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This study will assess the effects of VX-745 on markers of disease in the central nervous system of patients with MCI due to AD or with mild AD. The study will also evaluate the safety and tolerability of VX-745 in these patients during 6 weeks of dosing, as well as the plasma and cerebrospinal fluid concentrations of VX-745 during dosing.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| VX-745 dose level 1 | Experimental | Active Group 1: VX-745 dose level 1 twice daily |
|
| VX-745 dose level 2 | Experimental | Active Group 1: VX-745 dose level 2 twice daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| VX-745 | Drug | Orally-active P38 MAP kinase alpha-selective inhibitor |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines | Cytokines: Of nine cytokines assessed, only CSF IL-8 quantifiable at all time points. And so, only IL-8 levels are being reported herein. The analysis was exploratory and no statistical analysis was performed. | Baseline and Day 42 of dosing with VX-745 |
| Measure | Description | Time Frame |
|---|---|---|
| Severe or Serious Adverse Events | Number of patients with severe or serious adverse events | At baseline and at each study visit during (days 1, 7, 14, 21, 28, 35 and 42) and after (day 51) dosing |
| Maximal CSF VX-745 Concentration |
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Inclusion Criteria:
Age 60 - 85 (inclusive)
Willing and able to provide informed consent
Clinical presentation consistent with MCI due to AD or of mild AD
Brain hypometabolism by 18F-2-fluoro-2-deoxyglucose (FDG)-PET
Participants may be taking medications for AD, provided that the dose of these medications has been stable for >3 months.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Hakop Gevorkyan, MD | Parexel | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Parexel International | Glendale | California | 91206 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33974419 | Derived | Tormahlen NM, Martorelli M, Kuhn A, Maier F, Guezguez J, Burnet M, Albrecht W, Laufer SA, Koch P. Design and Synthesis of Highly Selective Brain Penetrant p38alpha Mitogen-Activated Protein Kinase Inhibitors. J Med Chem. 2022 Jan 27;65(2):1225-1242. doi: 10.1021/acs.jmedchem.0c01773. Epub 2021 May 11. |
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During the course of the study, and after one subject had been enrolled in the 125 mg dose group, FDA mandated the removal of the 125 mg dose group. As a result, the number subjects was revised downward to 9, 8 as planned in the 40 mg dose group and 1 in the 125 mg dose group.
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| ID | Title | Description |
|---|---|---|
| FG000 | Neflamapimod (VX-745) Dose Level 1 | Active Group 1: VX-745 40 mg twice daily Neflamapimod (VX-745): Orally-active P38 MAP kinase alpha-selective inhibitor |
| FG001 | Neflamapimod (VX-745) Dose Level 2 | Active Group 1: VX-745 125 mg twice daily Neflamapimod (VX-745): Orally-active P38 MAP kinase alpha-selective inhibitor |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | VX-745 Dose Level 1 | Active Group 1: VX-745 dose level 1 twice daily VX-745: Orally-active P38 MAP kinase alpha-selective inhibitor |
| BG001 | VX-745 Dose Level 2 | Active Group 1: VX-745 dose level 2 twice daily VX-745: Orally-active P38 MAP kinase alpha-selective inhibitor |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines | Cytokines: Of nine cytokines assessed, only CSF IL-8 quantifiable at all time points. And so, only IL-8 levels are being reported herein. The analysis was exploratory and no statistical analysis was performed. | As there was only one subject in the 125 mg dose group (see Pre-Assignment Details), and the blood concentration levels in this subject was similar to that in 125 mg dose group, this subjects data was combined with the 40 mg dose group in this analysis. In addition, two subjects did not have Day 42 CSF samples available for analysis | Posted | Mean | Standard Deviation | percentage of baseline at Day 42 | Baseline and Day 42 of dosing with VX-745 |
|
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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 | Overall Study Population | Combined 40 mg and 125 mg subjects. As there was only one subject in the 125 mg dose group (see Pre-Assignment Details), and the blood concentration levels in this subject was similar to that in 125 mg dose group, this subjects data was combined with the 40 mg dose group in the adverse event analysis. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John Alam | EIP Pharma | 617-945-0794 | jalam@eippharma.com |
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| 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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| ID | Term |
|---|---|
| C464966 | VX-745 |
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Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken
| All samples with quantifiable CSF drug levels were included (n=12). Eight were obtained 3-hours post-dose, either on Day 1 (n=4) or Day 42 (n=4). 3 samples were at 6-hours post-dose on Day 42; and one was at 6-hours post-dose on Day 1. |
| Episodic Memory Function | Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function. | Change from baseline to Day 42 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | count of participants |
|
|
|
| Secondary | Severe or Serious Adverse Events | Number of patients with severe or serious adverse events | Posted | Count of Participants | Participants | At baseline and at each study visit during (days 1, 7, 14, 21, 28, 35 and 42) and after (day 51) dosing |
|
|
|
| Secondary | Maximal CSF VX-745 Concentration | Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken | As there was only one subject in the 125 mg dose group (see Pre-Assignment Details), and the blood concentration levels in this subject was similar to that in 125 mg dose group, this subjects data was combined with the 40 mg dose group in this analysis. | Posted | Mean | Standard Deviation | ratio of plasma drug concentration | All samples with quantifiable CSF drug levels were included (n=12). Eight were obtained 3-hours post-dose, either on Day 1 (n=4) or Day 42 (n=4). 3 samples were at 6-hours post-dose on Day 42; and one was at 6-hours post-dose on Day 1. |
|
|
|
| Secondary | Episodic Memory Function | Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function. | As there was only one subject in the 125 mg dose group (see Pre-Assignment Details), and the blood concentration levels in this subject was similar to that in 125 mg dose group, this subjects data was combined with the 40 mg dose group in all outcome measure analyses. In addition, one subject did not have a Day 42 HVLT-R analysis. | Posted | Mean | Standard Deviation | points on HLVT Total Recall (range 0-36) | Change from baseline to Day 42 |
|
|
|
| 0 |
| 9 |
| 9 |
| 9 |
| Headache | Nervous system disorders | Non-systematic Assessment |
|
| Somnolence | Nervous system disorders | Non-systematic Assessment |
|
| Orthostatic hypotension | Vascular disorders | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Hot flush | Vascular disorders | Non-systematic Assessment |
|
Clinical study was conducted at at clinical pharmacology unit owned by a contract research organization (CRO; Parexel) that was contracted by the sponsor to conduct the study. Site principal investigator is an employee of a contract research organization. As per the contract, the sponsor has "all rights, title and interest in the results".
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |