Clinical trial NCT01459016: A Non-drug Methods Study in Participants With Alzheimer's Disease
Official title: An Exploratory Study of Brain Imaging Biomarkers in Patients With Alzheimer's Pathology Receiving Standard of Care
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alzheimer's Disease
Keywords: Mild Cognitive Impairment
Brain Imaging Biomarkers
Magnetic resonance imaging biomarker
Positron Emission Tomography
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2011-10-25
Enrollment: 56
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) - Brain Boundary Shift Integral (BBSI) and Ventricular Boundary Shift Integral (VBSI)
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
measure: Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) - Hippocampus Volume Average Percent (%) Change (Chg)
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
measure: Change From Baseline in Resting State Functional Magnetic Resonance Imaging (rsfMRI)
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
measure: Change From Baseline in Diffusion Tensor Imaging (DTI) Using Fractional Anisotropy (FA)
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
measure: Change From Baseline in Diffusion Tensor Imaging (DTI) Using Mean Diffusivity (MD)
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
Secondary outcomes:
measure: Baseline Brain Amyloid Load Using Positron Emission Tomography (PET) and Florbetapir
timeFrame: Baseline
measure: Number of Participants With Vasogenic Edema on MRI Scan at a Field Strength of 3 Tesla (3T)
timeFrame: Baseline
measure: Number of Participants With Microhemorrhage on MRI Scan at a Field Strength of 3T
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
measure: Change From Baseline in the Mini Mental State Examination (MMSE) Total Score
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
measure: Change From Baseline in the Alzheimer's Disease Assessment Scale Extended Cognitive Subscale (ADAS-Cog14) Total Score
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
measure: Change From Baseline in the Clinical Dementia Rating (CDR) Total Score
timeFrame: Baseline, 6 Mos; Baseline, 12 Mos
Other outcomes:
Locations:
city: Cahors
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Castres
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Foix Cedex
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Lavaur
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Lille
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Limoges
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Léon
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Marseille
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Montauban Cedex
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Nancy
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Paris
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Rennes
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Strasbourg
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Toulouse
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Tours
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
city: Vic-En-Bigorre
country: France
facility: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
Study officials:
affiliation: Eli Lilly and Company
name: 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)
role: STUDY_DIRECTOR
References: