD trials; with existing consent for re-contact or possibility to obtain consent to re-contact. Potential research participants will be identified based on data in the PC, using a flexible search algorithm adapted to the types of data available in each PC. Recruitment will be complemented with research participants who are recruited from a clinical setting by their referring clinician. In case an individual or their referring clinician contacts a TDC, the referring clinician will check the flexible algorithm to confirm their suitability.

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in RBANS Composite score over time, units on a scale.
timeFrame: Measured at Baseline, 6 months, year 1, year 2, year 3.
Secondary outcomes:
measure: Change in other Secondary Cognitive Tests score: Working Memory, over time, units on a scale.
timeFrame: Measured at Baseline, 6 months, year 1, year 2, year 3
measure: Change in other Secondary Cognitive Tests score: Choice Reaction Time and Set Shifting, over time, units on a scale.
timeFrame: Measured at Baseline, 6 months, year 1, year 2, year 3
measure: Change in other Secondary Cognitive Tests score: Paired Associate Learning, over time, units on a scale.
timeFrame: Measured at Baseline, 6 months, year 1, year 2, year 3
measure: Change in cerebrospinal fluid (CSF) AD biomarkers over time
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in neuro-imaging assessment of hippocampal and whole brain volume, over time
timeFrame: Measured at Baseline, year 1, year 2, year 3
Other outcomes:
measure: Change in exploratory Cognitive Tests score: Allocentric space, over time, units on a scale.
timeFrame: Measured at Baseline, 6 months, year 1, year 2, year 3
measure: Change in exploratory Cognitive Tests score: Egocentric space, over time, units on a scale.
timeFrame: Measured at Baseline, 6 months, year 1, year 2, year 3
measure: Change in other secondary clinical outcome scale: Everyday functioning, total over time, units on a scale
timeFrame: Measured at Baseline, 6 months, year 1, year 2, year 3
measure: Changes in neuro-imaging assessments over time, Multi-regional Structural and Functional MRI & Functional regional and network measures, units on a scale
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in Lifestyle factors over time: Smoking
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in Lifestyle factors over time: Alcohol Consumption
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in Lifestyle factors over time: drug abuse/misuse
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in Lifestyle factors over time: diet HATICE (Healthy Aging through Internet Counselling in the Elderly), units on a scale
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in Lifestyle factors over time: physical activity frequency
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in Lifestyle factors over time: Life events over time
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Changes in Lifestyle factors over time: Self-rated health and fitness
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Change in Mini-Mental Satus Exam (MMSE) over time
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Change in Clinical Dementia Rating Scale (CDR) over time
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Change in other clinical outcome scale: Depression, total over time, units on a scale
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Change in other clinical outcome scale: Anxiety, total over time, units on a scale
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Change in other clinical outcome scale: Sleep, total over time, units on a scale
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Other neuro-imaging measure: Vascular Burden, over time, units on a scale
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Other clinical outcome: Dementia Diagnosed by a Participant's Physician
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Genetic Assessment of apolipoprotein E (ApoE) genotype
timeFrame: Measured at Baseline
measure: Sociodemographic Factors (subject to local regulations
timeFrame: Measured at Baseline
measure: Other clinical measure: Family History of AD
timeFrame: Measured at Baseline
measure: Other clinical measure: Medical History
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Other clinical measure: Current Medication
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Other clinical measure: Body Height
timeFrame: Measured at Baseline
measure: Other clinical measure: Body Weight
timeFrame: Measured at Baseline, year 1, year 2, year 3
measure: Other clinical measure: Hip-waist Circumference
timeFrame: Measured at Baseline, year 1, year 2, year 3
Locations:
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc ASBL, Neurology Department
city: Leuven
country: Belgium
facility: UZ Leuven, Campus Gasthuisberg
city: Lille
country: France
facility: CMRR du CHRU de Lille Hôpital Roger Salengro
city: Montpellier
country: France
facility: CHU Gui de Chauliac Département de Neurologie
city: Paris
country: France
facility: Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal
city: Paris
country: France
facility: Hôpital Universitaire de la Pitié Salpêtrière
city: Saint-Herblain
country: France
facility: CMRR- Hôpital Laënnec Nord - CIC Neurologie / CHU de Nantes
city: Toulouse
country: France
facility: Toulouse University Hospital / Gérontopôle-Research Clinical Center
city: Athens
country: Greece
facility: National and Kapodistran, University of Athens, 1st Department of Neurology, Aeginition Hospital
city: Perugia
country: Italy
facility: Univerita di Perugia, Centro Disturbi della Memoria, Clinica Neurologica
state: Loc. S Andrea Delle Fratte
city: Brescia
country: Italy
facility: IRCCS San Giovanni di Dio - Fatebenefratelli
city: Amsterdam
country: Netherlands
facility: VUmc Alzheimer Center and Alzheimer Research Center
state: Noord Holland
city: Santander
country: Spain
facility: Unidade Deterioro Cognitivo, Servicio de Neurologia, Hospital Universitario
state: Cantabria
city: Barcelona
country: Spain
facility: BarcelonaBeta Brain Research Centre
city: Barcelona
country: Spain
facility: Fundacion ACE, Institut Catala de Neurocienies Aplicades
city: San Sebastián
country: Spain
facility: Fundacion CITA-alzheimer Fundazioa, Center for Research and Advanced Therapies
city: Gothenburg
country: Sweden
facility: Neuropsychiatric Research Unit, Sahlgrenska University Hoospital
state: Vastra Gotaland
city: Stockholm
country: Sweden
facility: Karolinska Institutet
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève - HUG
city: Lausanne
country: Switzerland
facility: Centre Leenaards de la memoire- CHUV, Department of Neurosciences cliniques
city: Cumbernauld
country: United Kingdom
facility: Monklands University Hospital
state: Lanarkshire
city: Edinburgh
country: United Kingdom
facility: University of Edinburgh, Centre for Dementia Prevention
state: Midlothian
city: Aberdeen
country: United Kingdom
facility: NHS Grampian
city: Bristol
country: United Kingdom
facility: North Bristol NHS Trust
city: Cambridge
country: United Kingdom
facility: University of Cambridge; Department of Clinical Neurosciences
city: Dundee
country: United Kingdom
facility: NHS Tayside
city: Glasgow
country: United Kingdom
facility: Glasgow Clinical Research Facility; NHS Greater Glasgow and Clyde
city: London
country: United Kingdom
facility: West London Mental Health NHS Trust
city: Manchester
country: United Kingdom
facility: Greater Manchester Clinical Research Network
city: Oxford
country: United Kingdom
facility: University of Oxford, Department of Psychiatry
Study officials:
affiliation: University of Edinburgh
name: Craig Ritchie
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vermunt L, Muniz-Terrera G, Ter Meulen L, Veal C, Blennow K, Campbell A, Carrie I, Delrieu J, Fauria K, Huesa Rodriguez G, Ingala S, Jenkins N, Molinuevo JL, Ousset PJ, Porteous D, Prins ND, Solomon A, Tom BD, Zetterberg H, Zwan M, Ritchie CW, Scheltens P, Luscan G, Brookes AJ, Visser PJ; IMI-EPAD collaborators. Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings. Alzheimers Res Ther. 2020 Jan 6;12(1):8. doi: 10.1186/s13195-019-0576-y.
citation: Solomon A, Kivipelto M, Molinuevo JL, Tom B, Ritchie CW; EPAD Consortium. European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study protocol. BMJ Open. 2019 Feb 19;8(12):e021017. doi: 10.1136/bmjopen-2017-021017.