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

Primary Purpose

Alzheimer's Disease

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
[18F]MK-3328
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Alzheimer's Disease

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Experimental

    Arm Label

    Part I, Healthy Participants

    Part II, HE and AD Participants

    Part III, HE and AD Participants

    Arm Description

    Healthy participants will receive a single intravenous (IV) dose of ~150 megabecquerel (MBq) [18F]MK-3328 in Part I of the study

    HE and AD participants will receive a single IV dose of ~150 megabecquerel (MBq) [18F]MK-3328 in Part II of the study

    HE and AD participants will receive two separate IV doses of ~150 megabecquerel (MBq) [18F]MK-3328 in Part III of the study

    Outcomes

    Primary Outcome Measures

    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.
    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.
    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).
    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.
    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).
    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.

    Secondary Outcome Measures

    Full Information

    First Posted
    August 6, 2009
    Last Updated
    November 2, 2015
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00954538
    Brief Title
    Safety, Radiation Dosimetry, Biokinetics, and Effectiveness of [18F]MK3328 (MK-3328-001)
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2015
    Overall Recruitment Status
    Completed
    Study Start Date
    August 2009 (undefined)
    Primary Completion Date
    May 2011 (Actual)
    Study Completion Date
    May 2011 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Alzheimer's Disease

    7. Study Design

    Primary Purpose
    Diagnostic
    Study Phase
    Phase 1
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    19 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Part I, Healthy Participants
    Arm Type
    Experimental
    Arm Description
    Healthy participants will receive a single intravenous (IV) dose of ~150 megabecquerel (MBq) [18F]MK-3328 in Part I of the study
    Arm Title
    Part II, HE and AD Participants
    Arm Type
    Experimental
    Arm Description
    HE and AD participants will receive a single IV dose of ~150 megabecquerel (MBq) [18F]MK-3328 in Part II of the study
    Arm Title
    Part III, HE and AD Participants
    Arm Type
    Experimental
    Arm Description
    HE and AD participants will receive two separate IV doses of ~150 megabecquerel (MBq) [18F]MK-3328 in Part III of the study
    Intervention Type
    Drug
    Intervention Name(s)
    [18F]MK-3328
    Intervention Description
    IV dose of ~150 megabecquerel (MBq) [18F]MK-3328
    Primary Outcome Measure Information:
    Title
    Number of Participants With an Adverse Event (AE)
    Description
    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
    Title
    Number of Participants Who Discontinued Study Due to an AE
    Description
    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
    Title
    Effective Dose of [18F]MK-3328
    Description
    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
    Title
    Organ Effective Dose of [18F]MK-3328
    Description
    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
    Title
    Mean Brain Cortical [18F]MK-3328 Standard Uptake Value Ratio (SUVR) in AD Participants and HE Participants
    Description
    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
    Title
    Least Squares (LS) Mean [18F]MK-3328 SUVR in Brain Posterior Cingulate Gyrus in AD Participants and HE Participants
    Description
    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

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    50 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    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

    12. IPD Sharing Statement

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

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