Alzheimer's Disease
Conditions
Brief summary
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.
Interventions
DRUGVX-745
Orally-active P38 MAP kinase alpha-selective inhibitor
Sponsors
EIP Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 85 Years
Healthy volunteers
No
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 * Gradual progressive decline in memory function over \>6 months * Amnestic presentation on neuropsychological testing with rapid forgetting (% reduction 1.5 standard deviations below the mean) * Clinical Dementia Rating (CDR) Sum of Box (SOB) score ≥0.5 * Mini-Mental State Examination (MMSE) range: 20 to 30 * 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
* Evidence of neurodegenerative disease other than AD * Inability for any reason to undergo MRI scans (e.g. pacemaker, vascular stent or stent graft). Patients who require sedation for screening procedures such as MRI may receive a short-acting sedative. * Psychiatric disorder that would compromise ability to comply with study requirements * History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years * Significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder or metabolic/endocrine disorders or other disease that would preclude treatment with p38 MAP kinase inhibitor and/or assessment of drug safety and efficacy * Recent (\<90 days) changes to AD medications prescribed for cognitive reasons or with the potential to impact cognition * Psychotropic drugs taken within 1 month. Anticoagulant drugs taken within 1 week. * Participation in a study of an investigational drug less than 6 months or 5 half-lives of the investigational drug, whichever is longer, before enrollment in the study * Male subjects with female partner of child-bearing potential who are unwilling or unable to adhere to contraception requirements * Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingoophorectomy * Positive urine or serum pregnancy test or plans desires to become pregnant during the course of the trial * Donation of \>500 mL of blood or blood products within 2 months * History of alcohol and/or illicit drug abuse within 6 months. * Infection with hepatitis A, B or C or HIV. * Any factor deemed by the investigator to be likely to interfere with study conduction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines | Baseline and Day 42 of dosing with VX-745 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Number of patients with severe or serious adverse events |
| Maximal CSF VX-745 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. | Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken |
| Episodic Memory Function | Change from baseline to Day 42 | Total Recall in Hopkins Verbal Learning Test (HVLT). Range is 0-36, with increases in score indicating improvement in cognitive function. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 8 |
| 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 | 1 |
| Total | 9 |
Baseline characteristics
| Characteristic | VX-745 Dose Level 1 | VX-745 Dose Level 2 | Total |
|---|---|---|---|
| Age, Continuous | 71 years | 68 years | 71 years |
| Region of Enrollment United States | 8 count of participants | 1 count of participants | 9 count of participants |
| Sex: Female, Male Female | 5 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 0 / 9 |
Outcome results
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.
Time frame: Baseline and Day 42 of dosing with VX-745
Population: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Study Population | Percent Change From Baseline to End of Treatment in Cerebrospinal Fluid Levels of Cytokines | 137 percentage of baseline at Day 42 | Standard Deviation 115 |
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.
Time frame: Change from baseline to Day 42
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Study Population | Episodic Memory Function | 3.5 points on HLVT Total Recall (range 0-36) | Standard Deviation 3.6 |
Secondary
Maximal CSF VX-745 Concentration
Ratio fo CSF to plasma drug concentration at time matched time points. Samples taken
Time frame: 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.
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Study Population | Maximal CSF VX-745 Concentration | 0.062 ratio of plasma drug concentration | Standard Deviation 0.01 |
Secondary
Severe or Serious Adverse Events
Number of patients with severe or serious adverse events
Time frame: At baseline and at each study visit during (days 1, 7, 14, 21, 28, 35 and 42) and after (day 51) dosing
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Overall Study Population | Severe or Serious Adverse Events | 0 Participants |
| Neflamapimod (VX-745) Dose Level 2 | Severe or Serious Adverse Events | 0 Participants |