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| ID | Type | Description | Link |
|---|---|---|---|
| MK-6884-001 | Other Identifier | Merck Protocol Number | |
| 2015-001631-20 | EudraCT Number |
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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%.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1, Healthy Participants | Experimental | Healthy participants receive a single intravenous (IV) dose of ~370 megabecquerel (MBq) [11C]MK-6884 in Part 1 of the study. |
|
| Part 2, Healthy Elderly Participants | Experimental | 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. |
|
| Part 3, Participants with AD | Experimental | Participants with AD receive a single IV dose of ~370 MBq [11C]MK-6884 in Part 3 of the study. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| [11C]MK-6884 | Drug | IV bolus dose of ~370 MBq [11C]MK-6884 |
|
| 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. |
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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:
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:
Part 3 Only:
Moderate to severe AD as defined by:
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:
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:
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
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Merck Sharp & Dohme LLC | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35020407 | Result | Li W, Wang Y, Lohith TG, Zeng Z, Tong L, Mazzola R, Riffel K, Miller P, Purcell M, Holahan M, Haley H, Gantert L, Hesk D, Ren S, Morrow J, Uslaner J, Struyk A, Wai JM, Rudd MT, Tellers DM, McAvoy T, Bormans G, Koole M, Van Laere K, Serdons K, de Hoon J, Declercq R, De Lepeleire I, Pascual MB, Zanotti-Fregonara P, Yu M, Arbones V, Masdeu JC, Cheng A, Hussain A, Bueters T, Anderson MS, Hostetler ED, Basile AS. The PET tracer [11C]MK-6884 quantifies M4 muscarinic receptor in rhesus monkeys and patients with Alzheimer's disease. Sci Transl Med. 2022 Jan 12;14(627):eabg3684. doi: 10.1126/scitranslmed.abg3684. Epub 2022 Jan 12. |
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N=20 participants were enrolled, with N=20 receiving ≥1 dose of [11C]MK-6884. N=1 participant in Part 2 withdrew from study before receiving the second dose of [11C]MK-6884.
Healthy participants (Part 1), healthy elderly participants (Part 2), and participants with Alzheimer's Disease (AD; Part 3) were enrolled in this study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part 1, Healthy Participants | Healthy participants receive a single intravenous (IV) dose of ~370 megabecquerel (MBq) [11C]MK-6884 in Part 1 of the study. |
| FG001 | Part 2, Healthy Elderly Participants | 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. |
| FG002 | Part 3, Participants With AD | Participants with AD receive a single IV dose of ~370 MBq [11C]MK-6884 in Part 3 of the study. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The baseline analysis population includes all randomized participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | Part 1, Healthy Participants | Healthy participants receive a single IV dose of ~370 MBq [11C]MK-6884 in Part 1 of the study. |
| BG001 | Part 2, Healthy Elderly Participants | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Includes all participants receiving ≥1 dose of [11C]MK-6884 in Parts 1, 2, or 3. | Posted | Count of Participants | Participants | Up to 15 days |
|
Up to 15 days
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. All participants receiving ≥1 dose of [11C]MK-6884 in study Parts 1, 2, or 3 are included.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part 1, Healthy Participants | Healthy participants receive a single IV dose of ~370 MBq [11C]MK-6884 in Part 1 of the study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Tendon rupture | Injury, poisoning and procedural complications | MedDRA 20.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Vice President, Global Clinical Development | Merck Sharp & Dohme LLC | 1-800-672-6372 | ClinicalTrialsDisclosure@merck.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 24, 2017 | Sep 28, 2018 | Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| 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 |
| BG002 | Part 3, Participants With AD | Participants with AD receive a single IV dose of ~370 MBq [11C]MK-6884 in Part 3 of the study. |
| BG003 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Part 2, Healthy Elderly Participants | 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. |
| OG002 | Part 3, Participants With AD | Participants with AD receive a single IV dose of ~370 MBq [11C]MK-6884 in Part 3 of the study. |
|
|
| Primary | 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. | Includes all participants receiving ≥1 dose of [11C]MK-6884 in Parts 1, 2, or 3. | Posted | Count of Participants | Participants | Up to 15 days |
|
|
|
| Primary | [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. | Includes only healthy participants in Part 1 (N=3). Per protocol, participants in Parts 2 and 3 were not tested for ED of [11C]MK-6884 and are excluded. | Posted | Mean | Standard Deviation | mSv / MBq | Up to 2 hours post-dose |
|
|
|
| Primary | [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. | Includes only healthy participants in Part 1 (N=3), having estimable data for the individual organ. Per protocol, participants in Parts 2 and 3 were not tested for organ ED of [11C]MK-6884 and are excluded. | Posted | Mean | Standard Deviation | mSv / MBq | Up to 2 hours post dose |
|
|
|
| Primary | [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. | Includes only healthy elderly participants in Part 2 receiving 2 doses of [11C]MK-6884 who sufficiently comply with study protocol (N=6). Per protocol, participants in Part 1 were not tested for mean BPND of [11C]MK-6884 and are excluded. Mean BPND data for Part 3 participants are presented in a separate table. | Posted | Mean | Standard Deviation | Ratio | Up to 90 minutes post dose |
|
|
|
| Primary | [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. | Includes only healthy elderly participants in Part 2 receiving 2 doses of [11C]MK-6884 who sufficiently comply with study protocol (N=6). Per protocol, participants in Parts 1 and 3 were not tested for intra-subject T-RT variability of BPND of [11C]MK-6884 and are excluded. | Posted | Mean | Standard Deviation | Percent variability | Up to 24 hours post dose |
|
|
|
| Primary | [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. | Includes only participants with AD in Part 3 receiving [11C]MK-6884 who sufficiently comply with study protocol (N=10). Per protocol, participants in Part 1 were not tested for mean BPND of [11C]MK-6884 and are excluded. Mean BPND data for Part 2 participants are presented in a separate table. | Posted | Mean | Standard Deviation | Ratio | Up to 90 minutes post dose |
|
|
|
| 0 |
| 3 |
| 0 |
| 3 |
| 1 |
| 3 |
| EG001 | Part 2, Healthy Elderly Participants | 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. | 0 | 7 | 1 | 7 | 4 | 7 |
| EG002 | Part 3, Participants With AD | Participants with AD receive a single IV dose of ~370 MBq [11C]MK-6884 in Part 3 of the study. | 0 | 10 | 0 | 10 | 1 | 10 |
| Dry mouth | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
|
| Glossodynia | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
|
| Lip dry | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 20.1 | Systematic Assessment |
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| Catheter site pain | General disorders | MedDRA 20.1 | Systematic Assessment |
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| Influenza like illness | General disorders | MedDRA 20.1 | Systematic Assessment |
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| Procedural nausea | Injury, poisoning and procedural complications | MedDRA 20.1 | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 20.1 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 20.1 | Systematic Assessment |
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| Dizziness postural | Nervous system disorders | MedDRA 20.1 | Systematic Assessment |
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| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA 20.1 | Systematic Assessment |
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The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| Brain |
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| Breasts |
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| Gallbladder Wall |
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| Lower Large Intestine Wall |
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| Small Intestine |
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| Stomach Wall |
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| Upper Large Intestine Wall |
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| Heart Wall |
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| Kidneys |
|
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| Liver |
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| Lungs |
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| Muscle |
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| Ovaries (Female Participants Only) |
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| Pancreas |
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| Red Marrow |
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| Osteogenic Cells |
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| Skin |
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| Spleen |
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| Testes (Male Participants Only) |
|
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| Thymus |
|
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| Thyroid |
|
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| Urinary Bladder Wall |
|
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| Uterus |
|
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| Title | Measurements |
|---|---|
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| Temporal Cortex |
|
| Hippocampus |
|
| Title | Measurements |
|---|---|
|
| Temporal Cortex |
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| Hippocampus |
|