Safety, Radiation Dosimetry, Biokinetics, and Effectiveness of [18F]MK3328 (MK-3328-001)

Study Overview
=================
Brief Summary
-----------------
This study will estimate the radiochemical and radiation safety and assess the efficacy of [18F]MK-3328, a novel positron emission tomography (PET) tracer. The study safety hypotheses will test whether [18F]MK-3328 is sufficiently safe and well-tolerated, based on an assessment of clinical and laboratory evaluations and adverse experiences in healthy participants, including healthy elderly (HE) participants, and Alzheimer's disease (AD) participants, to permit continued investigation. The study efficacy hypothesis will test whether [18F]MK-3328 can discriminate between AD participants and cognitively normal elderly control participants based on tracer volume of distribution, or one of its surrogates, in brain posterior cingulate gyrus.

Official Title
-----------------
A Three Part Study to Evaluate the Safety, Radiation Dosimetry, Biokinetics, and Effectiveness of [18F]MK-3328, a Radiotracer for Use in Positron Emission Tomography

Conditions
-----------------
Alzheimer's Disease

Intervention / Treatment
-----------------
* Drug: [18F]MK-3328


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Part I: Participant is male or female of non-reproductive potential between 50 and 65 years old. Participant is less than 6'5 tall Participant is in good health Participant has been a non-smoker for at least 10 years Parts II and III: Male or female of non-reproductive potential at least 55 years of age Participant is cognitively normal (HE participants), or has probable mild-to moderate AD (AD participants) Participant is willing to have an arterial catheter placed in the radial artery (Part II only) Exclusion Criteria: Part I: Participant has a history of stroke, seizures, or neurological disorder Participant has or has a history of any disease or condition, or takes any medication that would interfere with assessment of the tracer or make participation unsafe or unduly uncomfortable Parts II and III: Participant has a history or current evidence of any neurological or neurodegenerative disorder other than AD that is associated with altered cognition Participant has or has a history of any disease or condition, or takes any medication that would interfere with assessment of the tracer or make participation unsafe or unduly uncomfortable Participant is living in a nursing home or skilled nursing facility

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I, Healthy Participants<br>Healthy participants will receive a single intravenous (IV) dose of  150 megabecquerel (MBq) [18F]MK-3328 in Part I of the study | Drug: [18F]MK-3328<br>* IV dose of  150 megabecquerel (MBq) [18F]MK-3328<br>|
| Experimental: Part II, HE and AD Participants<br>HE and AD participants will receive a single IV dose of  150 megabecquerel (MBq) [18F]MK-3328 in Part II of the study | Drug: [18F]MK-3328<br>* IV dose of  150 megabecquerel (MBq) [18F]MK-3328<br>|
| Experimental: Part III, HE and AD Participants<br>HE and AD participants will receive two separate IV doses of  150 megabecquerel (MBq) [18F]MK-3328 in Part III of the study | Drug: [18F]MK-3328<br>* IV dose of  150 megabecquerel (MBq) [18F]MK-3328<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Adverse Event (AE) | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. | Up to 14 days after last dose | 
| Number of Participants Who Discontinued Study Due to an AE | An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. | Up to 14 days after last dose | 
| Effective Dose of [18F]MK-3328 | Using PET whole body images acquired after dosing, regions of interest (ROIs) were drawn in all organs showing visible [18F]MK-3328 accumulation. Time activity curves (TACs) showing total [18F]MK-3328 retention as a function of time were determined for each organ. Residence times were calculated from the area under each organ TAC. Radiation exposure of the body and critical organs was calculated from the [18F]MK-3328 residence times using OLINDA (Organ Level Internal Dose Assessment) software. For each organ, the equivalent dose, which is the absorbed radiation dose weighted for the degree of the biological effect of different types of radiation, was calculated. The total radiation exposure to the body is expressed as the effective dose, which is the sum of the equivalent doses in each organ multiplied by a weighting factor for the type of tissue exposed. Effective dose is the primary surrogate for radiation risk. The unit of effective dose is the Sievert (Sv). | Up to approximately 6 hours post dose | 
| Organ Effective Dose of [18F]MK-3328 | Using PET whole body images acquired after dosing, ROIs were drawn in all organs showing visible [18F]MK-3328 accumulation. TACs showing total [18F]MK-3328 retention as a function of time were determined for each organ. Residence times were calculated from the area under each organ TAC. Radiation exposure of the body and critical organs was calculated from the [18F]MK-3328 residence times using OLINDA software. For each organ, the equivalent dose, which is the absorbed radiation dose weighted for the degree of the biological effect of different types of radiation, was calculated. The organ effective dose is the equivalent dose in each organ multiplied by a weighting factor for the type of tissue exposed. The unit of organ effective dose is Sv. | Up to approximately 6 hours post dose | 
| Mean Brain Cortical [18F]MK-3328 Standard Uptake Value Ratio (SUVR) in AD Participants and HE Participants | Using PET brain images acquired after dosing, regions of interest (ROIs) were drawn in identified brain areas. The ROIs were projected onto all frames of the dynamic PET scans in order to generate [18F]MK-3328 tissue TACs. SUVR is calculated as the ratio of the average [18F]MK-3328 uptake over 60-90 minutes post dose in the target brain region and the cerebellum. Cortical SUVR is reported, which is a mean SUVR derived from SUVR from multiple brain regions (frontal cortex, parietal cortex, anterior cingulate gyrus, posterior cingulate gyrus, temporal cortex, lateral temporal cortex and occipital cortices). | 60-90 minutes post dose | 
| Least Squares (LS) Mean [18F]MK-3328 SUVR in Brain Posterior Cingulate Gyrus in AD Participants and HE Participants | Using PET brain images acquired after the second dose of [18F]MK-3328, regions of interest (ROIs) were drawn in identified brain areas. The ROIs were projected onto all frames of the dynamic PET scans in order to generate [18F]MK-3328 tissue TACs. Posterior cingulate gyrus SUVR was calculated as the ratio of the average [18F]MK-3328 uptake over 60-90 minutes post dose in the target brain region and the cerebellum. | 60-90 minutes after second dose |