Alzheimer's Disease
Conditions
Brief summary
This study consists of 2 periods: \[1\] Study Period A - evaluating the efficacy and safety of Crenezumab versus Placebo in participants who carry the PSEN1 E280A autosomal-dominant mutation and do not meet the criteria for mild cognitive impairment due to AD or dementia due to AD and are thus, in a preclinical phase of AD. Participants will be randomised in a 1:1 ratio to receive either Crenezumab or Placebo subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks. A cohort of participants (non-mutation carriers) will also be enrolled and will be dosed solely on Placebo and \[2\] Study Period B - Participants will be offered the opportunity to continue to receive study drug until the results of the study are known and post trial access to Crenezumab is started or development of Crenezumab is discontinued.
Interventions
DRUGCrenezumab
Crenezumab will be administered as per the schedule specified in the treatment arm.
DRUGPlacebo
Placebo will be administered as per the schedule specified in the treatment arm.
Sponsors
Banner Alzheimer's Institute
National Institute on Aging (NIA)
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Membership in PSEN1 E280A mutation carrier kindred * Agrees to conditions of, and is willing to undergo, genetic testing (for example \[e.g.\], apolipoprotein E \[APOE\], PSEN1 E280A, and other genetic testing) * PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during the screening period * Mini-Mental Stage Examination (MMSE) greater than or equal to (\>=) 24 for participants with less than (\<) 9 years of education or MMSE \>=26 for participants with 9 or more years of education * Does not meet criteria for dementia due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (McKhann et al. 2011) criteria * Does not meet criteria for mild cognitive impairment (MCI) due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (Albert et al. 2011) criteria * Adequate vision and hearing in the investigator's judgment to be able to complete testing * If female, and not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, willing to undergo pregnancy tests at protocol-specific timepoints * For women who are not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of \<1 percent (%) per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner, tubal ligation) during the treatment period and for at least 16 weeks after the last dose of study drug * For men with partners of childbearing potential (that is \[i.e.\], women who are not surgically sterile and are not postmenopausal), agreement to remain abstinent or use a condom as a method of contraception during the treatment period and for at least 8 weeks after the last dose of study drug * Study partner who agrees to participate in the study and is capable of and willing to: accompany the participant to all required visits; provide information for required telephone assessments; spend sufficient time with the participant to be familiar with his/her overall function and behavior and be able to provide adequate information about the participant including knowledge about domestic activities, hobbies, routines, social skills and basic activities of daily life; work and educational history; cognitive performance including memory abilities, language abilities, temporal and spatial orientation, judgment and problem solving; emotional and psychological state; and general health status * Participant and study partner have evidence of adequate premorbid functioning (e.g., intellectual, visual, and auditory) and are fluent in, and able to read, the language in which study assessments are administered * Willing and able to undergo neuroimaging (PET and MRI) * Serum thyroid stimulating hormone (TSH) and B12 levels within normal or expected ranges for the testing laboratory or if TSH and B12 values are out of range they are judged by the investigator not to be clinically significant. If participant is undergoing thyroid replacement therapy, TSH levels must be within normal or expected ranges for the testing laboratory or, if TSH values are out of range, they do not require any therapeutic actions (treatment or surveillance). If participant is receiving vitamin B12 injections or oral vitamin B12 therapy, B12 levels must be at or above the lower limit of normal for the testing laboratory or, if B12 values are out of range, they do not require any therapeutic actions (treatment or surveillance) * In good general health with no known co-morbidities expected to interfere with participation in the study
Exclusion criteria
* Significant medical, psychiatric, or neurological condition or disorder documented by history, physical, neurological, laboratory, or electrocardiogram (ECG) examination that would place the participant at undue risk in the investigator's judgment or impact the interpretation of efficacy * History of stroke. Participants with a history of transient ischemic attack may be enrolled if the event occurred \>=2 years prior to screening * History of severe, clinically significant (persistent neurological deficit or structural brain damage) central nervous system trauma (e.g. cerebral contusion) * Body weight \<45 or \>120 kilograms (kg) * History or presence of atrial fibrillation that poses a risk for future stroke in the investigator's judgment * Clinically significant laboratory or ECG abnormalities (e.g., abnormally prolonged or shortened QTc interval) in the investigator's judgment * Current presence of bipolar disorder or other clinically significant major psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders 4th Edition Text Revision (DSM-IV-TR) or symptom (e.g., hallucinations, agitation, paranoia) that could affect the participant's ability to complete evaluations * Clinically significant depression, based in part by a Geriatric Depression Scale (short form) (15-point scale) score \>9 at screening * History of seizures (excluding febrile seizures of childhood, or other isolated seizure episodes that were not due to epilepsy in the judgment of the investigator, and required at most time-limited anticonvulsant treatment, and which occurred more than 7 years prior to the screening visit) * Myocardial infarction within 2 years, congestive heart failure, atrial fibrillation, or uncontrolled hypertension * Pregnant or nursing women, or women who intend to become pregnant or to nurse infants during the conduct of this trial * Clinically significant infection within the last 30 days prior to screening * Positive urine test for drugs of abuse at screening * History of alcohol or substance dependence within the previous two years * Use of any other medications with the potential to significantly affect cognition; intermittent or short-term use of these medications may be allowed if deemed medically necessary for the treatment of a non-excluded medical condition with approval from the Medical Monitor. In addition, use of tricyclic antidepressants or benzodiazepines will be permitted if used in stable, low doses for the treatment of a non-excluded medical condition with approval from the Medical Monitor * Use of typical anti-psychotics or barbiturates * Use of non-anti-cholinergic antidepressant medications or atypical anti-psychotics unless maintained on a stable dose regimen for at least 6 weeks prior to screening * Use of any Food and Drug Administration (FDA)/Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA)-approved medications for treatment of late onset Alzheimer's disease (LOAD) at screening/baseline. Cholinesterase inhibitors and/or memantine are prohibited during the study except in participants enrolled in the study that develop AD dementia * Use of anti-coagulant medication (heparinoids, heparin, warfarin, thrombin inhibitors, Factor Xa inhibitors), or known coagulopathy or platelet count \<100,000 cells/microliter, within 4 weeks of the screening visit; Anti-platelet medications (e.g., aspirin, clopidigrel, dipyridamole) are permitted if on a stable dose for 4 or more weeks prior to screening. Short-term, peri-operative use of anti-coagulants may not result in discontinuation from the study; however, any such use must be discussed with the Medical Monitor * Treatment with any biologic therapy within five half-lives or 3 months prior to screening, whichever is longer, with the exception of routinely recommended vaccinations, which are allowed * Use of anti-seizure medication (except in childhood for febrile seizures or if used for non-seizure indications), anti-parkinsonian, or stimulant (e.g., methylphenidate) medications * Use of investigational drug, device, or experimental medication within 60 days (or five half-lives, whichever is longer) of the screening visit * Previous treatment with crenezumab or any other therapeutic that targets A-beta * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins * Contraindication to MRI scan procedures or clinically significant claustrophobia that would contraindicate a brain MRI scan * Contraindication to PET scan procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Period A: Annualized Rate of Change in the Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score | Baseline up to approximately Week 416 | API ADAD Composite Cognitive Test is a combination of tests, most sensitive to detect cognitive decline & progression. API ADAD Composite Cognitive Test total score were computed from: Consortium to Establish a Registry for AD (CERAD) Word List: Recall (score range=0-10); Multilingual Naming Test (score range=0-15); Mini-Mental State Examination (MMSE) for orientation to time (score range=0-5); CERAD Constructional Praxis (measure of visuospatial ability) (score range=0-11); Raven's Progressive Matrices (measure of nonverbal fluid reasoning & visuospatial abilities), Set A (score range=0-12). ADAD-API Cognitive Composite Test total score = \[(Multilingual Naming Test Score/15)+(MMSE Score/5)+(Raven's Progressive Matrices Score/12)+(CERAD Word List Recall Score/10)+(CERAD Constructional Praxis Score/11)\]\*20. Total score ranges=0-100. Higher score=better results. Annualized rate of change in API ADAD Composite Cognitive Test was estimated using random coefficient regression model. |
| Period A: Annualized Rate of Change in an Episodic Memory Measure: Free and Cued Selective Reminding Task (FCSRT) Cueing Index | Baseline up to approximately Week 416 | FCSRT assesses immediate & delayed verbal episodic memory, using Controlled Learning to optimize encoding specificity for more effective recall. Participants were to remember a list of 16 items presented on cards. Participant's task was to learn & attempt a free recall of the items, followed by a semantically cued recall of items not spontaneously produced during free recall. There were a total of three learning trials, each preceded by 20 seconds of interfering cognitive task. For first two trials, participants were reminded of any item not recalled in cued recall. Free recall (score range: 0-48) & cued recall (score range: 0-64) assessment occurred immediately, after each of three learning trials, & after a delay of approx. 30 minutes. Higher scores indicate better performance. FCSRT Cueing Index=(FCSRT Total Free Recall score-FCSRT Total Recall score)/(FCSRT Total Free Recall score-48). Score range for FCSRT Cueing Index is 0-1, with higher score=better results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB) | Baseline up to approximately Week 416 | The CDR-SB is a rater administered scale and impairment is scored in the following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment was scored on a scale in which no dementia = 0, questionable dementia = 0.5, mild dementia = 1, moderate dementia = 2 and severe dementia = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher scores indicating greater impairment. Annualized rate of change in CDR Scale - SOB was calculated using RCRM. |
| Period A: Annualized Rate of Change in a Measure of Overall Neurocognitive Functioning: RBANS | Baseline up to approximately Week 416 | RBANS is a clinical tool designed to detect and characterize the earliest neurocognitive changes associated with dementia. The RBANS comprised of 12 subtests which generates age-adjusted index scores for five neurocognitive domains: Immediate Memory, Visuospatial/Constructional, Language, Attention and Delayed Memory, which are used to calculate a Total Scale Index score. RBANS Total Score = Index Score based on the (Index Score for Immediate Memory + Index Score for Visuospatial/Constructional + Index Score for Language + Index Score for Attention + Index Score for Delayed Memory). Index scores and total scores range from 40-160. A higher score indicates better cognitive functioning. Annualized rate of change in RBANS was calculated using RCRM. |
| Period A: Annualized Rate of Change in Mean Cerebral Fibrillar Amyloid Accumulation Using Florbetapir Positron Emission Tomography (PET) | Baseline up to approximately Week 416 | Amyloid deposition in brain is one of the defining neuropathologic findings of AD. Cerebral amyloid burden & effect of crenezumab on cerebral amyloid were assessed using 18F- Florbetapir PET. Florbetapir exhibits high affinity specific binding to amyloid plaques, which allows for a measurement of the relative amyloid burden as the ratio of the standard uptake values (SUVR) in a cortical composite region of interest (including the frontal, temporal, parietal, and cingulate cortices with a subcortical white matter reference region). Annualized rate of change in cerebral fibrillar amyloid accumulation was calculated using RCRM. |
| Period A: Annualized Rate of Change in Regional Cerebral Metabolic Rate of Glucose (CMRgI) Using Fluorine-18-Labeled 2-Deoxyglucose (FDG)-PET in a Predefined ROI | Baseline up to approximately Week 416 | Regional CMRgl and the effect of crenezumab on regional CMRgl was assessed using FDG-PET. FDG PET evaluates the regional brain metabolic rates for glucose as a sensitive, in vivo metabolic index of brain function. Regional CMRgl was derived from FDG PET images using an empirically predefined statistical ROI (sROI) known to be preferentially affected by CMRgl decline in participants with AD. Results are reported as standardized uptake value ratios. Annualized rate of change in CMRgI was calculated using RCRM. |
| Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) | Baseline up to approximately Week 416 | Cerebral atrophy correlates closely with the gradual cognitive decline in AD and can be visualized by MRI. The change in brain atrophy after treatment with crenezumab was measured by volumetric measurements using MRI which measures volumes of the key brain structures-hippocampus, ventricles, and other brain structures-and compares the volumes to standard norms based on the age, gender and cranial volume. The regions of interest for atrophy measurement included whole brain, bilateral hippocampus, and bilateral ventricles. The annualized rate of change in brain atrophy was calculated using RCRM. |
| Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau) | Baseline up to approximately Week 416 | CSF biomarker tTau has been considered as a general marker of neurodegeneration. CSF phospho-tau is an indicator of neuronal injury and neurodegeneration. An elevation in levels of tau, as well as specific pTau species, is thought to be a marker for progressive cellular degeneration in AD. Annualized rate of change in tTau and pTau was estimated using RCRM. |
| Period A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Baseline up to approximately Week 416 | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal; life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s); considered a significant medical event by the investigator. Pooled data has been reported for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group. |
| Period A: Number of Participants Who Withdrew From the Study Treatment Due to AEs | From Baseline up to approximately Week 416 | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Participants who withdrew from the study due to AEs are reported here. Pooled data has been reported for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group. |
| Period A: Number of Participants With Adverse Events of Special Interest (AESIs) | From Baseline up to approximately Week 416 | AE=any unfavorable & unintended sign, symptom/disease temporally associated with use of an investigational product/other protocol-imposed intervention, regardless of attribution. Amyloid-related imaging abnormalities (ARIA)=spectrum of image abnormalities detected on MRI. Two types of ARIAs reported are: Amyloid-related Imaging Abnormalities-Edema/Effusion (ARIA-E)=MRI alterations thought to represent vasogenic edema (VE) & related extravasated fluid phenomena, & Amyloid-related Imaging Abnormalities-Hemosiderin Deposition (ARIA-H)=MRI alterations attributable to microhemorrhages (microbleeds \[MBs\]) & leptomeningeal hemosiderosis. Cerebral macrohemorrhages were read on MRI scans. Occurrence of pneumonia were verified by imaging (e.g., chest X-ray). Other AESIs were drug induced liver injury & suspected transmission of infectious agent via medicinal products. Pooled data has been reported for this outcome measure to maintain blinding of participant's mutation status & treatment group. |
| Period A: Time to Progression From Preclinical AD to Mild Cognitive Impairment (MCI) Due to AD or From Preclinical AD to Dementia Due to AD | Baseline up to approximately Week 416 | Time to progression was calculated from the time at baseline to first confirmed diagnosis of progression from preclinical AD to MCI or from preclinical AD to dementia due to AD whichever occurred first. Preclinical AD was defined as participants who were at certain risk of developing AD dementia but did not have overt symptoms and did not meet criteria for MCI or dementia. |
| Period A: Number of Participants With Anti-Crenezumab Antibodies | Baseline up to approximately Week 260 | The number of participants with positive results for ADA against crenezumab at any of the post-baseline assessment time-points were reported. Participants positive at any post-baseline time points were post-baseline evaluable participants determined to have Treatment-induced ADAs during the study period. Treatment-induced ADA = a participant with negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result. |
| Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration | Predose: Baseline (Day 1), Weeks 104 and 260; early termination visit and unscheduled visit (up to approximately Week 416) | — |
| Period A: Serum Crenezumab Concentration | Baseline (Day 1), Weeks 4, 12, 16, 17, 26, 38, 52, 78, 104, 128, 130, 156, 180, 182, 208, 232, 234, 260, 284, 312, 336, 364, 388, early termination visit and unscheduled visit (up to approximately Week 416) | — |
| Period A: Annualized Rate of Change in Plasma Concentrations of Amyloid Beta 1(Aβ1)-40 and Amyloid Peptide Beta 42 (Aβ1-42) | Baseline up to approximately Week 416 | Amyloid beta is a peptide fragment of the amyloid precursor protein. The annualized rate of change in plasma concentration of Aβ1-40 and Aβ1-42 were estimated using a linear mixed effects model with random intercept and slope. |
| Period B: Number of Participants With AEs and SAEs | From Day 1 (Period B) up to 67 weeks | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal; life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s); considered a significant medical event by the investigator. During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned. |
| Period B: Number of Participants Who Withdraw From the Study Treatment Due to AEs | From Day 1 (Period B) up to 67 weeks | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned. |
| Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia | From Day 1 (Period B) up to 67 weeks | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. ARIA are a spectrum of image abnormalities detected on MRI. The two types of ARIA reported will include: ARIA-E: refers to the MRI alterations thought to represent VE and related extravasated fluid phenomena, and ARIA-H: refers to the MRI alterations attributable to MBs and leptomeningeal hemosiderosis. Cerebral macrohemorrhages will be read on MRI scans. Occurrence of pneumonia will be verified by imaging (e.g., chest X-ray). During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned. |
| Period B: Number of Participants With Injection Reactions and IRRs | From Day 1 (Period B) up to 67 weeks | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Infusion and injection-related reactions are defined as any AEs that occurred during or within 24 hours after the study drug injection or infusion. During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned. |
| Period A: Number of Participants Injection Reactions and Infusion-related Reaction (IRRs) | Baseline (Day 1) up to approximately Week 416 | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Infusion and injection-related reactions were defined as any AEs that occurred during or within 24 hours after the study drug injection or infusion. Pooled data has been reported for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group. |
| Period A: Time to Progression to Non-zero in CDR Scale Global Score | Baseline up to approximately Week 416 | Time to progression was defined as the time at baseline to first increase in the CDR global score i.e., score of \> zero on the CDR Global scale. The standard CDR global scale describes five degrees of impairment in performance on each of six categories of cognitive functioning, including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The ratings of degree of impairment obtained on each of the six categories of function was synthesized into one global rating of dementia with a score ranging from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia). A higher score indicates a greater degree of impairment. |
Countries
Colombia
Participant flow
Recruitment details
Participants who were carriers and non-carriers of presenilin 1 (PSEN1) E280A mutation of autosomal-dominant Alzheimer's disease (ADAD) took part in the study at four investigative sites in Colombia from 20 December 2013 to 08 August 2023.
Pre-assignment details
252 participants were enrolled to receive their assigned treatment. Study consisted of 2 periods: Study Period A & B. Participants who completed Study Period A had an option to continue treatment in Study Period B. 74 participants from Crenezumab - Mutation Carriers arm, 73 from Placebo - Mutation Carrier arm, and 72 from Placebo - Non-Carriers of Mutation arm choose to continue treatment in Period B.
Participants by arm
| Arm | Count |
|---|---|
| Study Period A: Crenezumab - Mutation Carrier Participants who were PSEN1 E280A mutation carriers, received crenezumab, 720 mg, SC, Q2W, or 60 mg/kg, IV, Q4W, for a minimum of 260 weeks during Period A. | 85 |
| Study Period A: Placebo - Mutation Carriers Participants who were PSEN1 E280A mutation carriers, received crenezumab matching placebo, SC, Q2W or IV, Q4W for a minimum of 260 weeks during Period A. | 84 |
| Study Period A: Placebo - Non-Carriers of Mutation Participants who were non-carriers of PSEN1 E280A mutation, received crenezumab matching placebo, SC, Q2W or IV, Q4W for a minimum of 260 weeks during Period A. | 83 |
| Total | 252 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Study Period A | Reason Not Disclosed to Prevent Genetic Unblinding | 6 | 6 | 3 | 0 | 0 |
| Study Period B | Reason Not Disclosed to Prevent Genetic Unblinding | 0 | 0 | 0 | 7 | 2 |
Baseline characteristics
| Characteristic | Study Period A: Crenezumab - Mutation Carrier | Study Period A: Placebo - Mutation Carriers | Study Period A: Placebo - Non-Carriers of Mutation | Total |
|---|---|---|---|---|
| Age, Continuous | 36.8 years STANDARD_DEVIATION 5.3 | 36.9 years STANDARD_DEVIATION 6.3 | 43.3 years STANDARD_DEVIATION 7.2 | 39.0 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 85 Participants | 84 Participants | 83 Participants | 252 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 6 Participants | 3 Participants | 6 Participants | 15 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized More than one race | 25 Participants | 24 Participants | 33 Participants | 82 Participants |
| Race/Ethnicity, Customized Others | 13 Participants | 16 Participants | 8 Participants | 37 Participants |
| Race/Ethnicity, Customized White | 37 Participants | 40 Participants | 35 Participants | 112 Participants |
| Sex: Female, Male Female | 44 Participants | 59 Participants | 57 Participants | 160 Participants |
| Sex: Female, Male Male | 41 Participants | 25 Participants | 26 Participants | 92 Participants |
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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 84 | 0 / 84 | 0 / 83 | 0 / 251 | 0 / 147 | 0 / 72 | 1 / 219 |
| other Total, other adverse events | 84 / 84 | 84 / 84 | 83 / 83 | 251 / 251 | 95 / 147 | 54 / 72 | 149 / 219 |
| serious Total, serious adverse events | 23 / 84 | 21 / 84 | 12 / 83 | 56 / 251 | 9 / 147 | 3 / 72 | 12 / 219 |
Outcome results
Primary
Period A: Annualized Rate of Change in an Episodic Memory Measure: Free and Cued Selective Reminding Task (FCSRT) Cueing Index
FCSRT assesses immediate & delayed verbal episodic memory, using Controlled Learning to optimize encoding specificity for more effective recall. Participants were to remember a list of 16 items presented on cards. Participant's task was to learn & attempt a free recall of the items, followed by a semantically cued recall of items not spontaneously produced during free recall. There were a total of three learning trials, each preceded by 20 seconds of interfering cognitive task. For first two trials, participants were reminded of any item not recalled in cued recall. Free recall (score range: 0-48) & cued recall (score range: 0-64) assessment occurred immediately, after each of three learning trials, & after a delay of approx. 30 minutes. Higher scores indicate better performance. FCSRT Cueing Index=(FCSRT Total Free Recall score-FCSRT Total Recall score)/(FCSRT Total Free Recall score-48). Score range for FCSRT Cueing Index is 0-1, with higher score=better results.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in an Episodic Memory Measure: Free and Cued Selective Reminding Task (FCSRT) Cueing Index | -0.03 points on scale per year | Standard Error 0.004 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in an Episodic Memory Measure: Free and Cued Selective Reminding Task (FCSRT) Cueing Index | -0.04 points on scale per year | Standard Error 0.004 |
Comparison: Analysis was based on RCRM using unstructured covariance matrix: FCSRT Cueing Index = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.1695% CI: [-0.003, 0.02]RCRM
Primary
Period A: Annualized Rate of Change in the Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score
API ADAD Composite Cognitive Test is a combination of tests, most sensitive to detect cognitive decline & progression. API ADAD Composite Cognitive Test total score were computed from: Consortium to Establish a Registry for AD (CERAD) Word List: Recall (score range=0-10); Multilingual Naming Test (score range=0-15); Mini-Mental State Examination (MMSE) for orientation to time (score range=0-5); CERAD Constructional Praxis (measure of visuospatial ability) (score range=0-11); Raven's Progressive Matrices (measure of nonverbal fluid reasoning & visuospatial abilities), Set A (score range=0-12). ADAD-API Cognitive Composite Test total score = \[(Multilingual Naming Test Score/15)+(MMSE Score/5)+(Raven's Progressive Matrices Score/12)+(CERAD Word List Recall Score/10)+(CERAD Constructional Praxis Score/11)\]\*20. Total score ranges=0-100. Higher score=better results. Annualized rate of change in API ADAD Composite Cognitive Test was estimated using random coefficient regression model.
Time frame: Baseline up to approximately Week 416
Population: Modified Intent-to-Treat (mITT) population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in the Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score | -1.10 points on scale per year | Standard Error 0.29 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in the Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score | -1.42 points on scale per year | Standard Error 0.29 |
Comparison: Analysis was based on random coefficient regression model (RCRM) using unstructured covariance matrix: API Composite Endpoint=Treatment \* Analysis Year + interactive voice or Web-based response system (IxRS) defined Age Group + IxRS defined Education History + IxRS defined apolipoprotein E4 (APOE4) Carrier Status + IxRS defined CDR Global Score.p-value: 0.4395% CI: [-0.48, 1.13]RCRM
Secondary
Period A: Annualized Rate of Change in a Measure of Overall Neurocognitive Functioning: RBANS
RBANS is a clinical tool designed to detect and characterize the earliest neurocognitive changes associated with dementia. The RBANS comprised of 12 subtests which generates age-adjusted index scores for five neurocognitive domains: Immediate Memory, Visuospatial/Constructional, Language, Attention and Delayed Memory, which are used to calculate a Total Scale Index score. RBANS Total Score = Index Score based on the (Index Score for Immediate Memory + Index Score for Visuospatial/Constructional + Index Score for Language + Index Score for Attention + Index Score for Delayed Memory). Index scores and total scores range from 40-160. A higher score indicates better cognitive functioning. Annualized rate of change in RBANS was calculated using RCRM.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in a Measure of Overall Neurocognitive Functioning: RBANS | -0.23 points on scale per year | Standard Error 0.21 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in a Measure of Overall Neurocognitive Functioning: RBANS | -0.40 points on scale per year | Standard Error 0.21 |
Comparison: Analysis was based on RCRM using unstructured covariance matrix: RBANS Total Score = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.5595% CI: [-0.4, 0.75]RCRM
Secondary
Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI)
Cerebral atrophy correlates closely with the gradual cognitive decline in AD and can be visualized by MRI. The change in brain atrophy after treatment with crenezumab was measured by volumetric measurements using MRI which measures volumes of the key brain structures-hippocampus, ventricles, and other brain structures-and compares the volumes to standard norms based on the age, gender and cranial volume. The regions of interest for atrophy measurement included whole brain, bilateral hippocampus, and bilateral ventricles. The annualized rate of change in brain atrophy was calculated using RCRM.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) | Whole Brain | -721.91 cubic millimeter (mm^3)/year | Standard Error 65.33 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) | Bilateral Hippocampus | -92.62 cubic millimeter (mm^3)/year | Standard Error 12.25 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) | Bilateral Ventricles | 808.16 cubic millimeter (mm^3)/year | Standard Error 150.14 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) | Whole Brain | -829.69 cubic millimeter (mm^3)/year | Standard Error 65.42 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) | Bilateral Hippocampus | -102.22 cubic millimeter (mm^3)/year | Standard Error 12.27 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) | Bilateral Ventricles | 788.25 cubic millimeter (mm^3)/year | Standard Error 150.29 |
Comparison: Whole Brain: Analysis was based on RCRM using unstructured covariance matrix: MRI Whole Brain (Derived) = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.2595% CI: [-74.5, 290.05]RCRM
Comparison: Bilateral Hippocampus: Analysis was based on RCRM using unstructured covariance matrix: MRI Bilateral Hippocampus = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.5895% CI: [-24.74, 43.94]RCRM
Comparison: Ventricles: Analysis was based on RCRM using unstructured covariance matrix: MRI Ventricles = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.9395% CI: [-400.78, 440.62]RCRM
Secondary
Period A: Annualized Rate of Change in Mean Cerebral Fibrillar Amyloid Accumulation Using Florbetapir Positron Emission Tomography (PET)
Amyloid deposition in brain is one of the defining neuropathologic findings of AD. Cerebral amyloid burden & effect of crenezumab on cerebral amyloid were assessed using 18F- Florbetapir PET. Florbetapir exhibits high affinity specific binding to amyloid plaques, which allows for a measurement of the relative amyloid burden as the ratio of the standard uptake values (SUVR) in a cortical composite region of interest (including the frontal, temporal, parietal, and cingulate cortices with a subcortical white matter reference region). Annualized rate of change in cerebral fibrillar amyloid accumulation was calculated using RCRM.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Mean Cerebral Fibrillar Amyloid Accumulation Using Florbetapir Positron Emission Tomography (PET) | 0.017 SUVR per year | Standard Error 0.001 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Mean Cerebral Fibrillar Amyloid Accumulation Using Florbetapir Positron Emission Tomography (PET) | 0.017 SUVR per year | Standard Error 0.001 |
Comparison: Analysis was based on RCRM using unstructured covariance matrix: PET SUVR = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.6995% CI: [-0.0037, 0.0024]RCRM
Secondary
Period A: Annualized Rate of Change in Plasma Concentrations of Amyloid Beta 1(Aβ1)-40 and Amyloid Peptide Beta 42 (Aβ1-42)
Amyloid beta is a peptide fragment of the amyloid precursor protein. The annualized rate of change in plasma concentration of Aβ1-40 and Aβ1-42 were estimated using a linear mixed effects model with random intercept and slope.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Plasma Concentrations of Amyloid Beta 1(Aβ1)-40 and Amyloid Peptide Beta 42 (Aβ1-42) | Aβ1-40 | 6836.37 (pg/mL)/year | Standard Error 236.49 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Plasma Concentrations of Amyloid Beta 1(Aβ1)-40 and Amyloid Peptide Beta 42 (Aβ1-42) | Aβ1-42 | 509.44 (pg/mL)/year | Standard Error 17.74 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Plasma Concentrations of Amyloid Beta 1(Aβ1)-40 and Amyloid Peptide Beta 42 (Aβ1-42) | Aβ1-40 | -686.18 (pg/mL)/year | Standard Error 234.84 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Plasma Concentrations of Amyloid Beta 1(Aβ1)-40 and Amyloid Peptide Beta 42 (Aβ1-42) | Aβ1-42 | -46.59 (pg/mL)/year | Standard Error 17.61 |
Comparison: Aβ1-40: Analysis was based on RCRM using unstructured covariance matrix: APlasma Amyloid Beta 1-40 =Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: <0.000195% CI: [6903.44, 8141.65]RCRM
Comparison: Aβ1-42: Analysis was based on RCRM using unstructured covariance matrix: Plasma Amyloid Peptid Beta 42 =Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: <0.000195% CI: [508.63, 603.44]RCRM
Secondary
Period A: Annualized Rate of Change in Regional Cerebral Metabolic Rate of Glucose (CMRgI) Using Fluorine-18-Labeled 2-Deoxyglucose (FDG)-PET in a Predefined ROI
Regional CMRgl and the effect of crenezumab on regional CMRgl was assessed using FDG-PET. FDG PET evaluates the regional brain metabolic rates for glucose as a sensitive, in vivo metabolic index of brain function. Regional CMRgl was derived from FDG PET images using an empirically predefined statistical ROI (sROI) known to be preferentially affected by CMRgl decline in participants with AD. Results are reported as standardized uptake value ratios. Annualized rate of change in CMRgI was calculated using RCRM.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Regional Cerebral Metabolic Rate of Glucose (CMRgI) Using Fluorine-18-Labeled 2-Deoxyglucose (FDG)-PET in a Predefined ROI | -0.012 SUVR per year | Standard Error 0.002 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Regional Cerebral Metabolic Rate of Glucose (CMRgI) Using Fluorine-18-Labeled 2-Deoxyglucose (FDG)-PET in a Predefined ROI | -0.015 SUVR per year | Standard Error 0.002 |
Comparison: Analysis was based on RCRM using unstructured covariance matrix: FDG-PET = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.2595% CI: [-0.002, 0.007]RCRM
Secondary
Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau)
CSF biomarker tTau has been considered as a general marker of neurodegeneration. CSF phospho-tau is an indicator of neuronal injury and neurodegeneration. An elevation in levels of tau, as well as specific pTau species, is thought to be a marker for progressive cellular degeneration in AD. Annualized rate of change in tTau and pTau was estimated using RCRM.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau) | tTau | 4.91 picograms per milliliters (pg/mL)/year | Standard Error 2.16 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau) | pTau | 0.84 picograms per milliliters (pg/mL)/year | Standard Error 0.32 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau) | tTau | 6.88 picograms per milliliters (pg/mL)/year | Standard Error 2.19 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau) | pTau | 1.34 picograms per milliliters (pg/mL)/year | Standard Error 0.33 |
Comparison: tTau: Analysis was based on RCRM using unstructured covariance matrix: CSF tTau = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.5395% CI: [-8.17, 4.23]RCRM
Comparison: pTau: Analysis was based on RCRM using unstructured covariance matrix: CSF pTau = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.2895% CI: [-1.43, 0.43]RCRM
Secondary
Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB)
The CDR-SB is a rater administered scale and impairment is scored in the following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment was scored on a scale in which no dementia = 0, questionable dementia = 0.5, mild dementia = 1, moderate dementia = 2 and severe dementia = 3. The 6 individual category ratings, or box scores, were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher scores indicating greater impairment. Annualized rate of change in CDR Scale - SOB was calculated using RCRM.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB) | 0.30 points on scale per year | Standard Error 0.06 |
| Study Period A: Placebo - Mutation Carriers | Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB) | 0.33 points on scale per year | Standard Error 0.06 |
Comparison: Analysis was based on RCRM using unstructured covariance matrix: CDR-SB = Treatment \* Analysis Year + IxRS defined Age Group + IxRS defined Education History + IxRS defined APOE4 Carrier Status + IxRS defined CDR Global Score.p-value: 0.6495% CI: [-0.15, 0.09]RCRM
Secondary
Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration
Time frame: Predose: Baseline (Day 1), Weeks 104 and 260; early termination visit and unscheduled visit (up to approximately Week 416)
Population: PK-evaluable population included all safety-evaluable participants with at least 1 plasma sample, provided sufficient dosing information (dose and dosing time) is available. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration | Week 104 | 0.198 micrograms per milliliters (µg/ml) | Geometric Coefficient of Variation 81.6 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration | Baseline (Day 1) | NA micrograms per milliliters (µg/ml) | — |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration | Week 260 | 0.311 micrograms per milliliters (µg/ml) | Geometric Coefficient of Variation 214.6 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration | Early Termination Visit | 0.238 micrograms per milliliters (µg/ml) | Geometric Coefficient of Variation 190.4 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration | Unscheduled Visit | 2.23 micrograms per milliliters (µg/ml) | — |
Secondary
Period A: Number of Participants Injection Reactions and Infusion-related Reaction (IRRs)
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Infusion and injection-related reactions were defined as any AEs that occurred during or within 24 hours after the study drug injection or infusion. Pooled data has been reported for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group.
Time frame: Baseline (Day 1) up to approximately Week 416
Population: Safety population included all randomized participants who received at least 1 dose of study drug; participants were grouped according to the actual treatment received and the mutation status.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants Injection Reactions and Infusion-related Reaction (IRRs) | Injection Reaction | 92 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants Injection Reactions and Infusion-related Reaction (IRRs) | Infusion Related Reaction | 70 Participants |
Secondary
Period A: Number of Participants Who Withdrew From the Study Treatment Due to AEs
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Participants who withdrew from the study due to AEs are reported here. Pooled data has been reported for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group.
Time frame: From Baseline up to approximately Week 416
Population: Safety population included all randomized participants who received at least 1 dose of study drug; participants were grouped according to the actual treatment received and the mutation status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants Who Withdrew From the Study Treatment Due to AEs | 1 Participants |
Secondary
Period A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal; life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s); considered a significant medical event by the investigator. Pooled data has been reported for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group.
Time frame: From Baseline up to approximately Week 416
Population: Safety population included all randomized participants who received at least 1 dose of study drug; participants were grouped according to the actual treatment received and the mutation status.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 251 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 56 Participants |
Secondary
Period A: Number of Participants With Adverse Events of Special Interest (AESIs)
AE=any unfavorable & unintended sign, symptom/disease temporally associated with use of an investigational product/other protocol-imposed intervention, regardless of attribution. Amyloid-related imaging abnormalities (ARIA)=spectrum of image abnormalities detected on MRI. Two types of ARIAs reported are: Amyloid-related Imaging Abnormalities-Edema/Effusion (ARIA-E)=MRI alterations thought to represent vasogenic edema (VE) & related extravasated fluid phenomena, & Amyloid-related Imaging Abnormalities-Hemosiderin Deposition (ARIA-H)=MRI alterations attributable to microhemorrhages (microbleeds \[MBs\]) & leptomeningeal hemosiderosis. Cerebral macrohemorrhages were read on MRI scans. Occurrence of pneumonia were verified by imaging (e.g., chest X-ray). Other AESIs were drug induced liver injury & suspected transmission of infectious agent via medicinal products. Pooled data has been reported for this outcome measure to maintain blinding of participant's mutation status & treatment group.
Time frame: From Baseline up to approximately Week 416
Population: Safety population included all randomized participants who received at least 1 dose of study drug; participants were grouped according to the actual treatment received and the mutation status.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events of Special Interest (AESIs) | ARIA-H | 6 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events of Special Interest (AESIs) | ARIA-E | 1 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events of Special Interest (AESIs) | Cerebral Macrohemorrhage | 0 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events of Special Interest (AESIs) | Drug Induced Liver Injury | 1 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events of Special Interest (AESIs) | Suspected Transmission of Infectious Agents via a Medicinal Product | 0 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Adverse Events of Special Interest (AESIs) | Pneumonia | 0 Participants |
Secondary
Period A: Number of Participants With Anti-Crenezumab Antibodies
The number of participants with positive results for ADA against crenezumab at any of the post-baseline assessment time-points were reported. Participants positive at any post-baseline time points were post-baseline evaluable participants determined to have Treatment-induced ADAs during the study period. Treatment-induced ADA = a participant with negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result.
Time frame: Baseline up to approximately Week 260
Population: Safety population included all randomized participants who received at least 1 dose of study drug; participants were grouped according to the actual treatment received and the mutation status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Number of Participants With Anti-Crenezumab Antibodies | 5 Participants |
Secondary
Period A: Serum Crenezumab Concentration
Time frame: Baseline (Day 1), Weeks 4, 12, 16, 17, 26, 38, 52, 78, 104, 128, 130, 156, 180, 182, 208, 232, 234, 260, 284, 312, 336, 364, 388, early termination visit and unscheduled visit (up to approximately Week 416)
Population: PK-evaluable population included all safety-evaluable participants with at least 1 plasma sample, provided sufficient dosing information (dose and dosing time) is available. Number analyzed is the number of participants with data available for analysis at specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Baseline (Day 1) | NA µg/ml | — |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 4 | 69.2 µg/ml | Geometric Coefficient of Variation 39.1 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 12 | 93.9 µg/ml | Geometric Coefficient of Variation 51.8 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 16 | 85.8 µg/ml | Geometric Coefficient of Variation 37.2 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 17 | 114 µg/ml | Geometric Coefficient of Variation 37.3 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 26 | 96.5 µg/ml | Geometric Coefficient of Variation 86.3 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 38 | 98.0 µg/ml | Geometric Coefficient of Variation 121.6 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 52 | 82.9 µg/ml | Geometric Coefficient of Variation 285.3 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 78 | 75.9 µg/ml | Geometric Coefficient of Variation 777 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 104 | 86.2 µg/ml | Geometric Coefficient of Variation 680.2 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 128 | 124 µg/ml | Geometric Coefficient of Variation 28.6 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 130 | 72.3 µg/ml | Geometric Coefficient of Variation 1514.9 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 156 | 80.7 µg/ml | Geometric Coefficient of Variation 1445.4 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 180 | 56.1 µg/ml | Geometric Coefficient of Variation 3140.6 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 182 | 85.5 µg/ml | Geometric Coefficient of Variation 1135.4 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 208 | 94.3 µg/ml | Geometric Coefficient of Variation 983 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 232 | 69.4 µg/ml | Geometric Coefficient of Variation 3990.1 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 234 | 62.3 µg/ml | Geometric Coefficient of Variation 2724.2 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 260 | 101 µg/ml | Geometric Coefficient of Variation 1417.7 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 284 | 131 µg/ml | Geometric Coefficient of Variation 690.6 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 312 | 116 µg/ml | Geometric Coefficient of Variation 645 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 336 | 117 µg/ml | Geometric Coefficient of Variation 544.7 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 364 | 227 µg/ml | Geometric Coefficient of Variation 38.2 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Week 388 | 162 µg/ml | Geometric Coefficient of Variation 79.8 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Early Termination Visit | 223 µg/ml | Geometric Coefficient of Variation 135.5 |
| Study Period A: Crenezumab - Mutation Carrier | Period A: Serum Crenezumab Concentration | Unscheduled | 98.4 µg/ml | — |
Secondary
Period A: Time to Progression From Preclinical AD to Mild Cognitive Impairment (MCI) Due to AD or From Preclinical AD to Dementia Due to AD
Time to progression was calculated from the time at baseline to first confirmed diagnosis of progression from preclinical AD to MCI or from preclinical AD to dementia due to AD whichever occurred first. Preclinical AD was defined as participants who were at certain risk of developing AD dementia but did not have overt symptoms and did not meet criteria for MCI or dementia.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Time to Progression From Preclinical AD to Mild Cognitive Impairment (MCI) Due to AD or From Preclinical AD to Dementia Due to AD | NA days |
| Study Period A: Placebo - Mutation Carriers | Period A: Time to Progression From Preclinical AD to Mild Cognitive Impairment (MCI) Due to AD or From Preclinical AD to Dementia Due to AD | NA days |
Comparison: Stratification factors used: Age Group, Education History, APOE4 Carrier Status, Clinical Dementia Rating (CDR) Global Score.p-value: 0.4895% CI: [0.41, 1.52]Stratified Log Rank
Secondary
Period A: Time to Progression to Non-zero in CDR Scale Global Score
Time to progression was defined as the time at baseline to first increase in the CDR global score i.e., score of \> zero on the CDR Global scale. The standard CDR global scale describes five degrees of impairment in performance on each of six categories of cognitive functioning, including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The ratings of degree of impairment obtained on each of the six categories of function was synthesized into one global rating of dementia with a score ranging from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia). A higher score indicates a greater degree of impairment.
Time frame: Baseline up to approximately Week 416
Population: mITT population included all randomized participants who were mutation carriers and were treated with any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period A: Time to Progression to Non-zero in CDR Scale Global Score | 2759.0 days |
| Study Period A: Placebo - Mutation Carriers | Period A: Time to Progression to Non-zero in CDR Scale Global Score | NA days |
Comparison: Stratification factors used: Age Group, Education History, APOE4 Carrier Status.p-value: 0.7695% CI: [0.53, 1.59]Stratified Log Rank
Secondary
Period B: Number of Participants Who Withdraw From the Study Treatment Due to AEs
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned.
Time frame: From Day 1 (Period B) up to 67 weeks
Population: Safety population included all randomized participants who received at least 1 dose of study drug in Study Period B; participants are grouped according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants Who Withdraw From the Study Treatment Due to AEs | 0 Participants |
Secondary
Period B: Number of Participants With AEs and SAEs
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. An SAE is any AE that is fatal; life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to the investigational product(s); considered a significant medical event by the investigator. During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned.
Time frame: From Day 1 (Period B) up to 67 weeks
Population: Safety population included all randomized participants who received at least 1 dose of study drug in Study Period B; participants are grouped according to the actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AEs and SAEs | Participants with AEs | 219 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AEs and SAEs | Participants with SAEs | 12 Participants |
Secondary
Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. ARIA are a spectrum of image abnormalities detected on MRI. The two types of ARIA reported will include: ARIA-E: refers to the MRI alterations thought to represent VE and related extravasated fluid phenomena, and ARIA-H: refers to the MRI alterations attributable to MBs and leptomeningeal hemosiderosis. Cerebral macrohemorrhages will be read on MRI scans. Occurrence of pneumonia will be verified by imaging (e.g., chest X-ray). During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned.
Time frame: From Day 1 (Period B) up to 67 weeks
Population: Safety population included all randomized participants who received at least 1 dose of study drug in Study Period B; participants are grouped according to the actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia | Pneumonia | 1 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia | ARIA-H | 0 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia | ARIA-E | 0 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia | Cerebral Macrohemorrhage | 0 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia | Drug Induced Liver Injury | 0 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia | Suspected Transmission of Infectious Agents via a Medicinal Product | 0 Participants |
Secondary
Period B: Number of Participants With Injection Reactions and IRRs
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Infusion and injection-related reactions are defined as any AEs that occurred during or within 24 hours after the study drug injection or infusion. During Study Period B, after the results of Study Period A were available, participants had an option to learn their mutation carrier status. Since all participants did not choose to learn their mutation status, pooled data has been presented for this outcome measure in order to maintain blinding of the participant's mutation status and treatment group assigned.
Time frame: From Day 1 (Period B) up to 67 weeks
Population: Safety population included all randomized participants who received at least 1 dose of study drug in Study Period B; participants are grouped according to the actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With Injection Reactions and IRRs | Injection Reaction | 1 Participants |
| Study Period A: Crenezumab - Mutation Carrier | Period B: Number of Participants With Injection Reactions and IRRs | Infusion Related Reaction | 12 Participants |