[18F]MK-6240 Positron Emission Tomography (PET) Tracer First-in-Human Validation Study (MK-6240-001)

NCT02562989 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: 6240-0012015-001659-58MK-6240-001
• Study Type: interventional
• Target: 13
• Locations: 0 countries
• Sites: N/A

Brief Summary

This 2-part, open-label study was designed to investigate the safety, tolerability, and efficacy of \[18F\]MK-6240, a Positron Emission Tomography (PET) imaging agent, for the quantification of neurofibrillary tangle (NFT) deposition in the brain. Brain NFT deposition is a pathologic finding in Alzheimer's Disease (AD), with brain NFT density shown to correlate with the severity of cognitive impairment in AD. The objectives of the study include performing the following with respect to \[18F\]MK-6240 administered as a PET imaging agent: 1) assess safety and tolerability; 2) determine radiation safety profile; 3) determine optimal imaging protocol parameters for quantification of brain NFTs in AD; 4) compare tracer binding in brain PET scans from participants with AD, participants with amnestic mild cognitive impairment (MCI) and healthy elderly participants; and 5) evaluate intra-subject test-retest (T-RT) variability of tracer uptake in brain regions of interest.

Conditions

Alzheimer's Disease; Amnestic Mild Cognitive Impairment

Outcome Measures

Primary Outcomes (6)

• Number of Participants With Adverse Events (AEs)

  The number of participants experiencing an adverse event (AE) was monitored. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.

  Part 1: Up to 5 weeks; Part 2: up to 16 weeks

• Number of Participants Who Discontinued Study Due to an AE

  The number of participants discontinuing study due to an AE was monitored.

  Part 1: Up to 5 weeks; Part 2: up to 16 weeks

• Effective Dose of [18F]MK-6240

  Mean effective dose (ED) of \[18F\]MK-6240 was calculated from whole-body (WB) PET scans of healthy young participants included in Part 1 of study. ED, reported as microsieverts (µSv) / megabecquerel (MBq), is a measure of WB radiation exposure risk that accounts for differences in individual organ exposure and organ susceptibility to ionizing radiation. Following \[18F\]MK-6240 PET tracer administration, organ-specific time-activity curves (TACs) and radioactivity residence times were utilized to calculate exposure risk for individual organs. These values calculated for individual organs were then entered into a human biodistribution model to determine ED of \[18F\]MK-6240.

  Up to approximately 5 hours following [18F]MK-6240 administration

• Organ Effective Dose of [18F]MK-6240

  Mean organ ED of \[18F\]MK-6240 was calculated from WB PET scans of healthy young participants included in Part 1 of study. Organ ED, reported as micrograys (µGy) / MBq, is a measure of organ-specific radiation exposure risk. Following \[18F\]MK-6240 PET tracer administration, organ-specific TACs and radioactivity residence times were utilized to calculate organ ED for specific organs of the body.

  Up to approximately 5 hours following [18F]MK-6240 administration

• Standardized Uptake Value Ratio (SUVR) of [18F]MK-6240 in Brain Regions of Interest

  As a surrogate of regional \[18F\[MK-6240 tracer distribution volume (VT), mean standardized uptake value ratios (SUVRs), were calculated for specific brain regions of interest (ROIs) in healthy elderly as well as AD/MCI elderly participants in Part 2 of the study. Calculated using calibrated PET scan images from each participant, SUVR is the relative ratio of pixel intensities at a specific brain ROI compared to a reference region (RR; cerebellar cortex, for this study). For an individual participant, the average SUVR for each brain ROI is calculated starting at 60 minutes and ending at 90 minutes following \[18F\]MK-6240 administration to quantify tracer retention; referred to as "SUVR (60-90min)." An SUVR (60-90 min) \< 1 indicates decreased tracer retention at brain ROI relative to RR. An SUVR (60-90 min) = 1 indicates no difference in tracer retention at brain ROI relative to RR. An SUVR (60-90 min) \> 1 indicates increased tracer retention at brain ROI relative to RR.

  From 60 to 90 minutes following [18F]MK-6240 administration

• Intra-subject Test-Retest (T-RT) Variability of Standardized Uptake Value Ratio (SUVR) in Brain Regions of Interest

  For each AD/MCI participant receiving 2 doses of MK-6240, the SUVR (60-90 min) during initial dose (SUVR\_1) was compared to the SUVR (60-90 min) during the second dose (SUVR\_2) to determine the percent test-retest (T-RT) variability of the SUVR (60-90 min) for each brain ROI. T-RT variability = (absolute value (SUVR\_1 - SUVR\_2) / average SUVR) \* 100. If T-RT variability = 0, indicates no variability between SUVR\_1 and SUVR\_2.

  Up to 16 weeks following initial dose of [18F]MK-6240

Study Arms (3)

Part 1, Healthy Young Participants

EXPERIMENTAL

Healthy young participants received a single intravenous (IV) dose of \~185 megabecquerel (MBq) \[18F\]MK-6240 in Part 1 of the study

Drug: [18F]MK-6240, ~185 MBq

Part 2, Healthy Elderly Participants

EXPERIMENTAL

Healthy elderly participants received a single IV dose of \~160 MBq \[18F\]MK-6240, in Part 2 of the study

Drug: [18F]MK-6240, ~160 MBq

Part 2, AD and Amnestic MCI Elderly Participants

EXPERIMENTAL

AD and amnestic MCI participants received up to two IV doses of \~160 MBq \[18F\]MK-6240 in Part 2 of the study

Drug: [18F]MK-6240, ~160 MBq

Interventions

[18F]MK-6240, ~185 MBq DRUG

IV dose of \~185 MBq \[18F\]MK-6240

Part 1, Healthy Young Participants

[18F]MK-6240, ~160 MBq DRUG

IV dose of \~160 MBq \[18F\]MK-6240

Part 2, AD and Amnestic MCI Elderly Participants; Part 2, Healthy Elderly Participants

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part 1 and Part 2:
• Male, or non-pregnant and non-breast feeding female; 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
• Post-menopausal female participant has been without menses for at least 1 year and has a documented follicle stimulating hormone (FSH) level in the postmenopausal range at screening
• Surgically sterile female participant may enroll in study if procedure (hysterectomy, oophorectomy, or tubal ligation) is documented/confirmed by medical records or protocol-defined examination/tests
• Nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 3 months
• Part 1 only:
• to 55 years of age
• Body Mass Index (BMI) between 18-32 kg/m\^2
• In good health based on medical history, physical examination, vital sign measurements, electrocardiogram (ECG) and laboratory safety tests
• Part 2 only:
• to 85 years of age
• Body weight \<136 kg
• In stable medical condition based on medical history, physical examination, vital sign measurements and ECG

You may not qualify if:

• Part 1 and Part 2:
• Subject has participated in another investigational trial within 4 weeks of screening
• Subject 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
• History within 2 years prior to screening, or current evidence of a psychotic disorder or a major depressive disorder
• History of alcoholism or drug dependency/abuse within the last 2 years before screening
• 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
• Has positive test result for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV)
• Participant has had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to screening
• QTc interval ≥470 msec (for males) or ≥480 msec (for females)
• Participant consumes \>3 servings of alcohol a day
• Participant consumes \>6 caffeine servings a day
• Participant 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
• Suffers from claustrophobia or an inability to tolerate confinement in small places and would be unable to undergo PET or (for Part 2 only) MRI scanning
• Part 1 Only:

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Lohith TG, Bennacef I, Vandenberghe R, Vandenbulcke M, Salinas CA, Declercq R, Reynders T, Telan-Choing NF, Riffel K, Celen S, Serdons K, Bormans G, Tsai K, Walji A, Hostetler ED, Evelhoch JL, Van Laere K, Forman M, Stoch A, Sur C, Struyk A. Brain Imaging of Alzheimer Dementia Patients and Elderly Controls with 18F-MK-6240, a PET Tracer Targeting Neurofibrillary Tangles. J Nucl Med. 2019 Jan;60(1):107-114. doi: 10.2967/jnumed.118.208215. Epub 2018 Jun 7.

  PMID: 29880509 RESULT

MeSH Terms

Conditions

Alzheimer Disease

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2015
• First Posted: September 29, 2015
• Study Start: October 19, 2015
• Primary Completion: December 27, 2016
• Study Completion: December 27, 2016
• Last Updated: September 18, 2018
• Results First Posted: July 23, 2018

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share