A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease (AD), Including a Placebo-Treated Non-Carrier Cohort

Study Overview
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Brief Summary
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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.

Official Title
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A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo, and in Non-Randomized, Placebo-Treated Non-Carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Crenezumab in the Treatment of Autosomal-Dominant Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Crenezumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mutation Carriers: Crenezumab<br>Study Period A: Participants will receive Crenezumab subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks. Study Period B: Participants will be offered the opportunity to continue to receive blinded study drug until the results of the study are known and post-trial access to Crenezumab is started or development of Crenezumab is discontinued. | Drug: Crenezumab<br>* Crenezumab will be administered as per the schedule specified in the treatment arm.<br>* Other names: MABT5102A;|
| Placebo Comparator: Mutation Carriers: Placebo<br>Study Period A: Participants will receive Placebo subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks. Study Period B: All mutation carriers entering Study Period B will, receive Crenezumab until the results of the study are known and post-trial access to Crenezumab is started or development of Crenezumab is discontinued. | Drug: Placebo<br>* Placebo will be administered as per the schedule specified in the treatment arm.<br>|
| Placebo Comparator: Non-carriers of Mutation: Placebo<br>Study Period A: Participants will receive Placebo subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks. Study Period B: All non-mutation carriers entering Study Period B will continue to receive Placebo, until the results of the study are known and post trial access to Crenezumab is started or development of Crenezumab is discontinued. | Drug: Placebo<br>* Placebo will be administered as per the schedule specified in the treatment arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 416 | 
| 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. | From Baseline up to approximately Week 416 | 
| 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. | From Baseline up to approximately Week 416 | 
| 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. | From Baseline up to approximately Week 416 | 
| 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. | Baseline (Day 1) up to approximately Week 416 | 
| 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. | Baseline up to approximately Week 260 | 
| 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) | 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. | Baseline up to approximately Week 416 | 
| 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. The data will be presented one year after study completion date. | Up to approximately 3.5 years | 
| 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. The data will be presented one year after study completion date. | Up to approximately 3.5 years | 
| 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 microhemorrhages (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). The data will be presented one year after study completion date. | Up to approximately 3.5 years | 
| Period B: Number of Participants 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. The data will be presented one year after study completion date. | Up to approximately 3.5 years |