Dementia With Lewy Bodies, Parkinson Disease Dementia
Conditions
Keywords
Parkinson's Disease Dementia, Dementia with Lewy Bodies, Dementia, HGF/MET, Hepatocyte Growth Factor, Neurotrophic, ATH-1017, Event-Related Potential, ERP P300
Brief summary
This study is designed to evaluate the safety and treatment effects of fosgonimeton (ATH-1017) in subjects with Parkinson's Disease Dementia or Dementia with Lewy Bodies, with a randomized treatment duration of 26 weeks.
Detailed description
The study is designed to evaluate the safety and treatment effects of ATH-1017 in subjects with Parkinson's Disease Dementia or Dementia with Lewy Bodies, with a randomized, double-blind, placebo-controlled, parallel-arm treatment duration of 26 weeks.
Interventions
DRUGATH-1017
Daily subcutaneous injection of ATH-1017 in a pre-filled syringe
DRUGPlacebo
Daily subcutaneous injection of Placebo in a pre-filled syringe
Sponsors
Athira Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with confirmed diagnosis of Parkinson's disease or Dementia with Lewy Bodies * MoCA score 11 to 23, inclusive, at screening * Probable Parkinson's Disease Dementia or Lewy Body Dementia * BMI between ≥ 16and ≤ 35 kg/m2 for females and between≥ 18 and ≤ 35 kg/m2 for males at Screening * Reliable and capable support person/caregiver, who is willing to accept responsibility for supervising the treatment or, if required, administering study drug, and assessing the condition of the subject throughout the study in accordance with all protocol requirements
Exclusion criteria
* Hoehn-Yahr stage 5 * History of significant neurological disease other than PDD or DLB that may affect cognition at onset of dementia * Subjects on deep brain stimulation * History of brain MRI scan indicative of any other significant abnormality * History of unexplained loss of consciousness, and epileptic fits * Hearing test result considered unacceptable for auditory ERP P300 assessment * Diagnosis of severe major depressive disorder even without psychotic features (GDS score \[15-item scale\] \>7 at Screening) * Significant suicide risk based on C-SSRS * Significant psychosis (according to Diagnostic and Statistical Manual of Mental Disorders) * Moderate or severe substance abuse disorder (according to DSM-5) * Myocardial infarction or unstable angina within the last 6 months * Clinically significant cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: pacemaker is acceptable) * Clinically significant ECG abnormality at Screening * Chronic kidney disease (eGFR \< 45 mL/min using Cockcroft-Gault formula) * Hepatic impairment with alanine aminotransferase or aspartate aminotransferase \> 2 times the upper limit of normal, or Child-Pugh class B and C * Malignant tumor within 3 years before Screening * Memantine at any dose or combination * Donepezil at 23 mg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Statistical Test (GST) Score at Baseline | Baseline | The Global Statistical Test (GST) score is a composite of the change from baseline (CFB) z-scores to Week 26 in the Alzheimer's Disease Assessment Scale - Cognitive Subscale, 13-Item Version (ADAS-Cog13; range 0-85; higher scores indicate greater impairment) and Event Related Potential P300 Latency (ERP P300; longer latency (milliseconds) indicates greater impairment). This composite approach was used to assess overall change in disease status and treatment effects of ATH-1017. The GST score was defined as a single outcome variable based on standardizing and combining individual patient-level z-score of change from baseline cognition (ADAS-Cog13) and ERP P300 latency scores. The between-group difference was calculated by subtracting the mean GST score for placebo from the mean GST score for ATH-1017. A negative value based on GST scores (ATH-1017 minus placebo) indicates a favorable response to ATH-1017, while a positive value favors placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-related Potential (ERP) P300 Latency at Baseline | Baseline | ERP P300 was a method of recording brain activity elicited by external stimuli, for example (e.g.), an oddball auditory stimulus, particularly of working memory access. The participant had to perform a task related to auditory stimuli in order to assess the P300 component (latency). The stimulus consisted of an oddball paradigm with 2 sound stimuli. Stimuli were presented through headphones and auditory stimulation for P300 was assessed in a recording lasting up to 10 minutes. It was calculated as the average across the pre-dose values at Baseline visit. |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) at Baseline | Baseline | The Alzheimer's Disease Assessment Scale - Cognitive Subscale, 13-Item Version (ADAS-Cog13) is designed to measure cognitive symptom change. The test comprises 9 performance items and 4 clinician-rated items (total score ranging from 0 to 85). Higher scores indicate more severe cognitive impairment. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at a total of 7 centers in the United States (US).
Pre-assignment details
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study comparing ATH-1017 40 milligrams per day (mg/day) and ATH-1017 70 mg/day with placebo in participants with Parkinson's Disease Dementia or Dementia with Lewy Bodies.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive placebo via subcutaneous (SC) injection QD preferably during daytime. The first SC injection of study drug was performed at site under supervision. The participant should withhold study drug administration on the day of subsequent clinic visits; study drug administration was done on site under supervision of site staff at these visits. Clinic visits took place on Day 1 and thereafter at Weeks 2, 6, 12, 16, 20, and 26, with a safety follow-up visit scheduled 4 weeks after completion of the double-blind period at Week 30 | 9 |
| ATH-1017 40 mg Participants were randomized to receive ATH-1017 40 mg via subcutaneous (SC) injection QD preferably during daytime. The first SC injection of study drug was performed at site under supervision. The participant should withhold study drug administration on the day of subsequent clinic visits; study drug administration was done on site under supervision of site staff at these visits. Clinic visits took place on Day 1 and thereafter at Weeks 2, 6, 12, 16, 20, and 26, with a safety follow-up visit scheduled 4 weeks after completion of the double-blind period at Week 30 | 9 |
| ATH-1017 70 mg Participants were randomized to receive ATH-1017 70 mg via subcutaneous (SC) injection QD preferably during daytime. The first SC injection of study drug was performed at site under supervision. The participant should withhold study drug administration on the day of subsequent clinic visits; study drug administration was done on site under supervision of site staff at these visits. Clinic visits took place on Day 1 and thereafter at Weeks 2, 6, 12, 16, 20, and 26, with a safety follow-up visit scheduled 4 weeks after completion of the double-blind period at Week 30 | 10 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 3 |
| Overall Study | Undetermined | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | ATH-1017 40 mg | ATH-1017 70 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 74.9 years STANDARD_DEVIATION 4.86 | 70.7 years STANDARD_DEVIATION 9.89 | 74.2 years STANDARD_DEVIATION 7.5 | 73.3 years STANDARD_DEVIATION 7.62 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 9 Participants | 9 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 8 Participants | 9 Participants | 10 Participants | 27 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 8 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 1 / 10 |
| other Total, other adverse events | 7 / 9 | 9 / 9 | 9 / 10 |
| serious Total, serious adverse events | 1 / 9 | 1 / 9 | 1 / 10 |
Outcome results
Primary
Global Statistical Test (GST) Score at Baseline
The Global Statistical Test (GST) score is a composite of the change from baseline (CFB) z-scores to Week 26 in the Alzheimer's Disease Assessment Scale - Cognitive Subscale, 13-Item Version (ADAS-Cog13; range 0-85; higher scores indicate greater impairment) and Event Related Potential P300 Latency (ERP P300; longer latency (milliseconds) indicates greater impairment). This composite approach was used to assess overall change in disease status and treatment effects of ATH-1017. The GST score was defined as a single outcome variable based on standardizing and combining individual patient-level z-score of change from baseline cognition (ADAS-Cog13) and ERP P300 latency scores. The between-group difference was calculated by subtracting the mean GST score for placebo from the mean GST score for ATH-1017. A negative value based on GST scores (ATH-1017 minus placebo) indicates a favorable response to ATH-1017, while a positive value favors placebo.
Time frame: Baseline
Population: Modified intent to treat population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Global Statistical Test (GST) Score at Baseline | -0.222 Z-score | Standard Deviation 0.6365 |
| ATH-1017 40 mg | Global Statistical Test (GST) Score at Baseline | 0.332 Z-score | Standard Deviation 0.6337 |
| ATH-1017 70 mg | Global Statistical Test (GST) Score at Baseline | -0.036 Z-score | Standard Deviation 1.005 |
Secondary
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) at Baseline
The Alzheimer's Disease Assessment Scale - Cognitive Subscale, 13-Item Version (ADAS-Cog13) is designed to measure cognitive symptom change. The test comprises 9 performance items and 4 clinician-rated items (total score ranging from 0 to 85). Higher scores indicate more severe cognitive impairment.
Time frame: Baseline
Population: Modified intent to treat population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) at Baseline | 16.9 score on a scale | Standard Deviation 6.94 |
| ATH-1017 40 mg | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) at Baseline | 29.7 score on a scale | Standard Deviation 10.03 |
| ATH-1017 70 mg | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) at Baseline | 23.8 score on a scale | Standard Deviation 11.49 |
Secondary
Event-related Potential (ERP) P300 Latency at Baseline
ERP P300 was a method of recording brain activity elicited by external stimuli, for example (e.g.), an oddball auditory stimulus, particularly of working memory access. The participant had to perform a task related to auditory stimuli in order to assess the P300 component (latency). The stimulus consisted of an oddball paradigm with 2 sound stimuli. Stimuli were presented through headphones and auditory stimulation for P300 was assessed in a recording lasting up to 10 minutes. It was calculated as the average across the pre-dose values at Baseline visit.
Time frame: Baseline
Population: Modified intent to treat population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Event-related Potential (ERP) P300 Latency at Baseline | 381.84 Millisecond (ms) | Standard Deviation 51.739 |
| ATH-1017 40 mg | Event-related Potential (ERP) P300 Latency at Baseline | 373.19 Millisecond (ms) | Standard Deviation 18.669 |
| ATH-1017 70 mg | Event-related Potential (ERP) P300 Latency at Baseline | 367.84 Millisecond (ms) | Standard Deviation 45.635 |