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

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 1

Conditions: Alzheimer's Disease

Treatments: Drug: [11C]MK-6884

Study type: Interventional

Funder types: Industry

Identifiers

NCT02621606

MK-6884-001 (Other Identifier)

6884-001

2015-001631-20 (EudraCT Number)

Details and patient eligibility

About

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%.

Enrollment: 20 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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20 participants in 3 patient groups

Part 1, Healthy Participants

Experimental group

Description:

Healthy participants receive a single intravenous (IV) dose of \~370 megabecquerel (MBq) \[11C\]MK-6884 in Part 1 of the study.

Treatment:

Drug: [11C]MK-6884

Part 2, Healthy Elderly Participants

Experimental group

Description:

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.

Treatment:

Drug: [11C]MK-6884

Part 3, Participants with AD

Experimental group

Description:

Participants with AD receive a single IV dose of \~370 MBq \[11C\]MK-6884 in Part 3 of the study.

Treatment:

Drug: [11C]MK-6884