Alzheimer Disease, Dementia of Alzheimer Type
Conditions
Keywords
Alzheimer's Disease, Cognition, Dementia, ATH-1017, LIFT AD, Fosgonimeton
Brief summary
This study is designed to evaluate safety and efficacy of fosgonimeton (ATH-1017) in the treatment of mild to moderate Alzheimer's disease with a randomized treatment duration of 26-weeks.
Detailed description
The study is designed to evaluate safety and efficacy of ATH-1017 in mild to moderate AD subjects, with randomized, parallel-arm treatment duration of 26 weeks, and based on clinical diagnostic criteria of Alzheimer's disease. Clinical efficacy is demonstrated by improvement in cognition and global/functional assessments comparing treatment to placebo.
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
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) * Body mass index (BMI) of ≥ 18 and ≤ 35 kg/m2 at Screening * Reliable and capable support person/caregiver * Treatment-free (subjects not receiving acetylcholinesterase inhibitor \[AChEI\] treatment), defined as: * Treatment-naïve, OR * Subjects who received an AChEI in the past and discontinued at least 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 * 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 * 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 cardiac arrhythmia (including atrial fibrillation), cardiomyopathy, or cardiac conduction defect (note: pacemaker is acceptable) * Subject has either hypertension or symptomatic hypotension * Clinically significant ECG abnormality at Screening * Chronic kidney disease with estimated glomerular filtration rate (eGFR) \<45 mL/min * 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 * Acetylcholinesterase inhibitors in any dosage form * 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 |
|---|---|---|
| Global Statistical Test (GST) Score | Baseline and Week 26 | The Global Statistical Test (GST) score is a composite of cognition and function, calculated as the average of two change from baseline z-scores; the z-scores are calculated for the change from baseline scores for cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale \[ADAS-Cog11\]; lower value indicates improvement) and function (Alzheimer's Disease Cooperative Study - Activities of Daily Living, 23-item version \[ADCS-ADL23\] score; higher value indicates improvement). GST is a standardized score relative to the population mean. Therefore, a GST score of 0 is representative of the population mean. Since GST is a composite of two endpoints, a negative ADCS-ADL23 score is used in deriving GST. Therefore, a lower score indicates improvement, and a higher score indicates worsening. There are no defined clinically relevant thresholds for this GST score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11) Change From Baseline | Baseline and Week 26 | The ADAS-Cog11 was designed to measure cognitive symptom change in participants with Alzheimer's Disease (AD) and consisted of 11 tasks. 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. |
| Alzheimer's Disease Cooperative Study - Activities of Daily Living, 23-Item Version (ADCS-ADL23) Change From Baseline | Baseline and Week 26 | The ADCS-ADL23 is a 23-item assessment of functional impairment in terms of activities of daily living administered to the support person/caregiver. It comprises 23 questions about the subject's involvement and level of performance across items representing daily living. The questions range from basic to instrumental activities of daily living. Each item is rated from the highest level of independent performance to complete loss. The total score range is from 0 to 78, with lower scores indicating greater functional impairment. Baseline was defined as Day 1. |
| Plasma Neurofilament Light Chain (NfL) Concentrations Change From Baseline | Baseline and Week 26 | Neurofilament light chain (NfL) is an objective biomarker of neurodegeneration and was measured to quantitatively support the evaluation of ATH-1017. Higher concentrations of NfL in plasma are associated with neurodegeneration. |
Countries
United States
Participant flow
Recruitment details
The study was conducted in the United States.
Pre-assignment details
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the clinical efficacy of ATH-1017 treatment compared 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 once-daily (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 | 218 |
| ATH-1017 40 Milligrams (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 | 224 |
| 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 | 107 |
| Total | 549 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Primary Analysis Population | >1 Reason | 2 | 4 | 0 |
| Primary Analysis Population | Adverse Event | 6 | 9 | 0 |
| Primary Analysis Population | Protocol Violation | 1 | 1 | 0 |
| Primary Analysis Population | Undetermined | 7 | 3 | 0 |
| Primary Analysis Population | Withdrawal by Subject | 0 | 4 | 0 |
| Safety Population, >=1 Dose Administered | >1 Reason | 4 | 7 | 12 |
| Safety Population, >=1 Dose Administered | Adverse Event | 10 | 22 | 18 |
| Safety Population, >=1 Dose Administered | Lack of Efficacy | 1 | 1 | 0 |
| Safety Population, >=1 Dose Administered | Lost to Follow-up | 0 | 3 | 2 |
| Safety Population, >=1 Dose Administered | Physician Decision | 0 | 1 | 0 |
| Safety Population, >=1 Dose Administered | Protocol Violation | 2 | 1 | 0 |
| Safety Population, >=1 Dose Administered | Undetermined | 15 | 9 | 5 |
| Safety Population, >=1 Dose Administered | Withdrawal by Subject | 3 | 6 | 1 |
Baseline characteristics
| Characteristic | Placebo | ATH-1017 40 Milligrams (mg) | ATH-1017 70 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 73.4 years STANDARD_DEVIATION 7.22 | 72.7 years STANDARD_DEVIATION 7.24 | 71.0 years STANDARD_DEVIATION 6.8 | 72.6 years STANDARD_DEVIATION 7.19 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 39 Participants | 45 Participants | 6 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 179 Participants | 177 Participants | 101 Participants | 457 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 7 Participants | 1 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 19 Participants | 8 Participants | 41 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 | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 2 Participants | 1 Participants | 9 Participants |
| Race (NIH/OMB) White | 185 Participants | 194 Participants | 97 Participants | 476 Participants |
| Sex: Female, Male Female | 116 Participants | 115 Participants | 56 Participants | 287 Participants |
| Sex: Female, Male Male | 102 Participants | 109 Participants | 51 Participants | 262 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 218 | 0 / 224 | 0 / 107 |
| other Total, other adverse events | 65 / 218 | 185 / 224 | 104 / 107 |
| serious Total, serious adverse events | 15 / 218 | 11 / 224 | 3 / 107 |
Outcome results
Primary
Global Statistical Test (GST) Score
The Global Statistical Test (GST) score is a composite of cognition and function, calculated as the average of two change from baseline z-scores; the z-scores are calculated for the change from baseline scores for cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale \[ADAS-Cog11\]; lower value indicates improvement) and function (Alzheimer's Disease Cooperative Study - Activities of Daily Living, 23-item version \[ADCS-ADL23\] score; higher value indicates improvement). GST is a standardized score relative to the population mean. Therefore, a GST score of 0 is representative of the population mean. Since GST is a composite of two endpoints, a negative ADCS-ADL23 score is used in deriving GST. Therefore, a lower score indicates improvement, and a higher score indicates worsening. There are no defined clinically relevant thresholds for this GST score.
Time frame: Baseline and Week 26
Population: Primary Analysis Population (Placebo or 40 mg ATH-1017 mITT Participants not taking AChEIs)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Global Statistical Test (GST) Score | -0.126 Z-score | Standard Error 0.0683 |
| ATH-1017 40 Milligrams (mg) | Global Statistical Test (GST) Score | -0.208 Z-score | Standard Error 0.0707 |
Secondary
Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11) Change From Baseline
The ADAS-Cog11 was designed to measure cognitive symptom change in participants with Alzheimer's Disease (AD) and consisted of 11 tasks. 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: Baseline and Week 26
Population: Primary Analysis Population (Placebo or 40 mg ATH-1017 mITT Participants not taking AChEIs)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11) Change From Baseline | -0.39 score on a scale | Standard Error 0.54 |
| ATH-1017 40 Milligrams (mg) | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11) Change From Baseline | -1.09 score on a scale | Standard Error 0.56 |
Secondary
Alzheimer's Disease Cooperative Study - Activities of Daily Living, 23-Item Version (ADCS-ADL23) Change From Baseline
The ADCS-ADL23 is a 23-item assessment of functional impairment in terms of activities of daily living administered to the support person/caregiver. It comprises 23 questions about the subject's involvement and level of performance across items representing daily living. The questions range from basic to instrumental activities of daily living. Each item is rated from the highest level of independent performance to complete loss. The total score range is from 0 to 78, with lower scores indicating greater functional impairment. Baseline was defined as Day 1.
Time frame: Baseline and Week 26
Population: Primary Analysis Population (Placebo or 40 mg ATH-1017 mITT Participants not taking AChEIs)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Alzheimer's Disease Cooperative Study - Activities of Daily Living, 23-Item Version (ADCS-ADL23) Change From Baseline | -0.02 score on a scale | Standard Error 0.65 |
| ATH-1017 40 Milligrams (mg) | Alzheimer's Disease Cooperative Study - Activities of Daily Living, 23-Item Version (ADCS-ADL23) Change From Baseline | 0.65 score on a scale | Standard Error 0.67 |
Secondary
Plasma Neurofilament Light Chain (NfL) Concentrations Change From Baseline
Neurofilament light chain (NfL) is an objective biomarker of neurodegeneration and was measured to quantitatively support the evaluation of ATH-1017. Higher concentrations of NfL in plasma are associated with neurodegeneration.
Time frame: Baseline and Week 26
Population: Primary Analysis Population (Placebo or 40 mg ATH-1017 mITT Participants not taking AChEIs)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Plasma Neurofilament Light Chain (NfL) Concentrations Change From Baseline | 2.95 picogram / milliter | Standard Error 2.49 |
| ATH-1017 40 Milligrams (mg) | Plasma Neurofilament Light Chain (NfL) Concentrations Change From Baseline | -0.96 picogram / milliter | Standard Error 2.48 |