[11C]MK-6884 Positron Emission Tomography (PET) Tracer Validation Trial (MK-6884-001)

Study Overview
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Brief Summary
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The purpose of this open-label, 3-part study is to investigate the safety and efficacy of [11C]MK-6884 as a positron emission tomography (PET) imaging agent for quantifying muscarinic 4 (M4) positive allosteric modulator (PAM) receptor density in brain regions of interest. The study will enroll healthy participants (Parts 1 and 2) and participants with Alzheimer's Disease (AD) (Part 3). The primary efficacy hypothesis is that the average intra-subject test-retest (T-RT) variability of tracer uptake in brain regions of interest is ≤20%.

Official Title
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A Three-Part Trial to Qualify [11C]MK-6884 Positron Emission Tomography for Use as a Biomarker for Regional M4 PAM Receptor Density Quantification in the Human Brain

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: [11C]MK-6884


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1, 2 and 3: Male, or non-pregnant and non-breast feeding female of 18 to 55 years of age (Part 1) or 55 to 85 years of age (Parts 2 and 3); in addition: Male participant who is sexually active with females of childbearing potential must be willing to use a condom from the first dose of study drug until 3 months post the last dose of study drug Female participant with reproductive potential must have serum β-human chorionic gonadotropin (β-hCG) test result consistent with non-pregnant state at screening and agree to use two acceptable methods of birth control beginning at screening visit, during study and until 2 weeks after the last dose of study drug Female participant of non-childbearing potential must be post-menopausal female (participant has been without menses for at least 1 year and has a follicle stimulating hormone [FSH] level in the postmenopausal range at screening), or surgically sterile female (status post hysterectomy, oophorectomy, or tubal ligation) Body Mass Index (BMI) ≤35 kg/m^2, with height ≤195 cm and weight ≤136 kg In good health (Part 1) or generally healthy (Parts 2 and 3) based on medical history, physical examination, vital sign measurements and electrocardiogram (ECG) Nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 3 months Part 2 Only: Willing to allow placement of an arterial catheter in the radial artery Mini Mental Status Examination (MMSE) score ≥27 No history of subjective memory or other cognitive complaints No objective evidence of memory or cognitive impairment Part 3 Only: Moderate to severe AD as defined by: MMSE score ≤20 Meets National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD Meets Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) criteria for AD Rosen-Modified Hachinski score ≤4 Screening magnetic resonance imaging (MRI) scan consistent with a diagnosis of AD Clear history of cognitive and functional decline over ≥1 year On a stable dose of one of protocol-defined acetylcholinesterase inhibitors (AChEIs) (i.e., donepezil and rivastigmine) for symptomatic treatment of AD. Dose must be stable for at least the last 4 weeks before screening Has a reliable trial partner/caregiver who is able to accompany the participant to all clinic visits, if needed, and able to provide information to study investigator/staff via telephone contact Exclusion Criteria: Part 1, 2, and 3: Mentally or legally incapacitated, has significant emotional problems at the time of screening visit or expected during the conduct of the trial or has a history of clinically significant psychiatric disorder of the last 5 years, except (for Part 3 only) for psychiatric disorders associated with AD History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological abnormalities or diseases, unless (for Part 2 and 3 only) adequately controlled through a stable medication regimen History of cancer History of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food. For Part 2, this includes any known allergy to lidocaine which may be used as an anesthetic for the placement of the arterial catheter Has positive test result for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV) Has had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to screening Has participated in another investigational trial within 4 weeks of screening Corrected QT (QTc) interval ≥470 msec (for males) or ≥480 msec (for females) Is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies, beginning approximately 2 weeks prior to administration of the initial dose of study drug and throughout the study. Consumes >3 servings of alcohol a day Consumes >6 caffeine servings a day Is currently a regular or recreational user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 3 months Has participated in a PET research study or other study involving administration of a radioactive substance or ionizing radiation within 12 months prior to screening or has undergone an extensive radiological examination within this period Suffers from claustrophobia or an inability to tolerate confinement in small places and would be unable to undergo MRI or PET scanning Part 2 Only: - Has been administered an AChEI within the prior 3 months or will require administration of an AChEI during study Part 3 Only: Has been administered galantamine within the prior 7 days or will require administration of galantamine during study History within 2 years prior to screening, or current evidence of any neurological or neurodegenerative disorder other than AD that is associated with transient or sustained alterations in cognition History within 2 years prior to screening, or current evidence of a psychotic disorder or a major depressive disorder Part 2 and 3 Only: - Has or is suspected to have implanted or embedded metal objects, or fragments in the head or body that would present a risk during the MRI scanning procedure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, Healthy Participants<br>Healthy participants receive a single intravenous (IV) dose of  370 megabecquerel (MBq) [11C]MK-6884 in Part 1 of the study. | Drug: [11C]MK-6884<br>* IV bolus dose of  370 MBq [11C]MK-6884<br>|
| Experimental: Part 2, Healthy Elderly Participants<br>Healthy elderly participants receive two separate IV doses of  370 MBq [11C]MK-6884 in Part 2 of the study. Administration of the two doses is separated by at least 3 hours. | Drug: [11C]MK-6884<br>* IV bolus dose of  370 MBq [11C]MK-6884<br>|
| Experimental: Part 3, Participants with AD<br>Participants with AD receive a single IV dose of  370 MBq [11C]MK-6884 in Part 3 of the study. | Drug: [11C]MK-6884<br>* IV bolus dose of  370 MBq [11C]MK-6884<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing an Adverse Event (AE) | The number of participants experiencing an adverse event (AE) was assessed. An AE is defined as any unfavorable and unintended medical occurrence, sign, symptom, or disease temporally associated with the use of a pharmaceutical product or protocol-specified procedure, whether or not considered related to the pharmaceutical product or protocol-specified procedure. Any worsening of a preexisting condition, temporally associated with the use of the Sponsor's product, is also an AE. | Up to 15 days | 
| Number of Participants Discontinuing the Study Due to an Adverse Event (AE) | The number of participants discontinuing the study due to an AE was assessed. An AE is defined as any unfavorable and unintended medical occurrence, sign, symptom, or disease temporally associated with the use of a pharmaceutical product or protocol-specified procedure, whether or not considered related to the pharmaceutical product or protocol-specified procedure. Any worsening of a preexisting condition, temporally associated with the use of the Sponsor's product, is also an AE. | Up to 15 days | 
| [Part 1] Mean Effective Dose of [11C]MK-6884 | Mean effective dose (ED) of [11C]MK-6884 was calculated as a measure of risk associated with exposure of the whole body (WB) to low levels of ionizing radiation. Following [11C]MK-6884 injection, WB positron emission tomography (PET) scans were collected to visually identify organs absorbing [11C]MK-6884 in significant amounts. Around identified organs, three-dimensional (3D) volumes were drawn to estimate the percentage of injected activity absorbed. These data were converted into time-activity curves (TACs) and retention of radioactivity in these regions was entered into a human biodistribution model to determine ED of [11C]MK-6884. ED is expressed in units millisieverts (mSv) / MBq. | Up to 2 hours post-dose | 
| [Part 1] Mean Organ Effective Dose of [11C]MK-6884 | Mean organ ED of [11C]MK-6884 was calculated as a measure of risk associated with exposure of individual organs to low levels of ionizing radiation. Following [11C]MK-6884 injection, WB PET scans were collected to visually identify organs absorbing [11C]MK-6884 in significant amounts. Around identified organs, 3D volumes were drawn to estimate the percentage of injected activity absorbed. These data were converted into TACs and retention of radioactivity in these regions was used to calculate organ-specific ED of [11C]MK-6884. For sex organs (testes/ovaries), organ EDs were derived for participants of the respective sex. However, organ ED for the uterus was estimable in all participants as the male radiologic phantom was sufficiently hermaphroditic. | Up to 2 hours post dose | 
| [Part 2] Mean Non-displaceable Binding Potential (BPND) of [11C]MK-6884 in Brain Regions of Interest (ROI) | Mean BPND of [11C]MK-6884 in each brain ROI was assessed. BPND is the ratio at equilibrium of specifically bound [11C]MK-6884 to that of non-displaceable [11C]MK-6884 in tissue. At time 0, a single IV bolus of [11]MK-6884 is administered and PET scanning initiated, yielding brain regional TACs. These TACs are then used to determine peak standard uptake value (SUV) and area under the curve (AUC) in order to quantify brain regional [11C]MK-6884 uptake. The target region BPND is estimated using the cerebellum as the reference region with the transient equilibrium tissue ratio (TE-TR) method. Higher values indicate increased specific [11C]MK-6884 binding in the brain ROI. | Up to 90 minutes post dose | 
| [Part 2] Intra-subject Test-Retest (T-RT) Variability of Non-displaceable Binding Potential (BPND) of [11C]MK-6884 in Brain Regions of Interest (ROI) | Intra-subject T-RT variability in BPND of [11C]MK-6884 in each brain ROI was assessed. For each healthy elderly participant receiving 2 doses of [11C]MK-6884 in study Part 2, the BPND calculated during the first dose (BPND-1) was compared to the BPND calculated during the second dose (BPND-2) to determine the percent T-RT variability of the BPND of [11C]MK-6884 for each brain ROI. Percent T-RT variability = [absolute value (BPND-1 - BPND-2) / (average BPND)] * 100. A percent T-RT variability = 0, indicates no variability between BPND-1 and BPND-2. | Up to 24 hours post dose | 
| [Part 3] Mean Regional Non-displaceable Binding Potential (BPND) of [11C]MK-6884 in Brain Regions of Interest | Mean BPND of [11C]MK-6884 in each brain ROI was assessed. BPND is the ratio at equilibrium of specifically bound [11C]MK-6884 to that of non-displaceable [11C]MK-6884 in tissue. At time 0, a single IV bolus of [11]MK-6884 is administered and PET scanning initiated, yielding brain regional TACs. These TACs are then used to determine SUV and AUC in order to quantify brain regional [11C]MK-6884 uptake. The target region BPND is estimated using the cerebellum as the reference region with the TE-TR method. Higher values indicate increased specific [11C]MK-6884 binding in the brain ROI. | Up to 90 minutes post dose |