Alzheimer Disease
Conditions
Brief summary
Preclinical models suggest that riluzole, the active metabolite of BHV-4157, may protect from AD-related pathology and cognitive dysfunction. Titrated dose of BHV-4157 to 280 mg, or placebo, were administered orally once daily. Duration of treatment is 48 weeks in double-blind phase. There is also a screening period of up to 42 days; and a 4-week post-treatment observation period. Eligible participants who completed the double-blind treatment phase had the opportunity to receive open-label troriluzole for up to 48 weeks in an open-label extension (OLE) phase.
Interventions
DRUGtroriluzole
Oral BHV-4157 will be given daily for up to 48 weeks
DRUGPlacebo oral capsule
Oral matching placebo will be given daily for up to 48 weeks
Sponsors
Alzheimer's Disease Cooperative Study (ADCS)
Biohaven Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Age 50 to 85 (inclusive) at screening * Diagnosed with probable Alzheimer's disease dementia: Core clinical criteria in accordance with NIA/Alzheimer's Association Guidelines. * Living in the community (includes assisted living facilities, but excludes long-term care nursing facilities). * Ambulatory, or able to walk with an assistive device, such as a cane or walker. * Participants must have a study partner who has frequent interaction with them (approximately \>3-4 times per week), will be present for all clinic visits, and can assist in compliance with study procedures. * An Mini-Mental State Examination score of 14 to 24, inclusive, at screening. * A brain MRI scan within 6 months of screening consistent with a diagnosis of Alzheimer's disease. * Participants should be treated with a stable dosage regimen of FDA-approved AD medications (acetylcholinesterase inhibitors (AchEI) and/or memantine) for at least 3 months prior to screening. Participants should be expected to remain on a stable dosage regimen of these medications for the duration of the trial. * Participants who are not being treated with FDA-approved AD medications at the time of screening, because they have contraindications to these medications, or because they have previously failed treatment with these medications, are also eligible for inclusion, if it is expected that they will not be treated with these medications for the duration of the trial. Key
Exclusion criteria
* Hepatic impairment defined as Child-Pugh class of A or more severe liver impairment. * Other neurodegenerative diseases and causes of dementias, including Parkinson's disease and Huntington's disease, vascular dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy Body dementia), PSP (Progressive Supranuclear Palsy), AIDS (Acquired Immunodeficiency Syndrome), or NPH (normal pressure hydrocephalus). * History of a major depressive episode within the past 6 months of screening. * Insulin-dependent diabetes or uncontrolled diabetes with HbA1c value \>8.0 %. * Cancer or a malignant tumor within the past 3 years, except patients who underwent potentially curative therapy with no evidence of recurrence for \>3 years. Patients with stable prostate cancer or non-melanoma skin cancers are not excluded. * Participation in another clinical trial for an investigational agent and having taken at least one dose of study medication, unless confirmed as having been on placebo, within 12 weeks prior to screening. The end of a previous investigational trial is defined as the date of the last dose of an investigational agent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-Sum of Boxes) Total Score at Week 48 | Baseline (Day 1) and Week 48 | The CDR-sum of boxes is a validated composite rating of cognition and everyday functioning used in longitudinal AD research which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview 3 cognitive domains including memory, orientation, and judgement/problem solving and 3 everyday functional domains including community affairs, home and hobbies and personal care. The individual domain score ranging from 0 (none) to 3 (severe) but the scores in each of these were combined to obtain a composite score (sum of boxes) ranging from 0 (best) to 18 (worst), with higher scores indicate poorer performance and greater impairment. The individual domain scores are added to create a sum of the box scores. |
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Total Score at Week 48 | Baseline (Day 1) and Week 48 | The ADAS-Cog is a structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing a letter in an envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions were also obtained. The test was scored in terms of errors on a scale ranging from 0 (best) to 70 (worse), with higher scores indicate poorer performance and greater impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 48 | Baseline (Day 1) and Week 48 | The ADCS-ADL inventory scale is validated questionnaire developed by the ADCS to assess instrumental and basic activities of daily living based on a 23-item structured interview of the AD study participant's partner. The scale ranging from 0 (none) to 78 (severe), with lower scores indicate greater impairment. |
| Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 48 | Baseline (Day 1) and Week 48 | The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in AD dementia based on the results of an interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric features, including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability and lability, and aberrant motor behavior, as well as evaluates sleep and appetite/eating disorders. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously). Severity assessments range from 1 (mild) to 3 (severe). The total score is the sum of all subscales ranging from 1 (mild) to 7 (severe), with higher scores indicate greater impairment. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs were reported from first dose of study drug up to end of study treatment, maximum of 96 weeks. | An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the other serious outcomes. An AE is considered Related for causality designations of possible, probable and definite. |
| Change From Baseline in Mini-Mental Status Examination (MMSE) Total Score at Week 48 | Baseline (Day 1) and Week 48 | The MMSE is a frequently used screening instrument for AD drug studies. It evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy 2 intersecting pentagons. The MMSE scale ranging from 0 (worse) to 30 (best), with a lower score indicate more cognitive impairment. |
| Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 | Baseline (Day 1) and Week 48 | Volumetric MRI allows the in vivo assessment of brain structure volume and provides a measure of atrophy rate. Results from MRI studies suggest that the patterns of atrophy in AD, which mirror the pathological progression of the disease, can reliably be detected and tracked across time. Hippocampal volume derived from MRI correlates with histological hippocampal volume and degree of neuronal loss and AD pathology, and entorhinal cortical thickness change appears to be an early and sensitive indicator of neurodegeneration associated with AD. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 in Mild Subgroup | Baseline (Day 1) and Week 48 | Subgroup of participants MMSE Category = Mild. The MMSE scale ranging from 0 (worse) to 30 (best), with a lower score indicating more cognitive impairment. Mild are participants with a baseline MMSE score greater than or equal to 20. |
Countries
United States
Participant flow
Recruitment details
This Phase 2, randomized, double-blind, placebo-controlled study was conducted in participants with mild to moderate alzheimer's disease (AD) at 44 centers in the US between 31-Jul-2018 and 23-Dec-2021.
Pre-assignment details
A total of 687 participants were screened, of which 350 participants were randomized in a 1:1 ratio to receive troriluzole or placebo. 337 participants were not randomized due to screen failure, adverse events, lost to follow-up, withdrawal of consent, or unspecified reasons.
Participants by arm
| Arm | Count |
|---|---|
| Troriluzole Randomization phase (Randomization through Week 48): Participants received starting dose of troriluzole 140 mg capsules orally once daily for 2 weeks, followed by 280 mg once daily for the remaining 46 weeks of the double-blind phase.
OLE phase (48 weeks): Participants who completed the double-blind treatment phase were offered the opportunity to enroll in an OLE phase to receive starting dose of troriluzole 140 mg capsules orally once daily for 2 weeks, followed by 280 mg orally once daily for the remaining 46 weeks. | 178 |
| Placebo Randomization phase (Randomization through Week 48): Participants received placebo matching with troriluzole for 48 weeks.
OLE phase (48 weeks): Participants who completed the double-blind treatment phase were offered the opportunity to enroll in an OLE phase to receive starting dose of troriluzole 140 mg capsules orally once daily for 2 weeks, followed by 280 mg orally once daily for the remaining 46 weeks. | 171 |
| Total | 349 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| OLE Phase (48 Weeks) | Adverse Event | 5 | 5 |
| OLE Phase (48 Weeks) | Death | 0 | 2 |
| OLE Phase (48 Weeks) | Lack of Efficacy | 6 | 5 |
| OLE Phase (48 Weeks) | Lost to Follow-up | 1 | 0 |
| OLE Phase (48 Weeks) | Other | 6 | 8 |
| OLE Phase (48 Weeks) | Physician Decision | 5 | 7 |
| OLE Phase (48 Weeks) | Progressive Disease | 2 | 0 |
| OLE Phase (48 Weeks) | Protocol Violation | 0 | 1 |
| OLE Phase (48 Weeks) | Study Terminated By Sponsor | 0 | 1 |
| OLE Phase (48 Weeks) | Withdrawal by Subject | 30 | 51 |
| Randomization Phase (Weeks 1 Through 48) | Adverse Event | 14 | 3 |
| Randomization Phase (Weeks 1 Through 48) | Death | 1 | 2 |
| Randomization Phase (Weeks 1 Through 48) | Lack of Efficacy | 2 | 2 |
| Randomization Phase (Weeks 1 Through 48) | Lost to Follow-up | 2 | 3 |
| Randomization Phase (Weeks 1 Through 48) | Non-compliance with study drug | 4 | 0 |
| Randomization Phase (Weeks 1 Through 48) | Other | 1 | 4 |
| Randomization Phase (Weeks 1 Through 48) | Physician Decision | 2 | 3 |
| Randomization Phase (Weeks 1 Through 48) | Progressive disease | 3 | 2 |
| Randomization Phase (Weeks 1 Through 48) | Protocol Violation | 1 | 1 |
| Randomization Phase (Weeks 1 Through 48) | Withdrawal by Subject | 18 | 19 |
Baseline characteristics
| Characteristic | Placebo | Total | Troriluzole |
|---|---|---|---|
| Age, Continuous | 71.6 years STANDARD_DEVIATION 7.91 | 71.7 years STANDARD_DEVIATION 7.91 | 71.8 years STANDARD_DEVIATION 7.93 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 9 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 165 Participants | 337 Participants | 172 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 9 Participants | 5 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 | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 163 Participants | 333 Participants | 170 Participants |
| Sex: Female, Male Female | 92 Participants | 202 Participants | 110 Participants |
| Sex: Female, Male Male | 79 Participants | 147 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 178 | 2 / 171 | 0 / 90 | 2 / 103 |
| other Total, other adverse events | 81 / 178 | 53 / 171 | 29 / 90 | 31 / 103 |
| serious Total, serious adverse events | 24 / 178 | 14 / 171 | 9 / 90 | 16 / 103 |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Total Score at Week 48
The ADAS-Cog is a structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing a letter in an envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions were also obtained. The test was scored in terms of errors on a scale ranging from 0 (best) to 70 (worse), with higher scores indicate poorer performance and greater impairment.
Time frame: Baseline (Day 1) and Week 48
Population: Modified Intent to Treat (mITT) population included randomized participants who received at least 1 dose of blinded study therapy (troriluzole or placebo) and who also had a baseline assessment and who have at least 1 efficacy evaluation following baseline. Participants results at Week 48 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Troriluzole | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Total Score at Week 48 | 6.7 units on a scale |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Total Score at Week 48 | 6.7 units on a scale |
Comparison: Model based summary statistics are from a mixed model with repeated measures, including fixed effects for pooled site ID, treatment, visit, treatment-by-visit interaction, baseline, baseline-by-visit interaction, mini-mental state examination (MMSE) randomization stratification, apolipoprotein E (APoE) status (carrier/non carrier), as covariates, and repeated measures for visit within participant.p-value: 0.980995% CI: [-1.8, 1.8]Mixed model with repeated measures
Primary
Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-Sum of Boxes) Total Score at Week 48
The CDR-sum of boxes is a validated composite rating of cognition and everyday functioning used in longitudinal AD research which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview 3 cognitive domains including memory, orientation, and judgement/problem solving and 3 everyday functional domains including community affairs, home and hobbies and personal care. The individual domain score ranging from 0 (none) to 3 (severe) but the scores in each of these were combined to obtain a composite score (sum of boxes) ranging from 0 (best) to 18 (worst), with higher scores indicate poorer performance and greater impairment. The individual domain scores are added to create a sum of the box scores.
Time frame: Baseline (Day 1) and Week 48
Population: The mITT population included randomized participants who received at least 1 dose of blinded study therapy (troriluzole or placebo) and who also had a baseline assessment and who have at least 1 efficacy evaluation following baseline. Participants results at Week 48 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Troriluzole | Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-Sum of Boxes) Total Score at Week 48 | 2.1 units on a scale |
| Placebo | Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-Sum of Boxes) Total Score at Week 48 | 1.9 units on a scale |
Comparison: Model based summary statistics are from a mixed model with repeated measures, including fixed effects for pooled site ID, treatment, visit, treatment-by-visit interaction, baseline, baseline-by-visit interaction, MMSE randomization stratification, APoE status (carrier/non carrier), as covariates, and repeated measures for visit within participant.p-value: 0.447495% CI: [-0.8, 0.3]Mixed model with repeated measures
Secondary
Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 48
The ADCS-ADL inventory scale is validated questionnaire developed by the ADCS to assess instrumental and basic activities of daily living based on a 23-item structured interview of the AD study participant's partner. The scale ranging from 0 (none) to 78 (severe), with lower scores indicate greater impairment.
Time frame: Baseline (Day 1) and Week 48
Population: The mITT population included randomized participants who received at least 1 dose of blinded study therapy (troriluzole or placebo) and who also had a baseline assessment and who have at least 1 efficacy evaluation following baseline. Participants results at Week 48 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Troriluzole | Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 48 | -8.9 units on a scale |
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 48 | -7.4 units on a scale |
Comparison: Model based summary statistics are from a mixed model with repeated measures, including fixed effects for pooled site ID, treatment, visit, treatment-by-visit interaction, baseline, baseline-by-visit interaction, MMSE randomization stratification, APOE status (carrier/non-carrier), as covariates, and repeated measures for visit within participant.p-value: 0.19595% CI: [-0.8, 3.9]Mixed model with repeated measures
Secondary
Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48
Volumetric MRI allows the in vivo assessment of brain structure volume and provides a measure of atrophy rate. Results from MRI studies suggest that the patterns of atrophy in AD, which mirror the pathological progression of the disease, can reliably be detected and tracked across time. Hippocampal volume derived from MRI correlates with histological hippocampal volume and degree of neuronal loss and AD pathology, and entorhinal cortical thickness change appears to be an early and sensitive indicator of neurodegeneration associated with AD.
Time frame: Baseline (Day 1) and Week 48
Population: The mITT population included randomized participants who received at least 1 dose of blinded study therapy (troriluzole or placebo) and who also had a baseline assessment and who have at least 1 efficacy evaluation following baseline. Participants results at Week 48 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Troriluzole | Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 | -1.1 percent deformation |
| Placebo | Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 | -1.1 percent deformation |
Comparison: Model based summary statistics were from an analysis of covariance (ANCOVA) with baseline MMSE total score as covariate.p-value: 0.86795% CI: [-0.6, 0.5]ANCOVA
Secondary
Change From Baseline in Mini-Mental Status Examination (MMSE) Total Score at Week 48
The MMSE is a frequently used screening instrument for AD drug studies. It evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy 2 intersecting pentagons. The MMSE scale ranging from 0 (worse) to 30 (best), with a lower score indicate more cognitive impairment.
Time frame: Baseline (Day 1) and Week 48
Population: The mITT population included randomized participants who received at least 1 dose of blinded study therapy (troriluzole or placebo) and who also had a baseline assessment and who have at least 1 efficacy evaluation following baseline. Participants results at Week 48 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Troriluzole | Change From Baseline in Mini-Mental Status Examination (MMSE) Total Score at Week 48 | -3.6 units on a scale |
| Placebo | Change From Baseline in Mini-Mental Status Examination (MMSE) Total Score at Week 48 | -3.2 units on a scale |
Comparison: Model based summary statistics are from a mixed model with repeated measures, including fixed effects for pooled site ID, treatment, visit, treatment-by-visit interaction, baseline, baseline-by-visit interaction, MMSE randomization stratification, APOE status (carrier/non-carrier), as covariates, and repeated measures for visit within participant.p-value: 0.419195% CI: [-0.6, 1.3]Mixed model with repeated measures
Secondary
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 48
The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in AD dementia based on the results of an interview with the study partner. The NPI evaluates both the frequency and severity of 10 neuropsychiatric features, including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability and lability, and aberrant motor behavior, as well as evaluates sleep and appetite/eating disorders. Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, once or more per day or continuously). Severity assessments range from 1 (mild) to 3 (severe). The total score is the sum of all subscales ranging from 1 (mild) to 7 (severe), with higher scores indicate greater impairment.
Time frame: Baseline (Day 1) and Week 48
Population: The mITT population included randomized participants who received at least 1 dose of blinded study therapy (troriluzole or placebo) and who also had a baseline assessment and who have at least 1 efficacy evaluation following baseline. Participants results at Week 48 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Troriluzole | Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 48 | 2.3 units on a scale |
| Placebo | Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 48 | 3.8 units on a scale |
Comparison: Model based summary statistics are from a mixed model with repeated measures, including fixed effects for pooled site ID, treatment, visit, treatment-by-visit interaction, baseline, baseline-by-visit interaction, MMSE randomization stratification, APOE status (carrier/non-carrier), as covariates, and repeated measures for visit within participant.p-value: 0.258395% CI: [-1.1, 4.1]Mixed model with repeated measures
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the other serious outcomes. An AE is considered Related for causality designations of possible, probable and definite.
Time frame: TEAEs were reported from first dose of study drug up to end of study treatment, maximum of 96 weeks.
Population: Treated population included enrolled and randomized participants who received at least 1 dose of blinded study therapy (troriluzole or placebo).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Troriluzole | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any fatal AE | 2 Participants |
| Troriluzole | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs | 24 Participants |
| Troriluzole | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs considered related | 3 Participants |
| Troriluzole | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAEs | 146 Participants |
| Troriluzole | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Drug withdrawn due to an TEAE | 16 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Drug withdrawn due to an TEAE | 3 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAEs | 116 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs | 14 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any fatal AE | 2 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs considered related | 1 Participants |
| Troriluzole - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAEs | 57 Participants |
| Troriluzole - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any fatal AE | 0 Participants |
| Troriluzole - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Drug withdrawn due to an TEAE | 5 Participants |
| Troriluzole - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs considered related | 0 Participants |
| Troriluzole - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs | 9 Participants |
| Placebo - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs considered related | 3 Participants |
| Placebo - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Drug withdrawn due to an TEAE | 12 Participants |
| Placebo - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any serious TEAEs | 16 Participants |
| Placebo - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any fatal AE | 2 Participants |
| Placebo - Randomization Phase/ Troriluzole - OLE Phase | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAEs | 66 Participants |
Other Pre-specified
Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 in Mild Subgroup
Subgroup of participants MMSE Category = Mild. The MMSE scale ranging from 0 (worse) to 30 (best), with a lower score indicating more cognitive impairment. Mild are participants with a baseline MMSE score greater than or equal to 20.
Time frame: Baseline (Day 1) and Week 48
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Troriluzole | Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 in Mild Subgroup | -1.1 percent deformation |
| Placebo | Change From Baseline in Magnetic Resonance Imaging (MRI) Hippocampal Volume at Week 48 in Mild Subgroup | -1.6 percent deformation |
Comparison: Model based summary statistics are from an ANCOVA with baseline MMSE total score as covariate.p-value: 0.22495% CI: [-1.2, 0.3]ANCOVA
Post Hoc
Number of Responders in Participants With ADAS-cog Total Change and MRI Hippocampal Volume Change at Week 48 in Mild APOE e4 Carrier Subgroup
Mild APOE e4 carrier subgroup are participants with a baseline MMSE score greater than or equal to 20 with APOE e4 genotype. Responder based on ADAS-cog Total Change less than or equal to 1 and MRI Hippocampal Volume Change greater than or equal to -2.09. ADAS-cog change and MRI Hippcampal volume change criteria based on 25th percentile.
Time frame: Baseline (Day 1) and Week 48
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Troriluzole | Number of Responders in Participants With ADAS-cog Total Change and MRI Hippocampal Volume Change at Week 48 in Mild APOE e4 Carrier Subgroup | 14 Participants |
| Placebo | Number of Responders in Participants With ADAS-cog Total Change and MRI Hippocampal Volume Change at Week 48 in Mild APOE e4 Carrier Subgroup | 4 Participants |
p-value: 0.0161Fisher Exact