Efficacy and Safety of the PET Imaging Agent [18F]NAV4694 in Subjects With Probable Alzheimer's Disease

A Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of [18F]NAV4694 PET in the Detection of Beta Amyloid in Subjects With Probable Alzheimer's Disease, Older Healthy Volunteers, and Young Healthy Volunteers

This is a phase 2, open-label, multiple-center, non-randomized single dose study to assess the safety and efficacy of [18F]NAV4694 PET imaging in detecting beta-amyloid plaque in the brain in subjects with probable AD compared with healthy volunteers.

Inclusion Criteria:

All participants:

• is able to provide informed consent or assent, and exhibits adequate visual, auditory, and communication capabilities to enable compliance with study procedures
• should be able to perform the psychometric testing
• has a modified Hachinski score ((Hachinski, et al., 2012; Rosen, et al., 1980) ≤ 4 at screening
• possesses a general health that permits adequate compliance with all study procedures as ascertained by a detailed review of the medical history, surgical history, laboratory and physical examination findings, which must be performed within 56 days prior to administration of [18F]NAV4694
• informed consent has been signed and dated by the subject and/or the subject's legally authorized representative (LAR; for probable AD subjects)

Healthy Volunteers Only

• is male or female and is between the age of 18 and 40 years (for younger HVs) or 55 to 85 years of age (for older HVs)
• if female does not have childbearing potential: must be confirmed by either: post-menopausal status; or history of surgical sterilization or of hysterectomy
• if female has childbearing potential: must demonstrate a negative serum beta-HCG level at screening and a negative urine pregnancy test on the day of injection (prior to injection) consistent with a non-gravid state and agree to use two acceptable forms of birth control
• has no evidence of cognitive impairment as indicated by a clinical dementia rating (CDR) (Morris, 1993) score of 0 (zero) and a score of ≥ 28 in the Mini-Mental State Examination (MMSE) (Folstein, et al., 1975)
• has MRI brain scan that has been judged as "normal (age-appropriate)" supporting the lack of cerebrovascular disease (e.g., a white matter lesion score of 0, 1, or 2 and a basal ganglia score of 0 to 1 on the ARWMC scale)

Probable Alzheimer's Disease Subjects Only

• is male or female and is ≥ 55 of age, whereby females must be without childbearing potential (confirmed by either:post-menopausal status; or history of surgical sterilization or of hysterectomy)
• presents with positive assessment for dementia of Alzheimer's type in accordance with the DSM-IV-TR and probable AD according to the NINCDS-ADRDA criteria and fulfills none of the exclusion criteria of either
• does not fulfill the International Consensus Criteria (ICC) for probable diffuse Lewy body disease (DLBD), the NINDS-AIREN for probable vascular dementia, or the Neary criteria for frontotemporal dementia (FTD) [Neary et al. 1998]
• has a MMSE score between 16 and 23
• has a CDR (Morris, 1993) score of 1 to 2
• has a Cornell Scale for Depression in Dementia (CSDD; (Alexopoulos, et al., 1988)) score less than or equal to 18 (definite major depression)
• MRI brain scan findings that do not reveal changes indicative of stroke and/or generalized cerebrovascular disease changes (limited to: a white matter lesion score of 0, 1, or 2 and a basal ganglia score of 0 or 1 on the ARWMC scale)
• has a caregiver who is willing and able to attend study visits and perform the psychometric tests requiring the presence of a caregiver

Exclusion Criteria:

• has any contraindication to MRI examination, e.g., metal implants or phobia
• is not able to lie down flat in the MRI and PET scanners
• is scheduled for surgery and/or another invasive procedure within the time period of up to 10 days after [18F]NAV4694 application
• is medically unstable and whose clinical course during the observation period is unpredictable, e.g., subjects within 14 days of myocardial infarction or stroke, unstable subjects with previous surgery (within 7 days), subjects with advanced heart insufficiency (NYHA stage IV), or with acute renal failure
• has a history of exposure to any radiation > 30 mSv in the last year (e.g., occupational, diagnostic imaging, or radiation therapy)
• is receiving drug therapy or other treatment that is known to lead to greatly fluctuating values of the hematological or chemical laboratory parameters or to severe side effects (e.g., chemotherapy)
• has received anti-amyloid immunotherapy
• has been previously enrolled in this study and received [18F]NAV4694 or participated in a clinical study involving an investigational pharmaceutical product within 30 days prior to screening, and/or any radiopharmaceutical within 10 radioactive half-lives prior to [18F]NAV4694 administration
• has a brain tumor or other intracranial lesion, a disturbance of cerebrospinal fluid (CSF) circulation (e.g., normal pressure hydrocephalus) and/or a history of serious head trauma or brain surgery
• has a history, physical, laboratory, or imaging findings indicative of a significant neurological or psychiatric illness (other than AD for the subjects with probable AD)
• has another untreated disease that can cause disturbance of brain function (e.g. vitamin B12 or folic acid deficiency, disturbed thyroid function, anemia)
• has a history of alcohol abuse or drug dependency in the 3 years prior to study entry or is an alcoholic or drug addict as determined by the investigator