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

NCT01998841 | Completed Phase 2 Results

• 1 other identifier: GN28352
• Study Type: interventional
• Target: 252
• Locations: 1 country
• Sites: 4

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.

Conditions

Alzheimer's Disease

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (20)

• 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

• Period A: Time to Progression to Non-zero in CDR Scale Global Score

  Baseline up to approximately Week 416

• Period A: Annualized Rate of Change in the CDR Scale - Sum of Boxes (SOB)

  Baseline up to approximately Week 416

• Period A: Annualized Rate of Change in a Measure of Overall Neurocognitive Functioning: RBANS

  Baseline up to approximately Week 416

• Period A: Annualized Rate of Change in Mean Cerebral Fibrillar Amyloid Accumulation Using Florbetapir Positron Emission Tomography (PET)

  Baseline up to approximately Week 416

Study Arms (3)

Mutation Carriers: Crenezumab

EXPERIMENTAL

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

Mutation Carriers: Placebo

PLACEBO COMPARATOR

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

Non-carriers of Mutation: Placebo

PLACEBO COMPARATOR

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

Interventions

Crenezumab DRUG

Crenezumab will be administered as per the schedule specified in the treatment arm.

Also known as: MABT5102A

Mutation Carriers: Crenezumab

Placebo DRUG

Placebo will be administered as per the schedule specified in the treatment arm.

Mutation Carriers: Placebo; Non-carriers of Mutation: Placebo

Eligibility Criteria

• Age: 30 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead
• Banner Alzheimer's Institute: collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (4)

Fundacion Cardiomet

Armenia, Colombia

Location

Clínica de Marly

Bogotá, Colombia

Location

Grupo Neurociencias de Antioquia

Medellín, Colombia

Location

Hospital San Juan de Dios

Yarumal, Colombia

Location

Related Publications (3)

• Tariot PN, Lopera FS, Rios-Romenets S, Sink KM, Giraldo-Chica M, Acosta-Baena N, Villegas G, Espinosa A, Castano ML, Munoz C, Ospina P, Bocanegra Y, Tirado V, Henao E, Cardona E, Luna E, Lopez H, Sanchez G, Collazos MM, Alvarez S, Aguillon D, Hu N, Clayton D, Bittner T, Schneider A, Dolton M, Poon V, Nguyen J, Thomas RG, Schneider LS, Chen K, Su Y, Alexander RC, Quiroz YT, Cai Y, Xu YR, Ostaszewski B, Selkoe DJ, Ashton NJ, Denkinger MN, Jakimovich LJ, Doody RS, Langbaum JB, Reiman EM. Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2026 Feb;25(2):147-159. doi: 10.1016/S1474-4422(25)00426-0.

  PMID: 41579901 DERIVED

• 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.

  PMID: 34252876 DERIVED

• 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.

  PMID: 30745123 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

crenezumab

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2013
• First Posted: December 2, 2013
• Study Start: December 20, 2013
• Primary Completion: March 22, 2022
• Study Completion: August 8, 2023
• Last Updated: July 30, 2024
• Results First Posted: September 22, 2023

Record last verified: 2024-07

Locations

CO (4)