Alzheimer Disease, Dementia of Alzheimer Type
Conditions
Keywords
Alzheimer's Disease, Cognition, Dementia, ATH-1017, Memory Loss
Brief summary
This study is designed to evaluate treatment effects of ATH-1017 (fosgonimeton) in mild to moderate Alzheimer's subjects with a randomized treatment duration of 26-weeks.
Detailed description
This study is designed to assess the correlation of the functional translational biomarker P300 latency and change in ADAS-Cog11 induced by ATH-1017 therapy, over 26-week randomized, double-blind treatment.
Interventions
DRUGATH-1017
Daily subcutaneous (SC) injection of ATH-1017 in a pre-filled syringe
DRUGPlacebo
Daily subcutaneous (SC) injection of Placebo in a pre-filled syringe
Sponsors
National Institute on Aging (NIA)
Athira Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, placebo-controlled, parallel-group study
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Age 55 to 85 years * Mild-to-moderate AD dementia subjects, MMSE 14-24, CDR 1 or 2 at Screening * Clinical diagnosis of dementia, due probably to AD, by Revised National Institute on Aging-Alzheimer's Association criteria (McKhann, 2011) * Reliable and capable support person/caregiver * Treatment-free or receiving stable acetylcholinesterase inhibitor (AChEI) treatment, defined as: * Treatment-naïve, OR * Subjects are on a stable, approved dose of an AChEI (except for donepezil at 23 mg PO) for at least 3 months before Screening OR * Subjects who received an AChEI in the past and discontinued 4 weeks prior to Screening Key
Exclusion criteria
* History of significant neurologic disease, other than AD, that may affect cognition, or concurrent with the onset of dementia * History of unexplained loss of consciousness, and epileptic fits (unless febrile) * Subject has atypical variant presentation of AD, if known from medical history, particularly non-amnestic AD * History of brain MRI scan indicative of any other significant abnormality * Hearing test result considered unacceptable for auditory ERP P300 assessment * Diagnosis of severe major depressive disorder even without psychotic features * Significant suicide risk * History within 2 years of Screening, or current diagnosis of psychosis * Myocardial infarction or unstable angina within the last 6 months * Clinically significant (in the judgment of the investigator) cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: pacemaker is acceptable) * Subject has either hypertension (supine diastolic blood pressure \> 95 mmHg), or symptomatic hypotension in the judgment of the investigator * Clinically significant ECG abnormality at Screening * Renal insufficiency (serum creatinine \> 2.0 mg/dL) * 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 in any form, combination or dosage within 4 weeks prior to Screening * Donepezil at 23 mg PO * The subject has received active amyloid or tau immunization (i.e., vaccination for Alzheimer's disease) at any time, or passive immunization (i.e., monoclonal antibodies for Alzheimer's disease) within 6 months of Screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-related Potential (ERP) P300 Latency at Baseline | At Baseline (Day 1) | 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. Baseline was defined as Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at Baseline | At Baseline (Day 1) | The ADAS-Cog11 was designed to measure cognitive symptom change in participants with Alzheimer's Disease (AD) and consisted of 11 tasks. It was performed to evaluate the correlation of ERP P300 latency and cognition. The standard 11 items (and corresponding score range) were: word recall (0-10), commands (0-5), constructional praxis (0-5), naming objects and fingers (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), spoken language ability (0-5), comprehension of spoken language (0-5), word-finding difficulty (0-5), and remembering test instructions (0-5). The test included 7 performance items and 4 clinician-rated items. The ADAS-Cog11 total score was the sum of all 11 individual items, with a total score ranging from 0 (no impairment) to 70 (severe impairment). Higher scores indicated more severe cognitive impairment. Baseline was defined as Day 1. |
Countries
Australia, United States
Participant flow
Recruitment details
The study was conducted at a total of 6 centers in Australia and 8 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 a clinical diagnosis of mild to moderate Alzheimer's disease (AD).
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 | 24 |
| ATH-1017 40 mg Participants were randomized to receive ATH-1017 40 mg via 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 | 27 |
| ATH-1017 70 mg Participants were randomized to receive ATH-1017 70 mg via 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 | 26 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | ATH-1017 40 mg | ATH-1017 70 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 70.0 Years STANDARD_DEVIATION 8.03 | 70.6 Years STANDARD_DEVIATION 6.54 | 73.4 Years STANDARD_DEVIATION 7.26 | 71.4 Years STANDARD_DEVIATION 7.32 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 27 Participants | 26 Participants | 74 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 | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 4 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 25 Participants | 24 Participants | 71 Participants |
| Sex: Female, Male Female | 12 Participants | 15 Participants | 12 Participants | 39 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 14 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 27 | 0 / 26 |
| other Total, other adverse events | 18 / 24 | 24 / 27 | 26 / 26 |
| serious Total, serious adverse events | 0 / 24 | 3 / 27 | 0 / 26 |
Outcome results
Primary
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. Baseline was defined as Day 1.
Time frame: At Baseline (Day 1)
Population: Modified Intent-to-Treat (mITT) Population: included all randomized participants who took at least one dose of the study medication and who completed at least one ERP P300 Baseline assessment and/or one post-Baseline ERP P300 assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Event-related Potential (ERP) P300 Latency at Baseline | 361.5 Milliseconds (ms) | Standard Deviation 32.23 |
| ATH-1017 40 mg | Event-related Potential (ERP) P300 Latency at Baseline | 382.3 Milliseconds (ms) | Standard Deviation 40.18 |
| ATH-1017 70 mg | Event-related Potential (ERP) P300 Latency at Baseline | 375.3 Milliseconds (ms) | Standard Deviation 35.77 |
Secondary
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at Baseline
The ADAS-Cog11 was designed to measure cognitive symptom change in participants with Alzheimer's Disease (AD) and consisted of 11 tasks. It was performed to evaluate the correlation of ERP P300 latency and cognition. The standard 11 items (and corresponding score range) were: word recall (0-10), commands (0-5), constructional praxis (0-5), naming objects and fingers (0-5), ideational praxis (0-5), orientation (0-8), word recognition (0-12), spoken language ability (0-5), comprehension of spoken language (0-5), word-finding difficulty (0-5), and remembering test instructions (0-5). The test included 7 performance items and 4 clinician-rated items. The ADAS-Cog11 total score was the sum of all 11 individual items, with a total score ranging from 0 (no impairment) to 70 (severe impairment). Higher scores indicated more severe cognitive impairment. Baseline was defined as Day 1.
Time frame: At Baseline (Day 1)
Population: mITT Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at Baseline | 23.0 Scores on a scale | Standard Deviation 7.96 |
| ATH-1017 40 mg | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at Baseline | 22.4 Scores on a scale | Standard Deviation 8.94 |
| ATH-1017 70 mg | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at Baseline | 20.7 Scores on a scale | Standard Deviation 7.18 |