The Swedish BioFINDER 2 Study (BioFINDER2)
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|ClinicalTrials.gov Identifier: NCT03174938|
Recruitment Status : Recruiting
First Posted : June 5, 2017
Last Update Posted : April 17, 2018
|First Submitted Date ICMJE||May 28, 2017|
|First Posted Date ICMJE||June 5, 2017|
|Last Update Posted Date||April 17, 2018|
|Actual Study Start Date ICMJE||May 15, 2017|
|Estimated Primary Completion Date||December 31, 2028 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT03174938 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||The Swedish BioFINDER 2 Study|
|Official Title ICMJE||The Swedish BioFINDER 2 Study|
The Swedish BioFINDER 2 study is a new study that will launch in 2017 and extends the previous cohorts of BioFINDER 1 study (www.biofinder.se). BioFINDER 1 is used e.g. to characterize the role of beta-amyloid pathology in early diagnosis of Alzheimer's disease (AD) using amyloid-PET (18F-Flutemetamol) and Aβ analysis in cerebrospinal fluid samples. The BioFINDER 1 study has resulted in more than 40 publications during the last three years, many in high impact journals, and some the of the results have already had important implications for the diagnostic work-up patients with AD in the clinical routine practice.
The original BioFINDER 1 cohort started to include participants in 2008. Since then there has been a rapid development of biochemical and neuroimaging technologies which enable novel ways to the study biological processes involved in Alzheimer's disease in living people. There has also been a growing interest in the earliest stages of AD and other neurodegenerative diseases. With the advent of new tau-PET tracers there is now an opportunity to elucidate the role of tau pathology in the pathogenesis of AD and other tauopathies. The Swedish BioFINDER 2 study has been designed to complement the BioFINDER 1 study and to e.g. address issues regarding the role of tau pathology in different dementias and in preclinical stages of different dementia diseases. Further, the clinical assessments and MRI methods have been further optimized compared to BioFINDER 1.
STUDY PLAN To reach the objectives above, we include well-characterized and clinically relevant populations of patients with dementia and/or parkinsonian symptoms and healthy individuals. We apply several state of the art methodologies in order to develop new brain imaging techniques, new biomarkers in blood and CSF as well as novel methods of assessing important clinical symptoms.
COGNITIVE TESTING Attention and executive function will be assessed with the Trail Making Test A and B (TMT), Symbol Digit Modalities Test (SDMT), and A Quick Test of cognitive speed (AQT). Visuospatial ability will be measured by two subtests from the Visual Objects and Space Perception (VOSP) battery, incomplete letters and cube analysis. Memory will be assessed with the Free and Cued Selective Reminding Test (FCSRT) in cohorts A and B. It will be complemented with the 10-word delayed recall test from ADAS-cog, including a recognition part. Verbal ability will be evaluated with the animal and letter S fluency tests and the 15-item short version of the Boston Naming Test. Global cognition will be assessed with the Mini-Mental State Examination (MMSE). In cohort A and B, a computerized cognitive battery focusing on memory and attention will also be performed.
ASSESSMENTS OF SYMPTOMS, FUNCTIONAL ABILITIES AND GLOBAL FUNCTION Cognitive symptoms. All subjects will rate his or her memory and attention/executive function in relation to others of the same age according the Brief Anosognosia Scale (BAS). We have also added similar questions to cover the other cognitive domains. These questions have been validated against neuropsychological testing but there are data indicating that self-reported cognitive complaints are only valid in a lesser degree of cognitive impairment. To assess a broader range of cognitive complaints, the Subjective Cognitive Decline questionnaire (SCD-q) will be administered to the research subjects. Subjects from cohorts C, D and E will be assessed with cognitive impairment questionnaire (CIMP-QUEST; filled out by an informant).
Functional ability. This will be evaluated with the informant-based Functional Activities Questionnaire (FAQ) or the Amsterdam IADL scale, both focus on instrumental activities of daily living (IADL) known to be affected early in cognitive decline.
Global function. The global cognitive status will be evaluated using the sum of boxes score from the Clinical Dementia Rating scale (CDR) and the global deterioration scale (GDS).
Behavioral and psychological symptoms in dementia (BPSD). BPSD will be assessed by clinicians using the Neuropsychiatric Inventory - Clinician rating scale (NPI-C) developed by Jeffrey Cummings. Mood and anxiety will be further assessed with the Hospital Anxiety and Depression scale (HADS). Frontal Behavioral Inventory (FBI) will be done in FTD-related conditions.
Quality of Life (QoL). The overall health status will be rated by the subjects using the EQ-5D from Euro-QoL. In demented patients this will also be rated by an informant, spouse or close relative.
Sleep. The presence of REM sleep behavior disorder will be evaluated with a single validated composite question derived from the Mayo Sleep Questionnaire. Sleep quality is assessed with the Sleep Scale from the Medical Outcome Study (MOS).
Cognitive reserve. Premorbid cognition and cognitive reserve is approximated from the Cognitive Reserve Index questionnaire (CRI-q; subitems "Education" and "Working activity", not "Leisure time").
CEREBROSPINAL FLUID (CSF) AND BLOOD SAMPLING AND ANALYZES Lumbar CSF samples will be collected according to a standardized protocol and will follow the principles of the Alzheimer's Association Flow Chart for CSF biomarkers. In short, lumbar puncture will be done between 9-12 am. 20-30 ml of CSF will be collected in Low Binding polypropylene tubes, which are stored on ice for 5-20 min until the CSF samples will be centrifuged (2000g, +4°C, 10 min). Thereafter, the CSF will be aliquoted in ca 1 ml portions into Low Binding polypropylene tubes followed by storage at -80°C until batch analyses.
Plasma collection will be done at the same visit as the lumbar puncture. Blood will be drawn into tubes containing either EDTA (5 x 6 ml tubes) or Lithium heparin (3 x 3 ml tubes) as anticoagulant. After centrifugation (2000g, +4°C, 10 min), plasma samples will be aliquoted into polypropylene tubes and stored at -80°C pending biochemical analyses. Further, EDTA-blood (2 x 6 ml) will also be obtained for genetic DNA analyses.
MAGNETIC RESONANCE IMAGING 3 Tesla MRI (Siemens Prisma) will be done in all study cohorts. A wide variety of magnetic resonance imaging (MRI) techniques will be used to study regional brain volume (three-dimensional magnetization-prepared rapid acquisition with gradient echo (3D MPRAGE)), metabolism (MR spectroscopy (MRS)), structural and functional connectivity of different brain regions (diffusion tensor imaging (DTI) and functional MRI (fMRI)), regional blood flow (arterial spin labeling (ASL)), iron deposition (susceptibility-weighted imaging (SWI)) and the presence of small vessel disease (MPRAGE, SWI and fluid-attenuated inversion recovery (FLAIR)). The protocol will take approximately 60 min to perform. No contrast-enhancing agent will be used.
Tau PET. PET imaging of tau aggregates will be done in all the included cohorts at baseline. In the present study, Tau PET imaging will be performed using 18F-RO6958948 developed by Hoffmann-La Roche that will provide the precursor for this PET ligand. This tau PET imaging agent has been shown to accurately detect tau pathology in cases with AD when compared to controls. We will perform a 20-30 min PET scan approximately 60 min post intravenous injection of 18F-RO6958948. The impact of the investigation on clinical diagnostic accuarcy and patient care will be investigated. 18F-RO6958948 has not yet been approved for use in clinical routine practice in Sweden, and can only be used in research studies, such as the present study.
Amyloid PET. PET imaging of Aβ aggregates (including 18F-flutemetamol PET) has been approved for use in clinical routine practice in Sweden. In the present study, 18F-flutemetamol PET will be done in non-demented cases only. In the cases with dementia CSF Aβ will be enough to determine the presence or absence of brain amyloid pathology. However, in the cognitively healthy cases and in the patients with SCD or MCI we are interested in following the spread of amyloid pathology throughout the brain during the preclinical stages of AD and the spatial relationship to tau pathology. Therefore, Amyloid PET will be done according to clinical routine procedures in addition to CSF Aβ measurements in these groups. In the present study Amyloid PET will be performed using 18F-flutemetamol. GE Healthcare will provide the precursor for 18F-flutemetamol. A 20 min scan will be performed between 90-110 min post injection of 18F-flutemetamol.
DaTSCAN. DaTSCAN is often used as part of clinical routine examinations of patients with parkinsonism to confirm the diagnosis. Here DaTSCAN will be done according to clinical routine procedures in cases with PD, PDD, DLB, MSA, PSP and CBD to confirm the clinical diagnosis if it has not been done in clinical routine praxis within one year from the baseline visit.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||December 31, 2028|
|Estimated Primary Completion Date||December 31, 2028 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
COHORT A: Cognitively healthy younger individuals (40-65 years of age) INCLUSION CRITERIA
COHORT B: Cognitively healthy elderly individuals (66-100 years of age) INCLUSION CRITERIA
COHORT C: Subjective cognitive decline and mild cognitive impairment INCLUSION CRITERIA
COHORT D: Dementia due to Alzheimer's disease INCLUSION CRITERIA
COHORT E: Other dementias INCLUSION CRITERIA
|Ages ICMJE||20 Years to 100 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Listed Location Countries ICMJE||Sweden|
|Removed Location Countries|
|NCT Number ICMJE||NCT03174938|
|Other Study ID Numbers ICMJE||BioFINDER 2|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Oskar Hansson, Skane University Hospital|
|Study Sponsor ICMJE||Skane University Hospital|
|Collaborators ICMJE||Lund University|
|PRS Account||Skane University Hospital|
|Verification Date||April 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP