Amnestic Mild Cognitive Impairment, Alzheimer's Disease, Prodromal Alzheimer's Disease
Conditions
Brief summary
This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.
Detailed description
As a result of protocol amendment, Study Part 2 will contain a Positron Emission Tomography (PET) imaging substudy to assess regional neurofibrillary tangle (NFT) expression.
Interventions
DRUGVerubecestat 12 mg (Parts 1 and 2)
Verubecestat 12 mg oral tablet, given once daily.
DRUGVerubecestat 40 mg (Parts 1 and 2)
Verubecestat 40 mg oral tablet, given once daily. Verubecestat 40 mg given to participants in Arm C continuing to study Part 2.
OTHERPlacebo (Part 1)
Placebo matching verubecestat, given once daily as an oral tablet.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of prodromal AD, including the following: 1. History of subjective memory decline with gradual onset and slow progression for at least one year corroborated by an informant, 2. Objective impairment in episodic memory by memory test performed at Screening, 3. Does not meet criteria for dementia, AND 4. Positive Screening amyloid imaging PET scan using \[18F\]flutametamol tracer or positive Screening CSF tau:amyloid-β42 (Aβ42) ratio (Participants with a prior positive amyloid imaging PET scan or a Screening PET scan with florbetaben or florbetapir may be enrolled without a Screening flutemetamol scan with Sponsor approval) 2. Able to read at a 6th grade level or equivalent 3. If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose must have been stable for at least three months before Screening 4. Must have a reliable and competent trial partner/informant who has a close relationship with the participant and is willing to accompany the participant to all required trial visits, and to monitor compliance of the administration of the trial medication Inclusion Criteria for Extension Period (Part 2): 1. Tolerated study drug and completed the initial 104-week period of the trial (Part 1) 2. Participant must have a reliable and competent trial partner who must have a close relationship with the subject
Exclusion criteria
1. History of stroke 2. Evidence of a clinically relevant neurological disorder other than the disease being studied (i.e., prodromal AD) 3. History of seizures or epilepsy within the last 5 years 4. Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission 5. Participant is at imminent risk of self-harm or of harm to others 6. History of alcoholism or drug dependency/abuse within the last 5 years before Screening 7. 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 8. History of hepatitis or liver disease that has been active within the 6 months prior to Screening 9. Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening 10. History of malignancy occurring within the 5 years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma 11. Clinically significant vitamin B12 or folate deficiency in the 6 months before Screening 12. Use of any investigational drugs or participation in clinical trials within the 30 days before Screening 13. History of a hypersensitivity reaction to more than three drugs 14. Has human immunodeficiency virus (HIV) by medical history 15. Participant is unwilling or has a contraindication to undergo PET scanning including but not limited to claustrophobia, excessive weight or girth 16. History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male participants) or ≥480 milliseconds (for female participants), or torsades de pointes 17. Close family member (including the trial partner, spouse or children) who is among the personnel of the investigational or sponsor staff directly involved with this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104 | Baseline and Week 104 in Part 1 | LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: 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). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. |
| Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130 | Baseline and Week 130 (i.e., Week 26 of Part 2) | Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: 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). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the baseline measurement obtained in Part 1. |
| Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1) | The percentage of participants experiencing an AE in Part 1 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 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | Up to Week 104 in Part 1 | The percentage of participants who discontinued from study drug due to an AE in Part 1 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 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2) | The percentage of participants experiencing an AE in Part 2 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 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2) | The percentage of participants who discontinued from study drug due to an AE in Part 2 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 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia | Up to Week 104 in Part 1 | The event-rate per 100 participant-years for progression to a clinical diagnosis of probable AD dementia was calculated. Adjudication of a potential case was triggered if either: 1) in the investigator's own expert judgment, they think the participant may have progressed to dementia and/or 2) the participant's CDR-SB score is ≥2 points higher compared to baseline. Cases of progression to probable AD dementia confirmed by an external adjudication committee were counted as events in the analysis. The event-rate was calculated as the number of events divided by total follow-up time (participant-years) x 100; unit of measure is event-rate / 100 participant-years. |
| Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104 | Baseline and Week 104 in Part 1 | Mean percent change from baseline at week 104 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 1, with testing occurring only at select trial sites. |
| Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment | Week 13 and Week 104 in Part 1 | LSM difference between weeks 104 and 13 was estimated for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment / problem solving; community affairs; home / hobbies; and personal care. For each domain, degree of impairment is scored by a semi-structured interview of the participant and the participant's caregiver (domain score range: 0 \[no impairment\] to 3 \[severe impairment\]). Domain scores sum to a total CDR-SB score (range: 0-18); higher scores indicate more severe cognitive impairment. Further, increased cognitive impairment is reflected by higher CDR-SB scores; larger differences between week 104 and week 13 scores indicates accelerated AD progression. |
| Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104 | Baseline and Week 104 in Part 1 | CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point \[Z = (observed value - study population mean at baseline) / study population standard deviation at baseline\]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline. |
| Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104 | Baseline and Week 104 in Part 1 | Least squares mean percent change from baseline at week 104 was calculated for THV as measured by volumetric magnetic resonance imaging (vMRI). Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy). |
| Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104 | Baseline and Week 104 in Part 1 | \[18F\]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer \[18F\]Flutemetamol was given intravenously (IV). After 90 minutes, participants were scanned for 20 minutes. Using the PET scan images, SUVRs, the ratio of tracer signal in a specific region compared to a reference region (RR; subcortical white matter) are calculated for brain regions of interest (ROIs). SUVRs from a selected set of brain regions are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load in selected brain regions, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load. |
| Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104 | Baseline and Week 104 in Part 1 | Least squares mean change from baseline at week 104 was assessed for the ADCS-ADL MCI score. The ADCS-ADL MCI is an 18-item assessment of recent, observed performance of activities of daily living administered to participants' trial partners in an interview format. For the 18 items, scores range from 0 (no independence) to (depending on the item) either 2 (5 items), 3 (9 items), or 4 (4 items), with higher scores indicating greater independence in activity performance. Scores from individual items sum to a total ADCS-ADL score (range: 0-53). 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. |
Participant flow
Recruitment details
N=1454 participants with prodromal Alzheimer's Disease (AD) were randomized, with N=1451 receiving study treatment.
Pre-assignment details
This trial was conducted in 2 parts: a Base Study (Part 1), followed by an Extension Study (Part 2). Participants completing Part 1 had the option to continue to Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) \[Part 1\] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). \[Part 2\] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 12 mg once daily for an additional 260 weeks. | 485 |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) \[Part 1\] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). \[Part 2\] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. | 484 |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) \[Part 1\] Placebo once daily for 104 weeks in Part 1 (Base Study). \[Part 2\] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive verubecestat 40 mg once daily for an additional 260 weeks. | 485 |
| Total | 1,454 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part 1 (Base Study) | Adverse Event | 24 | 37 | 15 |
| Part 1 (Base Study) | Death | 2 | 0 | 3 |
| Part 1 (Base Study) | Discontinued due to caregiver withdrawal | 7 | 8 | 10 |
| Part 1 (Base Study) | Lack of Efficacy | 3 | 1 | 4 |
| Part 1 (Base Study) | Lost to Follow-up | 1 | 3 | 6 |
| Part 1 (Base Study) | Non-compliance with study drug | 0 | 3 | 1 |
| Part 1 (Base Study) | Physician Decision | 3 | 7 | 4 |
| Part 1 (Base Study) | Screen failure | 1 | 0 | 1 |
| Part 1 (Base Study) | Site discontinued study participation | 2 | 0 | 0 |
| Part 1 (Base Study) | Study terminated by sponsor | 174 | 169 | 179 |
| Part 1 (Base Study) | Subject moved | 2 | 2 | 1 |
| Part 1 (Base Study) | Withdrawal by Subject | 32 | 23 | 22 |
| Part 2 (Extension Study) | Adverse Event | 1 | 1 | 10 |
| Part 2 (Extension Study) | Death | 0 | 3 | 0 |
| Part 2 (Extension Study) | Discontinued due to caregiver withdrawal | 1 | 3 | 0 |
| Part 2 (Extension Study) | Lack of Efficacy | 2 | 0 | 0 |
| Part 2 (Extension Study) | Lost to Follow-up | 2 | 1 | 1 |
| Part 2 (Extension Study) | Physician Decision | 2 | 0 | 2 |
| Part 2 (Extension Study) | Site discontinued study participation | 0 | 1 | 1 |
| Part 2 (Extension Study) | Study terminated by sponsor | 185 | 178 | 187 |
| Part 2 (Extension Study) | Subject moved | 0 | 0 | 1 |
| Part 2 (Extension Study) | Withdrawal by Subject | 5 | 4 | 2 |
Baseline characteristics
| Characteristic | Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Total | Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) |
|---|---|---|---|---|
| [18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR) | 0.86 Standard Uptake Value Ratio (SUVR) STANDARD_DEVIATION 0.07 | 0.86 Standard Uptake Value Ratio (SUVR) STANDARD_DEVIATION 0.07 | 0.85 Standard Uptake Value Ratio (SUVR) STANDARD_DEVIATION 0.06 | 0.87 Standard Uptake Value Ratio (SUVR) STANDARD_DEVIATION 0.07 |
| AD Cooperative Study-Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI) Score | 42.2 Score on a Scale STANDARD_DEVIATION 5.9 | 42.71 Score on a Scale STANDARD_DEVIATION 5.73 | 42.8 Score on a Scale STANDARD_DEVIATION 5.9 | 43.1 Score on a Scale STANDARD_DEVIATION 5.4 |
| Age, Continuous | 71.7 Years STANDARD_DEVIATION 7.1 | 71.4 Years STANDARD_DEVIATION 7.2 | 71.6 Years STANDARD_DEVIATION 7.1 | 71.0 Years STANDARD_DEVIATION 7.4 |
| APOE4 Genotype Missing | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| APOE4 Genotype Negative | 155 Participants | 449 Participants | 148 Participants | 146 Participants |
| APOE4 Genotype Positive | 328 Participants | 1000 Participants | 335 Participants | 337 Participants |
| Background Alzheimer's Disease (AD) Treatment No use of AChEI or memantine | 261 Participants | 782 Participants | 262 Participants | 259 Participants |
| Background Alzheimer's Disease (AD) Treatment Use of AChEI alone | 182 Participants | 553 Participants | 180 Participants | 191 Participants |
| Background Alzheimer's Disease (AD) Treatment Use of AChEI and memantine | 31 Participants | 91 Participants | 34 Participants | 26 Participants |
| Background Alzheimer's Disease (AD) Treatment Use of memantine alone | 9 Participants | 25 Participants | 8 Participants | 8 Participants |
| Baseline Use of Vitamin E ≤400 IU / day | 123 Participants | 343 Participants | 120 Participants | 100 Participants |
| Baseline Use of Vitamin E >400 IU / day | 9 Participants | 30 Participants | 9 Participants | 12 Participants |
| Baseline Use of Vitamin E No Use | 351 Participants | 1078 Participants | 355 Participants | 372 Participants |
| Cerebrospinal Fluid (CSF) Total Tau Concentration | 203.8 pg/mL STANDARD_DEVIATION 129.1 | 202.12 pg/mL STANDARD_DEVIATION 101.91 | 243.5 pg/mL STANDARD_DEVIATION 97 | 159.3 pg/mL STANDARD_DEVIATION 79 |
| Clinical Dementia Rating Sum of Boxes (CDR-SB) Score | 2.7 Score on a Scale STANDARD_DEVIATION 1.3 | 2.66 Score on a Scale STANDARD_DEVIATION 1.25 | 2.6 Score on a Scale STANDARD_DEVIATION 1.2 | 2.7 Score on a Scale STANDARD_DEVIATION 1.3 |
| Composite Cognition Score-3 Domain (CCS-3D) | 0.0 Z-score STANDARD_DEVIATION 1 | -0.01 Z-score STANDARD_DEVIATION 1 | -0.1 Z-score STANDARD_DEVIATION 1 | 0.0 Z-score STANDARD_DEVIATION 1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 86 Participants | 29 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 441 Participants | 1321 Participants | 441 Participants | 439 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 47 Participants | 15 Participants | 16 Participants |
| Geographic Region Europe / Australia / New Zealand | 163 Participants | 487 Participants | 161 Participants | 163 Participants |
| Geographic Region Japan | 57 Participants | 176 Participants | 59 Participants | 60 Participants |
| Geographic Region Other | 37 Participants | 112 Participants | 38 Participants | 37 Participants |
| Geographic Region United States / Canada | 226 Participants | 676 Participants | 226 Participants | 224 Participants |
| Mini-Mental State Examination (MMSE) Score Missing | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| Mini-Mental State Examination (MMSE) Score MMSE ≥24-26 | 270 Participants | 811 Participants | 270 Participants | 271 Participants |
| Mini-Mental State Examination (MMSE) Score MMSE ≥27 | 212 Participants | 637 Participants | 214 Participants | 211 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 79 Participants | 248 Participants | 84 Participants | 85 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 14 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 7 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 397 Participants | 1180 Participants | 391 Participants | 392 Participants |
| Sex: Female, Male Female | 229 Participants | 686 Participants | 213 Participants | 244 Participants |
| Sex: Female, Male Male | 256 Participants | 768 Participants | 272 Participants | 240 Participants |
| Total Hippocampal Volume (THV) | 6448.4 µL STANDARD_DEVIATION 1107.1 | 6450.55 µL STANDARD_DEVIATION 1063.87 | 6435.4 µL STANDARD_DEVIATION 987.2 | 6468.5 µL STANDARD_DEVIATION 1105.8 |
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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 483 | 1 / 484 | 3 / 484 | 0 / 197 | 3 / 191 | 0 / 204 |
| other Total, other adverse events | 221 / 483 | 223 / 484 | 202 / 484 | 39 / 197 | 31 / 191 | 40 / 204 |
| serious Total, serious adverse events | 124 / 483 | 101 / 484 | 96 / 484 | 10 / 197 | 22 / 191 | 24 / 204 |
Outcome results
Primary
Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104
LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: 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). Individual domain scores are summed to a total CDR-SB score (range: 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 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment in Part 1 who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; and 2) tested positive for cortical amyloid load by PET.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104 | 1.6 Score on a Scale |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104 | 2.0 Score on a Scale |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104 | 1.6 Score on a Scale |
p-value: 0.673497.51% CI: [-0.3, 0.4]Longitudinal ANCOVA
p-value: 0.014197.51% CI: [0, 0.8]Longitudinal ANCOVA
Primary
Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
The percentage of participants who discontinued from study drug due to an AE in Part 1 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 104 in Part 1
Population: All randomized participants in Part 1, receiving ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | 6.6 Percentage of Participants |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | 10.1 Percentage of Participants |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | 4.5 Percentage of Participants |
95% CI: [-0.84, 5.1]
95% CI: [2.35, 8.99]
Primary
Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
The percentage of participants experiencing an AE in Part 1 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 106 (up to 2 weeks following cessation of study treatment in Part 1)
Population: All randomized participants in Part 1, receiving ≥1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | 91.3 Percentage of Participants |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | 92.1 Percentage of Participants |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | 87.0 Percentage of Participants |
95% CI: [0.4, 8.31]
95% CI: [1.33, 9.09]
Primary
Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130
Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: 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). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the baseline measurement obtained in Part 1.
Time frame: Baseline and Week 130 (i.e., Week 26 of Part 2)
Population: All randomized participants continuing to Part 2, with: 1) both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; 2) a positive test for cortical amyloid load by PET; and 3) a CDR-SB observation at week 130.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130 | 2.0 Score on a Scale | Standard Deviation 2.5 |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130 | 1.9 Score on a Scale | Standard Deviation 2.2 |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130 | 1.5 Score on a Scale | Standard Deviation 2.1 |
Primary
Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
The percentage of participants who discontinued from study drug due to an AE in Part 2 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 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)
Population: All randomized participants continuing to Part 2, receiving ≥1 dose of trial treatment in Part 2. For included participants, the data reflect discontinuations occurring in Part 2 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | 1.0 Percentage of Participants |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | 1.0 Percentage of Participants |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE) | 3.4 Percentage of Participants |
95% CI: [-6.03, 0.61]
95% CI: [-6.01, 0.71]
Primary
Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
The percentage of participants experiencing an AE in Part 2 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 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)
Population: All randomized participants continuing to Part 2, receiving ≥1 dose of trial treatment in Part 2. For included participants, the data reflect AEs occurring in Part 2 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | 59.4 Percentage of Participants |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | 55.5 Percentage of Participants |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE) | 66.2 Percentage of Participants |
95% CI: [-16.16, 2.68]
95% CI: [-20.16, -1.04]
Secondary
Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment
LSM difference between weeks 104 and 13 was estimated for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment / problem solving; community affairs; home / hobbies; and personal care. For each domain, degree of impairment is scored by a semi-structured interview of the participant and the participant's caregiver (domain score range: 0 \[no impairment\] to 3 \[severe impairment\]). Domain scores sum to a total CDR-SB score (range: 0-18); higher scores indicate more severe cognitive impairment. Further, increased cognitive impairment is reflected by higher CDR-SB scores; larger differences between week 104 and week 13 scores indicates accelerated AD progression.
Time frame: Week 13 and Week 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment in Part 1 who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CDR-SB observation; and 2) tested positive for cortical amyloid load by PET.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment | 1.5 Score on a Scale |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment | 1.8 Score on a Scale |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment | 1.5 Score on a Scale |
p-value: 0.910997.51% CI: [-0.3, 0.4]Longitudinal ANCOVA
p-value: 0.082497.51% CI: [-0.1, 0.7]Longitudinal ANCOVA
Secondary
Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia
The event-rate per 100 participant-years for progression to a clinical diagnosis of probable AD dementia was calculated. Adjudication of a potential case was triggered if either: 1) in the investigator's own expert judgment, they think the participant may have progressed to dementia and/or 2) the participant's CDR-SB score is ≥2 points higher compared to baseline. Cases of progression to probable AD dementia confirmed by an external adjudication committee were counted as events in the analysis. The event-rate was calculated as the number of events divided by total follow-up time (participant-years) x 100; unit of measure is event-rate / 100 participant-years.
Time frame: Up to Week 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment in Part 1 who tested positive for cortical amyloid load by PET.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia | 24.5 Event-Rate / 100 Participant-Years |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia | 25.5 Event-Rate / 100 Participant-Years |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia | 19.3 Event-Rate / 100 Participant-Years |
p-value: 0.022297.51% CI: [1.005, 1.684]Regression, Cox
p-value: 0.00597.51% CI: [1.067, 1.79]Regression, Cox
Secondary
Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104
Least squares mean change from baseline at week 104 was assessed for the ADCS-ADL MCI score. The ADCS-ADL MCI is an 18-item assessment of recent, observed performance of activities of daily living administered to participants' trial partners in an interview format. For the 18 items, scores range from 0 (no independence) to (depending on the item) either 2 (5 items), 3 (9 items), or 4 (4 items), with higher scores indicating greater independence in activity performance. Scores from individual items sum to a total ADCS-ADL score (range: 0-53). 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 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose ADCS-ADL MCI observation; and 2) tested positive for cortical amyloid load by PET.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104 | -5.2 Score on a Scale |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104 | -5.8 Score on a Scale |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104 | -4.1 Score on a Scale |
p-value: 0.09697.51% CI: [-2.4, 0.4]Longitudinal ANCOVA
p-value: 0.01197.51% CI: [-3.2, -0.2]Longitudinal ANCOVA
Secondary
Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104
\[18F\]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer \[18F\]Flutemetamol was given intravenously (IV). After 90 minutes, participants were scanned for 20 minutes. Using the PET scan images, SUVRs, the ratio of tracer signal in a specific region compared to a reference region (RR; subcortical white matter) are calculated for brain regions of interest (ROIs). SUVRs from a selected set of brain regions are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load in selected brain regions, with negative changes in composite cortical SUVR over time indicating decreases in brain amyloid load.
Time frame: Baseline and Week 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose SUVR observation; and 2) tested positive for cortical amyloid load by PET.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104 | -0.03 Standard Uptake Value Ratio (SUVR) |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104 | -0.04 Standard Uptake Value Ratio (SUVR) |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104 | 0.02 Standard Uptake Value Ratio (SUVR) |
p-value: <0.000197.51% CI: [-0.06, -0.04]Longitudinal ANCOVA
p-value: <0.000197.51% CI: [-0.07, -0.05]Longitudinal ANCOVA
Secondary
Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104
CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point \[Z = (observed value - study population mean at baseline) / study population standard deviation at baseline\]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline.
Time frame: Baseline and Week 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose CCS-3D observation; and 2) tested positive for cortical amyloid load by PET.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104 | 0.8 Z-score |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104 | 0.8 Z-score |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104 | 0.8 Z-score |
p-value: 0.95197.51% CI: [-0.2, 0.2]Longitudinal ANCOVA
p-value: 0.939297.51% CI: [-0.2, 0.2]Longitudinal ANCOVA
Secondary
Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104
Least squares mean percent change from baseline at week 104 was calculated for THV as measured by volumetric magnetic resonance imaging (vMRI). Negative percent changes from baseline indicate decreases in THV (i.e. increased hippocampal atrophy).
Time frame: Baseline and Week 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose THV observation; and 2) tested positive for cortical amyloid load by PET.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104 | -6.5 Percent Change |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104 | -6.7 Percent Change |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104 | -6.1 Percent Change |
p-value: 0.113397.51% CI: [-1, 0.2]Longitudinal ANCOVA
p-value: 0.03197.51% CI: [-1.2, 0]Longitudinal ANCOVA
Secondary
Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104
Mean percent change from baseline at week 104 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 1, with testing occurring only at select trial sites.
Time frame: Baseline and Week 104 in Part 1
Population: Includes all participants receiving ≥1 dose of study treatment who: 1) had both a pre-dose baseline and ≥1 within-analysis-window, post-dose observation for CSF Total Tau concentration; and 2) tested positive for cortical amyloid load by PET. CSF Total Tau concentration was analyzed at select trial sites as a Part 1 substudy.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2) | Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104 | 33.2 Percent Change | Standard Deviation 44.3 |
| Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2) | Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104 | 42.8 Percent Change | Standard Deviation 39.7 |
| Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2) | Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104 | 10.2 Percent Change | Standard Deviation 27.9 |