Alzheimer Disease
Conditions
Brief summary
The study is a 24-week, randomized, double-blind, multi-site, placebo-controlled study in participants with mild cognitive impairment (MCI) or early dementia due to Alzheimer's disease (AD).
Detailed description
The study is a 24-week, randomized, double-blind, multi-site, placebo-controlled study in participants with mild cognitive impairment (MCI) or early dementia due to Alzheimer's disease (AD). The study is designed to evaluate the safety, tolerability, drug target engagement and neurobiological effects of treatment with AMX0035 over 24 weeks. The study is designed to yield deep phenotyping insight for the purposes of demonstrating the effects of AMX0035 on mechanistic targets of engagement and disease biology. The study will evaluate diverse disease-relevant markers and produce an informative dataset that will allow for evaluation and correlation of imaging-based markers, neurobiological changes, functional measures, and cognitive outcomes. Participants receive orally administered study drug twice daily for a treatment duration of approximately 24 weeks and attend clinic visits at Screening, Baseline, Week 6, Week 12, Week 18, and Week 24.
Interventions
DRUGAMX0035
Combination Therapy of PB and TURSO
DRUGPlacebo
Placebo
Sponsors
Alzheimer's Drug Discovery Foundation
Alzheimer's Association
Amylyx Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Placebo-Controlled, Double-Blind, Parallel-Group
Eligibility
Sex/Gender
ALL
Age
55 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
1. Ages 55-89, inclusive, male or female 2. Diagnosis of Probable Alzheimer's Disease or Mild Cognitive Impairment (amnestic or amnestic plus other) with biomarkers that suggest intermediate or high likelihood that the syndrome is due to AD, according to 2011 NIA-AA Workgroup criteria 3. MoCA score \>/=8 4. Able to read and write in English sufficiently to complete all study procedures 5. Geriatric Depression Scale \<7 6. Willing and able to complete all assessments and study procedures 7. Not pregnant, lactating or of child-bearing potential (women must be \>2 years post-menopausal or surgically sterile) 8. Study partner with at least two days per week with contact with patient willing to accompany patient to visits and complete partner study forms 9. No known hypersensitivity to TURSO or Phenylbutyrate 10. If on cholinesterase inhibitor and/or memantine, treatment must have started for no less than 3 months (84 days) prior to baseline and the dosing regimen must have remained stable for 6 weeks (42 days) prior to baseline. The Investigator anticipated that the dosing regimen at baseline would remain unchanged throughout participation in the study.
Exclusion criteria
1. Any CNS disease other than suspected AD, such as clinical stroke, brain tumor, normal pressure hydrocephalus, multiple sclerosis, significant head trauma with persistent neurological cognitive deficits or complaints, Parkinson's disease, frontotemporal dementia, or other neurodegenerative diseases 2. Abnormal liver function defined as AST and/or ALT \> 3 times the upper limit of normal 3. Renal insufficiency as defined by a serum creatinine \> 1.5 times the upper limit of normal 4. Recent (less than 1 year) cholecystectomy or the presence of post-cholecystectomy syndrome or biliary obstruction 5. Clinically significant unstable medical condition (other than AD) that in the Site Investigator opinion would pose a risk to the participant if they were to participate in the study 6. Any contraindication to undergo MRI studies such as: 1. History of a cardiac pacemaker or pacemaker wires 2. Metallic particles in the body 3. Vascular clips in the head 4. Prosthetic heart valves 5. Severe claustrophobia impeding ability to participate in an imaging study, or MRI findings that show one or more of the following: 1. More than 4 incidental microhemorrhages 2. Incidental lacunar infarct with attributable signs or symptoms and with history of stroke 3. Incidental meningiomas with attributable signs or symptoms 4. Newly recognized meningioma 7. Major active or chronic psychiatric illness (e.g. depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) that is not stable or well controlled within the previous year prior to baseline 8. Any significant neurodevelopmental disability 9. Current suicidal ideation or history of suicide attempt within 5 years of baseline or significant change from the screening and baseline C-SSRS at the discretion of the Site Investigator 10. History of alcohol or other substance abuse or dependence within the past 2 years 11. Any significant systemic illness or medical condition that could affect safety or compliance with study at the discretion of the Site Investigator 12. Laboratory abnormalities in B12, TSH, or other common laboratory parameters that might contribute to cognitive dysfunction 13. Current use of medications with psychoactive properties that may deleteriously affect cognition (e.g., anticholinergics, centrally-acting antihistamines, antipsychotics, sedative hypnotics, anxiolytics) 14. Use of any investigational therapy being used or evaluated for the treatment of AD is prohibited beginning 3 months (90 days) prior to the Baseline Visit and throughout the study. 15. Use of other investigational agents 1 month (28 days) prior to the Baseline Visit and for the duration of the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Event (TEAEs) | From first dose to 24 weeks | Comparison between the AMX0035 Group and Placebo of the number of participants with TEAEs |
| Effect of Treatment on a Global Composite Statistical Test of Cognition, Function, and Neuroanatomy (GST) | 24 weeks | Change from Baseline in GST (global statistical test combining three measures relevant to disease trajectory (cognition \[MADCOMS: Mild/Moderate Alzheimer's Disease Composite Score\], function \[FAQ: Functional Activities Questionnaire\], and total hippocampal volume on magnetic resonance imaging)) for AMX0035 relative to placebo. For MADCOMS and FAQ, a higher score indicates a worse outcome. A larger hippocampal volume is better, so it was reversed before being normalized. Each of the three were normalized against respective baseline means and standard deviations. The mean of the three normalized scores is the final GST. A higher GST score indicates a worse outcome. Standard deviations above the mean are worse; standard deviations below the mean are better. The expected value of the GST at baseline is 0 because it is the mean of three z-scores whose expected values at baseline are 0. AD is multifaceted and the GST was designed to be sensitive to changes in multiple dimensions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Treatment on Dementia Severity | 24 weeks | Impact of AMX0035 on Dementia Severity Rating Scale (DSRS) scores. Total score can range from 0 to 54, with higher scores indicating greater severity of dementia. |
| Effect of Treatment on Cognitive Impairment | 24 weeks | Impact of AMX0035 on the Montreal Cognitive Assessment (MoCA) scores. MoCA scores can range from 0 to 30, with lower scores indicating greater cognitive impairment. |
| Effect of Treatment on Cognition | 24 weeks | Impact of AMX0035 on clinical symptoms as measured by Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog). Scoring is in the range of 0 to 90 with a higher score indicating greater cognitive impairment. |
| Regional Brain Volume | 24 weeks | Impact of AMX0035 on levels of hippocampal atrophy, as assessed by volumetric Magnetic Resonance Imaging (vMRI) |
| Effect of Treatment on Neuropsychiatric Symptoms | 24 weeks | Impact of AMX0035 on neuropsychiatric symptoms as assessed by the Neuropsychiatric Inventory (NPI). The total score ranges from 0 to 36, with higher scores indicating a greater severity of symptoms. |
| Effect of Treatment on Functioning | 24 weeks | Impact of AMX0035 on Functional Activities Questionnaire (FAQ) scores. FAQ total score can range from 0 to 30, with higher scores indicating less functional independence. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active (AMX0035) AMX0035 twice daily--a combination of Sodium Phenylbutyrate (PB) and Taurursodiol (TURSO) | 51 |
| Placebo Taste-matched Placebo | 44 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 |
| Overall Study | Enrolled in other study, terminated by Sponsor, other | 6 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo | Active (AMX0035) |
|---|---|---|---|
| Age, Continuous | 70.7 years STANDARD_DEVIATION 7.48 | 70.7 years STANDARD_DEVIATION 7.3 | 70.7 years STANDARD_DEVIATION 7.69 |
| ApeE4 Gene Group 2 1 allele | 47 Participants | 18 Participants | 29 Participants |
| ApeE4 Gene Group 2 2 alleles | 17 Participants | 9 Participants | 8 Participants |
| ApeE4 Gene Group 2 Non-carrier | 28 Participants | 17 Participants | 11 Participants |
| ApeE4 Gene Group 2 Not reported | 3 Participants | 0 Participants | 3 Participants |
| ApoE4 Gene Group 1 Carrier | 64 Participants | 27 Participants | 37 Participants |
| ApoE4 Gene Group 1 Non-carrier | 28 Participants | 17 Participants | 11 Participants |
| ApoE4 Gene Group 1 Not reported | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 92 Participants | 43 Participants | 49 Participants |
| Region of Enrollment United States | 95 participants | 44 participants | 51 participants |
| Sex: Female, Male Female | 43 Participants | 19 Participants | 24 Participants |
| Sex: Female, Male Male | 52 Participants | 25 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 44 |
| other Total, other adverse events | 12 / 51 | 6 / 44 |
| serious Total, serious adverse events | 3 / 51 | 1 / 44 |
Outcome results
Primary
Effect of Treatment on a Global Composite Statistical Test of Cognition, Function, and Neuroanatomy (GST)
Change from Baseline in GST (global statistical test combining three measures relevant to disease trajectory (cognition \[MADCOMS: Mild/Moderate Alzheimer's Disease Composite Score\], function \[FAQ: Functional Activities Questionnaire\], and total hippocampal volume on magnetic resonance imaging)) for AMX0035 relative to placebo. For MADCOMS and FAQ, a higher score indicates a worse outcome. A larger hippocampal volume is better, so it was reversed before being normalized. Each of the three were normalized against respective baseline means and standard deviations. The mean of the three normalized scores is the final GST. A higher GST score indicates a worse outcome. Standard deviations above the mean are worse; standard deviations below the mean are better. The expected value of the GST at baseline is 0 because it is the mean of three z-scores whose expected values at baseline are 0. AD is multifaceted and the GST was designed to be sensitive to changes in multiple dimensions.
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active (AMX0035) | Effect of Treatment on a Global Composite Statistical Test of Cognition, Function, and Neuroanatomy (GST) | 0.24 score on a scale | Standard Error 0.049 |
| Placebo | Effect of Treatment on a Global Composite Statistical Test of Cognition, Function, and Neuroanatomy (GST) | 0.17 score on a scale | Standard Error 0.052 |
p-value: 0.3654Mixed Models Analysis
Primary
Number of Participants With Treatment-Emergent Adverse Event (TEAEs)
Comparison between the AMX0035 Group and Placebo of the number of participants with TEAEs
Time frame: From first dose to 24 weeks
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active (AMX0035) | Number of Participants With Treatment-Emergent Adverse Event (TEAEs) | 34 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Event (TEAEs) | 26 Participants |
Secondary
Effect of Treatment on Cognition
Impact of AMX0035 on clinical symptoms as measured by Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog). Scoring is in the range of 0 to 90 with a higher score indicating greater cognitive impairment.
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active (AMX0035) | Effect of Treatment on Cognition | 2.26 score on a scale | Standard Error 1.402 |
| Placebo | Effect of Treatment on Cognition | 1.52 score on a scale | Standard Error 1.496 |
p-value: 0.6698Mixed Models Analysis
Secondary
Effect of Treatment on Cognitive Impairment
Impact of AMX0035 on the Montreal Cognitive Assessment (MoCA) scores. MoCA scores can range from 0 to 30, with lower scores indicating greater cognitive impairment.
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active (AMX0035) | Effect of Treatment on Cognitive Impairment | -2.18 score on a scale | Standard Error 0.483 |
| Placebo | Effect of Treatment on Cognitive Impairment | -0.70 score on a scale | Standard Error 0.512 |
p-value: 0.0361Mixed Models Analysis
Secondary
Effect of Treatment on Dementia Severity
Impact of AMX0035 on Dementia Severity Rating Scale (DSRS) scores. Total score can range from 0 to 54, with higher scores indicating greater severity of dementia.
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active (AMX0035) | Effect of Treatment on Dementia Severity | 2.34 score on a scale | Standard Error 0.595 |
| Placebo | Effect of Treatment on Dementia Severity | 1.81 score on a scale | Standard Error 0.636 |
p-value: 0.5552Mixed Models Analysis
Secondary
Effect of Treatment on Functioning
Impact of AMX0035 on Functional Activities Questionnaire (FAQ) scores. FAQ total score can range from 0 to 30, with higher scores indicating less functional independence.
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active (AMX0035) | Effect of Treatment on Functioning | 2.61 score on a scale | Standard Error 0.79 |
| Placebo | Effect of Treatment on Functioning | 1.59 score on a scale | Standard Error 0.845 |
p-value: 0.3086Mixed Models Analysis
Secondary
Effect of Treatment on Neuropsychiatric Symptoms
Impact of AMX0035 on neuropsychiatric symptoms as assessed by the Neuropsychiatric Inventory (NPI). The total score ranges from 0 to 36, with higher scores indicating a greater severity of symptoms.
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active (AMX0035) | Effect of Treatment on Neuropsychiatric Symptoms | 0.15 score on a scale | Standard Error 0.49 |
| Placebo | Effect of Treatment on Neuropsychiatric Symptoms | -0.46 score on a scale | Standard Error 0.526 |
p-value: 0.3585Mixed Models Analysis
Secondary
Regional Brain Volume
Impact of AMX0035 on levels of hippocampal atrophy, as assessed by volumetric Magnetic Resonance Imaging (vMRI)
Time frame: 24 weeks
Population: ITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Active (AMX0035) | Regional Brain Volume | -75.18 mm^3 | Standard Error 25.429 |
| Placebo | Regional Brain Volume | -70.78 mm^3 | Standard Error 23.308 |
p-value: 0.8996Mixed Models Analysis