Alzheimer's Disease
Conditions
Brief summary
This study consists of two parts, Part I and Part II. The purpose of Part I of the study is to assess the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 78 weeks in the treatment of Alzheimer's Disease (AD). The primary study hypotheses for Part I are that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) score. The first approximately 400 participants entering Part I of the study are identified as the Safety Cohort. Participants who complete Part I of the study may choose to participate in Part II, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks.
Detailed description
Two substudies are included in Part I of the study: 1) a medical imaging substudy to evaluate changes in brain amyloid protein load using positron emission tomography (PET) and an amyloid tracer (\[18F\]flutemetamol); and 2) a cerebrospinal fluid (CSF) biomarker substudy to evaluate changes in CSF concentrations of amyloid-β related peptides, total tau, and phosphorylated tau (p-tau). The substudies will be conducted only at designated investigational sites. Participants are not required to take part in a substudy in order to take part in the larger trial.
Interventions
DRUGVerubecestat (Part I and Part II)
Single 12 mg verubecestat tablet once daily, taken orally
DRUGPlacebo (Part I)
Single placebo tablet matching verubecestat treatment once daily, taken orally
DRUGVerubecestat (Part II)
Single 40 mg verubecestat tablet once daily, taken orally
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of probable AD based on both a) the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria and b) the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for AD * AD is of mild to moderate severity * Clear history of cognitive and functional decline over at least one year that is either a) documented in medical records or b) documented by history from an informant who knows the subject well * Able to read at a 6th grade level or equivalent, and must have a history of academic achievement and/or employment sufficient to exclude mental retardation * If a participant is receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement (e.g., vitamin E) and/or herbal medications for AD, the dose must have been stable for at least three months before Screening, and the participant must be willing to remain on the same dose for the duration of the trial. Participants may need to be on AD treatments in accordance with local requirements * Participant must have a reliable and competent trial partner/caregiver who must have a close relationship with the subject Inclusion Criteria for Extension Period (Part II): * Tolerated study drug and completed the initial 78-week period of the trial (Part I) * Participant must have a reliable and competent trial partner who must have a close relationship with the subject
Exclusion criteria
* History of stroke * Evidence of a neurological disorder other than the disease being studied (i.e., probable AD) * History of seizures or epilepsy within the last 5 years before Screening * Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission * Participant is at imminent risk of self-harm or of harm to others * History of alcoholism or drug dependency/abuse within the last 5 years before Screening * Participant does not have a magnetic resonance imaging (MRI) scan obtained within 12 months of Screening and is unwilling or not eligible to undergo an MRI scan at the Screening Visit. With Sponsor approval, a head computed tomography (CT) scan may be substituted for MRI scan to evaluate eligibility * History of hepatitis or liver disease that has been active within the six months prior to Screening Visit * Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit (e.g., diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that participation in the trial would pose a significant medical risk to the subject. Controlled co-morbid conditions are not exclusionary if stable within three months of the Screening Visit * History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or torsades de pointes * History of malignancy occurring within the five years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma; or malignancy which has been treated with potentially curative therapy with no evidence of recurrence for ≥3 year post-therapy * Clinically significant vitamin B12 or folate deficiency in the six months before Screening Visit * Use of any investigational drugs within 30 days (or longer depending on drug) before Screening or participation in studies involving repeated cognitive testing within 30 days before Screening. Participation in an observational study, such as those involving annual cognitive assessments and/or neuroimaging, may be allowed if approved by Sponsor * History of a hypersensitivity reaction to more than three drugs * Has tested positive for human immunodeficiency virus (HIV) * Close family member (including the caregiver, the spouse or any children) who is among the personnel of the investigational or sponsor staff directly involved with this trial Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | From week 78 (end of treatment in Part I) up to week 260 of Part II | The number of participants discontinuing from study drug due to an AE in Part II was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE. |
| [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | Baseline and week 78 | Least squares mean change from baseline at week 78 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score. |
| [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | Baseline and week 78 | Least squares mean change from baseline at week 78 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score. |
| [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | Baseline and week 104 | Mean change from baseline at week 104 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I. |
| [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | Baseline and week 104 | Mean change from baseline at week 104 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I. |
| [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event | Up to week 80 (up to 2 weeks following cessation of study treatment in Part I) | The number of participants experiencing an adverse event (AE) in Part I was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE. |
| [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event | From week 78 (end of treatment in Part I) up to week 262 of Part II | The number of participants experiencing an adverse event (AE) in Part II was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE. |
| [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | Up to week 78 | The number of participants discontinuing from study drug due to an AE in Part I was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV) | Baseline and week 78 | Least squares mean percent change from baseline at week 78 was calculated for Total Hippocampal Volume (THV) as measured by volumetric magnetic resonance imaging (vMRI). Longitudinal analysis of within-participant THV is computed using a change analysis algorithm using tensor-based morphometry. This technique produces one measure of volume change calculated from the registration of serial vMRI scans at the follow-up time point relative to baseline. Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy). |
| [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau | Baseline and week 78 | Least squares mean fold change from baseline at week 78 was calculated for Total Tau concentration in CSF, a measure of brain tau pathology. Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part I, with testing occurring only at select trial sites. Least squares mean fold change from baseline \>1 indicates increased Total Tau concentration in the CSF. |
| [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR) | Baseline and week 78 | Least squares mean change from baseline at week 78 was calculated for SUVR, a measure of brain cortical amyloid load. Per protocol, SUVR was analyzed as part of a substudy in Part I, with testing occurring only at select trial sites. Participants receive the PET tracer \[18F\]Flutemetamol (IV). After 90 minutes, participants receive 4 PET scans (5 minutes each in duration). Using these PET scan images, specific brain ROIs (frontal, temporal, and parietal lobes; anterior and posterior cingulate and precuneus) are used to calculate regional SUVRs, defined as the relative ratio of pixel intensities at a specific ROI compared to a reference region (RR; subcortical white matter). These regional SUVRs are then averaged to compute a composite cortical SUVR for each participant. Higher composite cortical SUVR values indicate increased amyloid load, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load. |
| [Part I (Base Study)] Percentage of Participants Achieving Responder Status | Week 78 | The percentage of participants achieving responder status at week 78 was assessed. To determine which participants were considered responders, a linear regression was conducted at the participant level, yielding an estimated 78-week rate of change (i.e., a slope) for each participant with respect to ADAS-Cog and ADCS-ADL. To be declared a responder, a participant must have: 1) ADAS-Cog and ADCS-ADL observations at baseline and 78 weeks of treatment; 2) an ADAS-Cog slope \> 4.0 over 78 weeks, and 3) an ADCS-ADL slope \> -6.3 over 78 weeks. A participant failing to meet any of these criteria was designated as a non-responder at Week 78. |
| [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score | Baseline and week 78 | Least squares mean change from baseline at week 78 was assessed for NPI score. NPI is a clinical assessment of psychiatric status, covering 12 domains: delusion; hallucination; agitation/aggression; depression/dysphoria; anxiety; elation/euphoria; apathy/indifference; disinhibition; irritability/lability; aberrant motor behavior; sleep/nighttime behaviors; and appetite/eating disorders. Based on an interview of the participant's caregiver, each domain is assessed for symptom frequency \[range: 1 (occasional) to 4 (very frequent)\] and severity \[range: 1 (mild) to 3 (severe)\]. Domain scores \[range: 0 to 12\] are calculated as the product of the frequency and severity scores (i.e. frequency x severity); if no symptoms are present, domain score is 0. The 12 domain scores sum to a total NPI score \[range: 0 (no symptoms in any domain) to 144\]. Higher scores reflect more severe psychiatric impairment, with increases in impairment reflected by increases in NPI score. |
| [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score | Baseline and week 78 | Least squares mean change from baseline at week 78 was assessed for MMSE score. The MMSE is a cognitive assessment of 5 domains including: orientation; attention; memory; language; and constructional praxis. These domains are assessed over the course of 11 total questions related to the participant. Participants are scored based on the number of correct responses; depending on the question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question are summed to the total MMSE score, with total scores ranging from 0-30. Higher scores indicate better cognitive performance. Further, deterioration in cognitive performance would be reflected by decreases in MMSE score. |
| [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score | Baseline and week 78 | Least squares mean change from baseline at week 78 was assessed for CDR-SB score. The CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains including: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Scores from each individual domain are summed to the total CDR-SB score, with total scores ranging from 0-18. Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. |
Participant flow
Recruitment details
Part I began by enrolling approximately 50 participants per arm (200 total). Enrollment continued until the first 200 participants reached 13 weeks treatment; total enrollment at that time: \ 400. For these \ 400 participants (Safety Cohort), an interim analysis (IA) was conducted to assess safety. Following IA, enrollment continued (Main Cohort).
Pre-assignment details
2211 participants were randomized in Part I, with 2210 receiving treatment. As planned per protocol, no participants were randomized to the Verubecestat 60 mg arm (Arm C) in the Main Cohort. Participants completing Part I were eligible to continue to Part II. The trial was terminated early and did not complete as planned.
Participants by arm
| Arm | Count |
|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] \[Part I\] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. | 703 |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] \[Part I\] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. | 700 |
| Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] \[Part I\] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. | 103 |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] \[Part I\] Placebo once daily for 78 weeks in Study Part I (Base Study). \[Part II\] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. | 705 |
| Total | 2,211 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part I (Base Study) | Adverse Event | 41 | 52 | 8 | 33 |
| Part I (Base Study) | Death | 10 | 7 | 2 | 8 |
| Part I (Base Study) | Lack of Efficacy | 3 | 8 | 0 | 7 |
| Part I (Base Study) | Lost to Follow-up | 4 | 2 | 4 | 4 |
| Part I (Base Study) | Non-Compliance with Study Drug | 3 | 2 | 0 | 0 |
| Part I (Base Study) | Participant Moved | 4 | 3 | 1 | 7 |
| Part I (Base Study) | Physician Decision | 10 | 7 | 1 | 4 |
| Part I (Base Study) | Protocol Violation | 2 | 0 | 1 | 2 |
| Part I (Base Study) | Screen Failure | 2 | 0 | 0 | 0 |
| Part I (Base Study) | Site Discontinued Study Participation | 1 | 3 | 0 | 0 |
| Part I (Base Study) | Study Terminated by Sponsor | 72 | 73 | 0 | 86 |
| Part I (Base Study) | Trial Partner/Caregiver Withdrew Consent | 27 | 25 | 2 | 18 |
| Part I (Base Study) | Withdrawal by Subject | 23 | 21 | 7 | 20 |
| Part II (Extension Study) | Adverse Event | 10 | 11 | 7 | 26 |
| Part II (Extension Study) | Death | 3 | 3 | 2 | 6 |
| Part II (Extension Study) | Lack of Efficacy | 1 | 5 | 0 | 1 |
| Part II (Extension Study) | Lost to Follow-up | 3 | 4 | 0 | 1 |
| Part II (Extension Study) | Non-Compliance with Study Drug | 0 | 0 | 0 | 1 |
| Part II (Extension Study) | Participant Moved | 3 | 3 | 0 | 3 |
| Part II (Extension Study) | Physician Decision | 7 | 11 | 6 | 12 |
| Part II (Extension Study) | Study Terminated by Sponsor | 329 | 315 | 34 | 323 |
| Part II (Extension Study) | Trial Partner/Caregiver Withdrew Consent | 18 | 12 | 8 | 16 |
| Part II (Extension Study) | Withdrawal by Subject | 5 | 2 | 4 | 7 |
Baseline characteristics
| Characteristic | Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | Total | Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] |
|---|---|---|---|---|---|
| [18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR) | 0.89 SUVR STANDARD_DEVIATION 0.1 | 0.88 SUVR STANDARD_DEVIATION 0.1 | 0.88 SUVR STANDARD_DEVIATION 0.11 | 0.87 SUVR STANDARD_DEVIATION 0.11 | — |
| Age, Continuous | 71.2 Years STANDARD_DEVIATION 7.4 | 71.8 Years STANDARD_DEVIATION 7.5 | 72.4 Years STANDARD_DEVIATION 7.6 | 71.8 Years STANDARD_DEVIATION 7.6 | 72.3 Years STANDARD_DEVIATION 7.4 |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | 21.4 Score on a Scale STANDARD_DEVIATION 7.5 | 21.42 Score on a Scale STANDARD_DEVIATION 7.49 | 21.7 Score on a Scale STANDARD_DEVIATION 7.6 | 21.3 Score on a Scale STANDARD_DEVIATION 7.6 | 20.6 Score on a Scale STANDARD_DEVIATION 6.2 |
| Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | 63.0 Score on a Scale STANDARD_DEVIATION 9.5 | 62.74 Score on a Scale STANDARD_DEVIATION 9.93 | 62.1 Score on a Scale STANDARD_DEVIATION 10.4 | 62.9 Score on a Scale STANDARD_DEVIATION 9.8 | 63.5 Score on a Scale STANDARD_DEVIATION 10.3 |
| Cerebrospinal Fluid (CSF) Total Tau Concentration | 206.7 picograms (pg)/mL STANDARD_DEVIATION 90.4 | 232.2 picograms (pg)/mL STANDARD_DEVIATION 137.3 | 246.2 picograms (pg)/mL STANDARD_DEVIATION 192.9 | 231.5 picograms (pg)/mL STANDARD_DEVIATION 113.9 | 268.6 picograms (pg)/mL STANDARD_DEVIATION 136.2 |
| Clinical Dementia Rating Sum of Boxes (CDR-SB) Score | 5.4 Score on a Scale STANDARD_DEVIATION 2.1 | 5.43 Score on a Scale STANDARD_DEVIATION 2.17 | 5.6 Score on a Scale STANDARD_DEVIATION 2.3 | 5.3 Score on a Scale STANDARD_DEVIATION 2.1 | 5.5 Score on a Scale STANDARD_DEVIATION 2.3 |
| Mini-Mental State Examination (MMSE) Score | 20.4 Score on a Scale STANDARD_DEVIATION 3.3 | 20.3 Score on a Scale STANDARD_DEVIATION 3.3 | 20.3 Score on a Scale STANDARD_DEVIATION 3.2 | 20.2 Score on a Scale STANDARD_DEVIATION 3.3 | 20.6 Score on a Scale STANDARD_DEVIATION 3.3 |
| Neuropsychiatric Inventory (NPI) Score | 8.7 Score on a Scale STANDARD_DEVIATION 10.5 | 8.64 Score on a Scale STANDARD_DEVIATION 10.6 | 9.2 Score on a Scale STANDARD_DEVIATION 11.6 | 8.2 Score on a Scale STANDARD_DEVIATION 9.8 | 6.9 Score on a Scale STANDARD_DEVIATION 9.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 7 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 118 Participants | 369 Participants | 115 Participants | 125 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 30 Participants | 7 Participants | 13 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 10 Participants | 0 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 16 Participants | 2 Participants | 8 Participants | 0 Participants |
| Race (NIH/OMB) White | 566 Participants | 1779 Participants | 578 Participants | 547 Participants | 88 Participants |
| Sex: Female, Male Female | 383 Participants | 1218 Participants | 376 Participants | 403 Participants | 56 Participants |
| Sex: Female, Male Male | 320 Participants | 993 Participants | 329 Participants | 297 Participants | 47 Participants |
| Total Hippocampal Volume | 5894.1 Microliters STANDARD_DEVIATION 1231.5 | 5829.4 Microliters STANDARD_DEVIATION 1162.6 | 5800.7 Microliters STANDARD_DEVIATION 1069.2 | 5823.4 Microliters STANDARD_DEVIATION 1189.9 | 5653.5 Microliters STANDARD_DEVIATION 1148.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 702 | 13 / 700 | 3 / 103 | 6 / 705 | 6 / 379 | 4 / 365 | 4 / 61 | 8 / 394 |
| other Total, other adverse events | 408 / 702 | 440 / 700 | 66 / 103 | 337 / 705 | 135 / 379 | 102 / 365 | 37 / 61 | 144 / 394 |
| serious Total, serious adverse events | 134 / 702 | 162 / 700 | 24 / 103 | 121 / 705 | 57 / 379 | 56 / 365 | 22 / 61 | 69 / 394 |
Outcome results
Primary
[Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
Least squares mean change from baseline at week 78 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score.
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window ADCS-ADL observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | -8.4 Score on a Scale |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | -8.2 Score on a Scale |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | -8.9 Score on a Scale |
p-value: 0.492597.51% CI: [-1.1, 2.1]Longitudinal ANCOVA
p-value: 0.322197.51% CI: [-0.9, 2.3]Longitudinal ANCOVA
Primary
[Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
Least squares mean change from baseline at week 78 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score.
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window ADAS-Cog observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | 7.9 Score on a Scale |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | 8.0 Score on a Scale |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | 7.7 Score on a Scale |
p-value: 0.628797.51% CI: [-0.9, 1.3]Longitudinal ANCOVA
p-value: 0.462597.51% CI: [-0.8, 1.5]Longitudinal ANCOVA
Primary
[Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
The number of participants discontinuing from study drug due to an AE in Part I was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
Time frame: Up to week 78
Population: Includes all randomized participants in Part I receiving ≥1 dose of trial treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 57 Participants |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 64 Participants |
| Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 12 Participants |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 42 Participants |
Primary
[Part I (Base Study)] Number of Participants Who Experienced an Adverse Event
The number of participants experiencing an adverse event (AE) in Part I was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
Time frame: Up to week 80 (up to 2 weeks following cessation of study treatment in Part I)
Population: Includes all randomized participants in Part I receiving ≥1 dose of trial treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event | 630 Participants |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event | 646 Participants |
| Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event | 90 Participants |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event | 579 Participants |
Primary
[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
Mean change from baseline at week 104 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.
Time frame: Baseline and week 104
Population: All randomized participants continuing to Part II, with a baseline and ≥1 within-analysis-window ADAS-Cog observation subsequent to ≥1 dose of study drug (FAS population), having an ADAS-Cog observation at week 104. Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | 10.1 Score on a Scale | Standard Deviation 9.9 |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | 8.5 Score on a Scale | Standard Deviation 9.5 |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score | 9.6 Score on a Scale | Standard Deviation 9.5 |
Primary
[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
Mean change from baseline at week 104 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.
Time frame: Baseline and week 104
Population: All randomized participants continuing to Part II, with a baseline and ≥1 within-analysis-window ADCS-ADL observation subsequent to ≥1 dose of study drug (FAS population), having an ADCS-ADL observation at week 104. Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | -10.7 Score on a Scale | Standard Deviation 13.7 |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | -9.2 Score on a Scale | Standard Deviation 12.7 |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score | -9.3 Score on a Scale | Standard Deviation 12 |
Primary
[Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
The number of participants discontinuing from study drug due to an AE in Part II was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
Time frame: From week 78 (end of treatment in Part I) up to week 260 of Part II
Population: Includes all randomized participants continuing to Part II, receiving ≥1 dose of trial treatment in Part II. For included participants, the data reflect treatment discontinuations occurring in Part II only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 10 Participants |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 9 Participants |
| Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 6 Participants |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event | 29 Participants |
Primary
[Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event
The number of participants experiencing an adverse event (AE) in Part II was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
Time frame: From week 78 (end of treatment in Part I) up to week 262 of Part II
Population: Includes all randomized participants continuing to Part II, receiving ≥1 dose of trial treatment in Part II. For included participants, the data reflect AEs occurring in Part II only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event | 240 Participants |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event | 230 Participants |
| Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event | 51 Participants |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event | 264 Participants |
Secondary
[Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score
Least squares mean change from baseline at week 78 was assessed for CDR-SB score. The CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains including: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Scores from each individual domain are summed to the total CDR-SB score, with total scores ranging from 0-18. Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score.
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window CDR-SB observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score | 2.1 Score on a Scale |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score | 2.1 Score on a Scale |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score | 2.1 Score on a Scale |
p-value: 0.842697.51% CI: [-0.4, 0.3]Longitudinal ANCOVA
p-value: 0.826497.51% CI: [-0.3, 0.4]Longitudinal ANCOVA
Secondary
[Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)
Least squares mean change from baseline at week 78 was calculated for SUVR, a measure of brain cortical amyloid load. Per protocol, SUVR was analyzed as part of a substudy in Part I, with testing occurring only at select trial sites. Participants receive the PET tracer \[18F\]Flutemetamol (IV). After 90 minutes, participants receive 4 PET scans (5 minutes each in duration). Using these PET scan images, specific brain ROIs (frontal, temporal, and parietal lobes; anterior and posterior cingulate and precuneus) are used to calculate regional SUVRs, defined as the relative ratio of pixel intensities at a specific ROI compared to a reference region (RR; subcortical white matter). These regional SUVRs are then averaged to compute a composite cortical SUVR for each participant. Higher composite cortical SUVR values indicate increased amyloid load, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load.
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window SUVR observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat did not receive SUVR testing and were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR) | -0.02 SUVR |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR) | -0.04 SUVR |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR) | 0.00 SUVR |
p-value: 0.006695% CI: [-0.05, 0]Longitudinal ANCOVA
p-value: <0.000195% CI: [-0.06, -0.02]Longitudinal ANCOVA
Secondary
[Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score
Least squares mean change from baseline at week 78 was assessed for MMSE score. The MMSE is a cognitive assessment of 5 domains including: orientation; attention; memory; language; and constructional praxis. These domains are assessed over the course of 11 total questions related to the participant. Participants are scored based on the number of correct responses; depending on the question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question are summed to the total MMSE score, with total scores ranging from 0-30. Higher scores indicate better cognitive performance. Further, deterioration in cognitive performance would be reflected by decreases in MMSE score.
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window MMSE observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score | -3.9 Score on a Scale |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score | -3.6 Score on a Scale |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score | -4.1 Score on a Scale |
p-value: 0.472195% CI: [-0.3, 0.7]Longitudinal ANCOVA
p-value: 0.059995% CI: [0, 1]Longitudinal ANCOVA
Secondary
[Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score
Least squares mean change from baseline at week 78 was assessed for NPI score. NPI is a clinical assessment of psychiatric status, covering 12 domains: delusion; hallucination; agitation/aggression; depression/dysphoria; anxiety; elation/euphoria; apathy/indifference; disinhibition; irritability/lability; aberrant motor behavior; sleep/nighttime behaviors; and appetite/eating disorders. Based on an interview of the participant's caregiver, each domain is assessed for symptom frequency \[range: 1 (occasional) to 4 (very frequent)\] and severity \[range: 1 (mild) to 3 (severe)\]. Domain scores \[range: 0 to 12\] are calculated as the product of the frequency and severity scores (i.e. frequency x severity); if no symptoms are present, domain score is 0. The 12 domain scores sum to a total NPI score \[range: 0 (no symptoms in any domain) to 144\]. Higher scores reflect more severe psychiatric impairment, with increases in impairment reflected by increases in NPI score.
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window NPI observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score | 3.4 Score on a Scale |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score | 3.8 Score on a Scale |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score | 2.7 Score on a Scale |
p-value: 0.294995% CI: [-0.6, 2.1]Longitudinal ANCOVA
p-value: 0.137295% CI: [-0.4, 2.6]Longitudinal ANCOVA
Secondary
[Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau
Least squares mean fold change from baseline at week 78 was calculated for Total Tau concentration in CSF, a measure of brain tau pathology. Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part I, with testing occurring only at select trial sites. Least squares mean fold change from baseline \>1 indicates increased Total Tau concentration in the CSF.
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window CSF Total Tau observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau | 1.02 Fold Change |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau | 1.04 Fold Change |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau | 1.07 Fold Change |
p-value: 0.213895% CI: [0.87, 1.04]Longitudinal ANCOVA
p-value: 0.43395% CI: [0.9, 1.05]Longitudinal ANCOVA
Secondary
[Part I (Base Study)] Percentage of Participants Achieving Responder Status
The percentage of participants achieving responder status at week 78 was assessed. To determine which participants were considered responders, a linear regression was conducted at the participant level, yielding an estimated 78-week rate of change (i.e., a slope) for each participant with respect to ADAS-Cog and ADCS-ADL. To be declared a responder, a participant must have: 1) ADAS-Cog and ADCS-ADL observations at baseline and 78 weeks of treatment; 2) an ADAS-Cog slope \> 4.0 over 78 weeks, and 3) an ADCS-ADL slope \> -6.3 over 78 weeks. A participant failing to meet any of these criteria was designated as a non-responder at Week 78.
Time frame: Week 78
Population: All randomized participants in Part I receiving ≥1 dose of trial treatment. Per protocol, the first 200 participants enrolled prior to IA (across all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded from analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Percentage of Participants Achieving Responder Status | 20.1 Percentage of Participants |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Percentage of Participants Achieving Responder Status | 19.6 Percentage of Participants |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Percentage of Participants Achieving Responder Status | 19.3 Percentage of Participants |
Secondary
[Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)
Least squares mean percent change from baseline at week 78 was calculated for Total Hippocampal Volume (THV) as measured by volumetric magnetic resonance imaging (vMRI). Longitudinal analysis of within-participant THV is computed using a change analysis algorithm using tensor-based morphometry. This technique produces one measure of volume change calculated from the registration of serial vMRI scans at the follow-up time point relative to baseline. Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy).
Time frame: Baseline and week 78
Population: All randomized participants with a baseline and ≥1 within-analysis-window THV observation subsequent to ≥1 dose of study drug (FAS population). Per protocol, the 200 participants enrolled prior to IA (all arms) and all participants receiving 60mg Verubecestat (Arm C) were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] | [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV) | -5.6 Percent Change |
| Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] | [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV) | -5.7 Percent Change |
| Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] | [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV) | -5.0 Percent Change |
p-value: 0.000597.51% CI: [-1, -0.2]Longitudinal ANCOVA
p-value: 0.000297.51% CI: [-1.1, -0.3]Longitudinal ANCOVA