A Non-drug Methods Study in Participants With Alzheimer's Disease

Tracking Information
First Submitted Date ICMJE	October 12, 2011
First Posted Date ICMJE	October 25, 2011
Results First Submitted Date	December 21, 2016
Results First Posted Date	February 13, 2017
Last Update Posted Date	February 13, 2017
Study Start Date ICMJE	December 2011
Actual Primary Completion Date	December 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: December 21, 2016)	Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) - Brain Boundary Shift Integral (BBSI) and Ventricular Boundary Shift Integral (VBSI) [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]BBSI and VBSI were calculated based on the voxel-wise difference between co-registered baseline and follow-up scans. Least squares (LS) mean value was controlled for baseline value and visit.; Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) - Hippocampus Volume Average Percent (%) Change (Chg) [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]Automated hippocampal volumetry was performed using the Learning Embeddings for Atlas Propagation (LEAP) algorithm. LS mean value was controlled for baseline value and visit.; Change From Baseline in Resting State Functional Magnetic Resonance Imaging (rsfMRI) [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]Distributed functional connectivity in selected brain networks was calculated from the rsfMRI scans. Values were derived from low-frequency (0.01-0.1 hertz [Hz]) temporal correlations between different regions over the approximately 6-minute rsfMRI time series scan. Distributed measures of functional connectivity were calculated as the mean Pearson correlation between the average low-frequency time courses in predefined sets of regions of interest (ROI) within the default mode network (DMN), salience network (SN) and sensorimotor networks (SMN). LS mean value was controlled for baseline value and visit.; Change From Baseline in Diffusion Tensor Imaging (DTI) Using Fractional Anisotropy (FA) [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]DTI scans used FA to measure water diffusion directionality in selected white matter (WM) tracts. ROI: Corpus collosum (CC), internal capsule (IC), posterior cingulum bundle (PCB), temporal white matter (TWM), uncinate fasciculus (UF), superior longitudinal fasciculus (SLF). LS mean value was controlled for baseline value and visit.; Change From Baseline in Diffusion Tensor Imaging (DTI) Using Mean Diffusivity (MD) [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]DTI scans used MD to measure the overall magnitude of water diffusion in selected WM tracts, without specific regard to directionality. ROI: CC, IC, PCB, TWM, UF, SLF. LS mean value was controlled for baseline value and visit.
Original Primary Outcome Measures ICMJE; (submitted: October 24, 2011)	Change from baseline up to 9 months in volumetric magnetic resonance imaging (vMRI) [ Time Frame: Time zero equals baseline, up to 9 months ]; Change from baseline up to 9 months in resting state functional magnetic resonance imaging (rsfMRI) [ Time Frame: Time zero equals baseline, up to 9 months ]; Change from baseline up to 9 months in diffusion tensor imaging (DTI) [ Time Frame: Time zero equals baseline, up to 9 months ]
Change History	Complete list of historical versions of study NCT01459016 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: December 21, 2016)	Baseline Brain Amyloid Load Using Positron Emission Tomography (PET) and Florbetapir [ Time Frame: Baseline ]Composite summary standardized uptake value ratio (SUVR) normalized to mean whole cerebellum. Regions used for composite summary were posterior cingulum, anterior cingulum, parietal cortex, lateral temporal cortex and frontal cortex.; Number of Participants With Vasogenic Edema on MRI Scan at a Field Strength of 3 Tesla (3T) [ Time Frame: Baseline ]; Number of Participants With Microhemorrhage on MRI Scan at a Field Strength of 3T [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]; Change From Baseline in the Mini Mental State Examination (MMSE) Total Score [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]The MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures). Total score ranges from 0 to 30; lower score indicates greater disease severity. LS mean value was controlled for baseline value and visit.; Change From Baseline in the Alzheimer's Disease Assessment Scale Extended Cognitive Subscale (ADAS-Cog14) Total Score [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]The ADAS-Cog14 is the ADAS-Cog11 augmented with delayed free recall, digit cancellation, and maze completion measures. A score of 0 to 10 for delayed free recall and a conversion code of 0 to 5 for digit cancellation and maze completion provide total score ranges for this extended ADAS-Cog14 of 0 to 90. Higher scores indicate greater disease severity. LS mean value was controlled for baseline value and visit.; Change From Baseline in the Clinical Dementia Rating (CDR) Total Score [ Time Frame: Baseline, 6 Mos; Baseline, 12 Mos ]The CDR is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; Total score ranges from 0 to 18. Higher scores indicate greater disease severity. LS mean value was controlled for baseline value and visit.
Original Secondary Outcome Measures ICMJE; (submitted: October 24, 2011)	Baseline Brain Amyloid Load Using Positron Emission Tomography (PET) and Florbetapir [ Time Frame: Time zero equals baseline ]; Number of participants with vasogenic edema on MRI scan at a field strength of 3T [ Time Frame: Time zero equals baseline, up to 9 months ]; Number of Participants With Microhemorrhage on MRI Scan at a Field Strength of 3T [ Time Frame: Time zero equals baseline, up to 9 months ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	A Non-drug Methods Study in Participants With Alzheimer's Disease
Official Title ICMJE	An Exploratory Study of Brain Imaging Biomarkers in Patients With Alzheimer's Pathology Receiving Standard of Care
Brief Summary	This study will investigate the volume, function and composition of the brain using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning technology in participants with memory complaints or early signs of Alzheimer's pathology.
Detailed Description	After trial initiation, the protocol was amended to extend the single observation time period (6 to 9 months) to two time points (6 and 12 months), and to focus on prodromal AD (Mini-Mental State Examination [MMSE] 23-30 inclusive, Free and Cued Selective Reminding Test [FCSRT] less than or equal to [≤] 24 for free recall or ≤ 44 for total recall). Participants enrolled under the original protocol were allowed to continue in the extension study if they so desired, and if they met the new inclusion criteria. Due to the number of participants that completed the extended trial, no sub-group analysis was performed based on which amendment the participants entered under.
Study Type ICMJE	Interventional
Study Phase	Phase 1
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
Condition ICMJE	Alzheimer's Disease
Intervention ICMJE	Other: PET scan using florbetapir A single intravenous microdose of 260 MBq (7 mCi) 18F-AV-45 (florbetapir F 18) will be administered. Other Name: AV-45; Other: MRI Scan Three different measurements will be taken: volumetric MRI (vMRI), diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI). In addition, radiological MRI scans will be taken to monitor vasogenic edema and microhemorrhages.
Study Arms	Experimental: Imaging Biomarkers; Interventions: Other: PET scan using florbetapir; Other: MRI Scan
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: December 21, 2016)	56
Original Estimated Enrollment ICMJE; (submitted: October 24, 2011)	196
Actual Study Completion Date	December 2014
Actual Primary Completion Date	December 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Present with prodromal Alzheimer's Disease (AD) or mild AD based on the disease diagnostic criteria; Are men or post-menopausal women, at least 55 years of age. Post-menopausal women are defined as women who have had a hysterectomy and/or bilateral oophorectomy; or who have been amenorrheic for at least 2 years; Have a caretaker/study informant who provides a separate written informed consent to participate. If a caretaker/study informant cannot continue, one replacement is allowed; Gradual and progressive change in memory function reported by participants or informants over more than 6 months; Objective evidence of significantly impaired episodic memory characteristic of hippocampal dysfunction on testing: Free and Cued Selective Reminding Test (FCSRT): less than or equal to (≤) 16 for free recall or ≤ 40 for total recall. Protocol amendment: FCSRT ≤ 24 for free recall or ≤ 44 for total recall; Clinical Dementia Rating (CDR) equals 0.5 or 1, Memory box score greater than or equal to 0.5; Mini Mental Scale Examination (MMSE) 20-30. Protocol amendment: MMSE 23-30, inclusive; Positive florbetapir F 18 scan; Participants must meet all of the Disease Diagnostic Criteria to be considered for enrollment Exclusion Criteria: Diagnosis or history of other possible etiology of dementia, including but not limited to other neurodegenerative disorders; Frontotemporal dementia, Lewy body disease, vascular dementia, Huntington's Disease or concomitant Parkinson's disease, progressive supranuclear palsy (PSNP) or other movement disorder; Has B12 <200 pg/L or folate <7.5 nmol/L indicating vitamin deficiency; Has a history within the past 5 years of a serious infectious disease affecting the brain, including meningitis, or encephalitis; Significant history of alcoholism or substance abuse (at the judgment of the investigator); Severe or recurrent head injury that is clinically relevant to the disease under study, (that is, with permanent neurological/cognitive sequelae); Onset of dementia following heart surgery or cardiac arrest; Diagnosis or history of cerebrovascular disease (for example, stroke, transient ischemic attack), severe carotid stenosis, cerebral hemorrhage, intracranial tumor, subarachnoid hemorrhage, or subdural hematoma that could contribute to the subject's current cognitive or functional status, impair ability to fully participate in the trial or that may impact status; Has had a Positron Emission Tomography (PET) within 6 months of the scheduled imaging follow-up; Greater than 4 cerebral microhemorrhages (CMH) on T2* -weighted gradient-recalled echo sequences (regardless of their anatomical or diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis, or prior evidence of macrohemorrhage; Any indications of severe deep white matter lesions or vasogenic edema that present as hyperintense regions on the Fluid Attenuated Inversion Recovery (FLAIR) sequence, or other clinically relevant findings observed on the Magnetic Resonance Imaging (MRI) scans; Specific exclusionary brain MRI findings, as determined by the investigator in consultation with the sponsor, that could either contribute to the participant's current cognitive or functional decline impair ability to fully participate in the trial or that may impact status during the trial (for example, brain tumors or other non-vascular structural abnormalities like hydrocephalus); History within the past 5 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen (PSA) post resection; History of clinically significant cardiovascular or renal events; Diastolic blood pressure of 95 or more and systolic blood pressure of 160 or more in sitting position after at least 5 minutes of rest; Any history of seizure; History of clinically significant head trauma or clinically significant unexplained loss of consciousness within the last 5 years (as determined by the investigator in consultation with the Sponsor); A current Axis I diagnosis of major depressive disorder or other psychiatric illness (Diagnostic and Statistical Manual Revised Fourth Edition [DSM-IV-TR]) criteria per the investigator's judgment. (Note: Participants on a stable antidepressant and/or anxiolytic treatment may participate.); Having suicidal ideations, or attempted suicide in the past 15 years; History of schizophrenia, bipolar disorder, or other severe mental illness; Known history of alcohol or drug abuse (as defined by the DSM-IV-TR) within 5 years prior to enrolling or a positive result regarding use of illicit drugs on the drug screening test; Chronic hepatic diseases as indicated by liver function test abnormalities (alanine trasaminase [ALT], aspartate transaminase [AST], bilirubin, or gamma-glutamyl transferase [GGT] above 2 times upper limit of normal), positive serology for Hepatitis B or C, or other manifestations of liver disease; Has compromised renal function at screening, as determined by creatinine clearance <30 mL/min based on Cockcroft-Gault calculation of creatinine clearance; History of asthma, chronic obstructive pulmonary disease, or other chronic respiratory conditions; Known positive human immunodeficiency virus (HIV) status, history of syphilitic infection; A clinically significant abnormality in the 12-lead electrocardiograms (ECG), including complete heart block, bradycardia (heart rate <50 beats/minute), tachycardia (heart rate ≥95 beats/minute), sinus pauses >2 seconds, second or third degree heart block, QTc >450 msec for males or QTc >470 for females; Treatment with an investigational small molecule within 1 year preceding the first study period, or participation in a trial with active or passive immunization against amyloid if participant was assigned to the active treatment arm; Fulfillment of any contraindications to a 3T magnetic resonance imaging (MRI) scan (for example, subjects with non-removable ferromagnetic implants (such as cardiac pacemaker), aneurysm clips or other foreign bodies, or subjects with claustrophobic symptoms that would contraindicate an MRI scan); Sensitivity to florbetapir F 18; Are not capable of swallowing whole oral medications; Abnormal thyroid function Thyroid stimulating hormone (TSH) values are outside of the normal range 0.3-5.6 mIU/L. (NOTE: Participants with stable treatment of hypothyroidism and with normal value of TSH will be allowed to enter the study)
Sex/Gender	Sexes Eligible for Study: All
Ages	55 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	France
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01459016
Other Study ID Numbers ICMJE	14162; I4O-MC-BACH ( Other Identifier: Eli Lilly and Company )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Eli Lilly and Company
Study Sponsor ICMJE	Eli Lilly and Company
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri, 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
PRS Account	Eli Lilly and Company
Verification Date	December 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP