Alzheimer's Disease
Conditions
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.
Interventions
DRUG[18F]MK-3328
IV dose of \ 150 megabecquerel (MBq) \[18F\]MK-3328
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Adverse Event (AE) | Up to 14 days after last dose | 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. |
| Number of Participants Who Discontinued Study Due to an AE | Up to 14 days after last dose | 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. |
| Effective Dose of [18F]MK-3328 | Up to approximately 6 hours post dose | 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). |
| Organ Effective Dose of [18F]MK-3328 | Up to approximately 6 hours post dose | 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. |
| Mean Brain Cortical [18F]MK-3328 Standard Uptake Value Ratio (SUVR) in AD Participants and HE Participants | 60-90 minutes post dose | 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). |
| Least Squares (LS) Mean [18F]MK-3328 SUVR in Brain Posterior Cingulate Gyrus in AD Participants and HE Participants | 60-90 minutes after second dose | 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Participants (Part I) + HE Participants (Part II/III) This group includes Healthy participants (Part I) and HE participants (Part II/III). Participants were administered one or two IV doses of \
150 MBq \[18F\]MK-3328; all doses were followed by PET imaging of whole body or brain | 10 |
| AD Participants (Part II/III) This group includes AD participants (Part II/III). Participants were administered one or two IV doses of \
150 MBq \[18F\]MK-3328; all doses were followed by PET imaging of brain | 9 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part III | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Healthy Participants (Part I) + HE Participants (Part II/III) | AD Participants (Part II/III) | Total |
|---|---|---|---|
| Age, Continuous | 61.5 Years STANDARD_DEVIATION 6.3 | 70.7 Years STANDARD_DEVIATION 5.5 | 65.8 Years STANDARD_DEVIATION 7.4 |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 19 |
| serious Total, serious adverse events | 0 / 19 |
Outcome results
Primary
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).
Time frame: Up to approximately 6 hours post dose
Population: All participants who received \[18F\]MK-3328 in Part I of study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Study Participants | Effective Dose of [18F]MK-3328 | 18.2 µSv/MBq | Standard Deviation 2 |
Primary
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.
Time frame: 60-90 minutes after second dose
Population: All participants who received a second dose of \[18F\]MK-3328 in Part III of study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| All Study Participants | Least Squares (LS) Mean [18F]MK-3328 SUVR in Brain Posterior Cingulate Gyrus in AD Participants and HE Participants | 1.47 ratio |
| HE Participants (Part II) | Least Squares (LS) Mean [18F]MK-3328 SUVR in Brain Posterior Cingulate Gyrus in AD Participants and HE Participants | 1.35 ratio |
Comparison: A 90% confidence interval was calculated for the group difference (AD - HE) using the model results. As prespecified by the analysis plan, if the lower bound of the 90% confidence interval is above 0, then the hypothesis that \[18F\]MK-3328 can discriminate between AD patients and cognitively normal elderly controls as measured by regional tracer uptake following single IV doses of \[18F\]MK-3328 is supported.90% CI: [-0.04, 0.27]Linear Fixed Effects Model
Primary
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).
Time frame: 60-90 minutes post dose
Population: All participants who received \[18F\]MK-3328 in Part II of study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Study Participants | Mean Brain Cortical [18F]MK-3328 Standard Uptake Value Ratio (SUVR) in AD Participants and HE Participants | 1.75 ratio | Standard Deviation 0.14 |
| HE Participants (Part II) | Mean Brain Cortical [18F]MK-3328 Standard Uptake Value Ratio (SUVR) in AD Participants and HE Participants | 1.34 ratio | Standard Deviation 0.07 |
p-value: <0.01t-test, 2 sided
Primary
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.
Time frame: Up to 14 days after last dose
Population: All participants who received \[18F\]MK-3328
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Study Participants | Number of Participants Who Discontinued Study Due to an AE | 0 participants |
Primary
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.
Time frame: Up to 14 days after last dose
Population: All participants who received \[18F\]MK-3328
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Study Participants | Number of Participants With an Adverse Event (AE) | 8 participants |
Primary
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.
Time frame: Up to approximately 6 hours post dose
Population: All participants who received \[18F\]MK-3328 in Part I of study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Pancreas | 0.0399 µSv/MBq | Standard Deviation 0.0152 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Adrenals | 0.0404 µSv/MBq | Standard Deviation 0.0147 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Brain | 0.0635 µSv/MBq | Standard Deviation 0.0192 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Breasts | 0.307 µSv/MBq | Standard Deviation 0.0468 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Gallbladder Wall | 0 µSv/MBq | Standard Deviation 0 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Lower Large Intestine Wall | 2.57 µSv/MBq | Standard Deviation 0.101 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Small Intestine | 0.149 µSv/MBq | Standard Deviation 0.0716 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Stomach Wall | 1.25 µSv/MBq | Standard Deviation 0.195 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Upper Large Intestine Wall | 0.519 µSv/MBq | Standard Deviation 0.577 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Heart Wall | 0 µSv/MBq | Standard Deviation 0 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Kidneys | 0.963 µSv/MBq | Standard Deviation 1.38 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Liver | 1.35 µSv/MBq | Standard Deviation 0.302 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Lungs | 1.71 µSv/MBq | Standard Deviation 0.204 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Muscle | 0.0268 µSv/MBq | Standard Deviation 0.0103 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Ovaries | 3.06 µSv/MBq | Standard Deviation 0.226 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Red Marrow | 2.36 µSv/MBq | Standard Deviation 0.265 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Osteogenic Cells | 0.181 µSv/MBq | Standard Deviation 0.02 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Skin | 0.0575 µSv/MBq | Standard Deviation 0.00864 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Spleen | 0.0445 µSv/MBq | Standard Deviation 0.0133 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Testes | 0 µSv/MBq | Standard Deviation 0 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Thymus | 0.0247 µSv/MBq | Standard Deviation 0.00904 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Thyroid | 0.675 µSv/MBq | Standard Deviation 0.0864 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Urinary Bladder Wall | 2.75 µSv/MBq | Standard Deviation 0.598 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Uterus | 0.0502 µSv/MBq | Standard Deviation 0.0229 |
| All Study Participants | Organ Effective Dose of [18F]MK-3328 | Rest of Body | 0 µSv/MBq | Standard Deviation 0 |