Clinical trial NCT01998841: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Banner Alzheimer's Institute
name: National Institute on Aging (NIA)
First posted: 2013-12-02
Enrollment: 252
Sex: ALL
Minimum age (years): 30
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Period A: Annualized Rate of Change in the Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score
timeFrame: Baseline up to approximately Week 416
measure: Period A: Annualized Rate of Change in an Episodic Memory Measure: Free and Cued Selective Reminding Task (FCSRT) Cueing Index
timeFrame: Baseline up to approximately Week 416
Secondary outcomes:
measure: 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
timeFrame: Baseline up to approximately Week 416
measure: Period A: Time to Progression to Non-zero in CDR Scale Global Score
timeFrame: Baseline up to approximately Week 416
measure: Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB)
timeFrame: Baseline up to approximately Week 416
measure: Period A: Annualized Rate of Change in a Measure of Overall Neurocognitive Functioning: RBANS
timeFrame: Baseline up to approximately Week 416
measure: Period A: Annualized Rate of Change in Mean Cerebral Fibrillar Amyloid Accumulation Using Florbetapir Positron Emission Tomography (PET)
timeFrame: Baseline up to approximately Week 416
measure: 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
timeFrame: Baseline up to approximately Week 416
measure: Period A: Annualized Rate of Change in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI)
timeFrame: Baseline up to approximately Week 416
measure: Period A: Annualized Rate of Change in Tau-Based Cerebral Spinal Fluid (CSF) Biomarkers (Total Tau (tTau) and Phospho-tau (pTau)
timeFrame: Baseline up to approximately Week 416
measure: Period A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From Baseline up to approximately Week 416
measure: Period A: Number of Participants Who Withdrew From the Study Treatment Due to AEs
timeFrame: From Baseline up to approximately Week 416
measure: Period A: Number of Participants With Adverse Events of Special Interest (AESIs)
timeFrame: From Baseline up to approximately Week 416
measure: Period A: Number of Participants Injection Reactions and Infusion-related Reaction (IRRs)
timeFrame: Baseline (Day 1) up to approximately Week 416
measure: Period A: Number of Participants With Anti-Crenezumab Antibodies
timeFrame: Baseline up to approximately Week 260
measure: Period A: Cerebrospinal Fluid (CSF) Crenezumab Concentration
timeFrame: Predose: Baseline (Day 1), Weeks 104 and 260; early termination visit and unscheduled visit (up to approximately Week 416)
measure: Period A: Serum Crenezumab Concentration
timeFrame: 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)
measure: Period A: Annualized Rate of Change in Plasma Concentrations of Amyloid Beta 1(Aβ1)-40 and Amyloid Peptide Beta 42 (Aβ1-42)
timeFrame: Baseline up to approximately Week 416
measure: Period B: Number of Participants With AEs and SAEs
timeFrame: From Day 1 (Period B) up to 67 weeks
measure: Period B: Number of Participants Who Withdraw From the Study Treatment Due to AEs
timeFrame: From Day 1 (Period B) up to 67 weeks
measure: Period B: Number of Participants With AESIs: ARIA-E, ARIA-H, Cerebral Macrohemorrhages, and Pneumonia
timeFrame: From Day 1 (Period B) up to 67 weeks
measure: Period B: Number of Participants With Injection Reactions and IRRs
timeFrame: From Day 1 (Period B) up to 67 weeks
Other outcomes:
Locations:
city: Armenia
country: Colombia
facility: Fundacion Cardiomet
city: Bogota
country: Colombia
facility: Clínica de Marly
city: Medellin
country: Colombia
facility: Grupo Neurociencias de Antioquia
city: Yarumal
country: Colombia
facility: Hospital San Juan de Dios
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Ghisays V, Lopera F, Goradia DD, Protas HD, Malek-Ahmadi MH, Chen Y, Devadas V, Luo J, Lee W, Baena A, Bocanegra Y, Guzman-Velez E, Pardilla-Delgado E, Vila-Castelar C, Fox-Fuller JT, Hu N, Clayton D, Thomas RG, Alvarez S, Espinosa A, Acosta-Baena N, Giraldo MM, Rios-Romenets S, Langbaum JB, Chen K, Su Y, Tariot PN, Quiroz YT, Reiman EM; API ADAD Colombia Trial Group. PET evidence of preclinical cerebellar amyloid plaque deposition in autosomal dominant Alzheimer's disease-causing Presenilin-1 E280A mutation carriers. Neuroimage Clin. 2021;31:102749. doi: 10.1016/j.nicl.2021.102749. Epub 2021 Jul 4.
citation: Ramirez Aguilar L, Acosta-Uribe J, Giraldo MM, Moreno S, Baena A, Alzate D, Cuastumal R, Aguillon D, Madrigal L, Saldarriaga A, Navarro A, Garcia GP, Aguirre-Acevedo DC, Geier EG, Cochran JN, Quiroz YT, Myers RM, Yokoyama JS, Kosik KS, Lopera F. Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 2019 May;15(5):709-719. doi: 10.1016/j.jalz.2018.12.010. Epub 2019 Feb 10.