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Report for Clinical Trial NCT01998841

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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

This randomized, double-blind, placebo-controlled, parallel group, adaptive study will evaluate the efficacy and safety of crenezumab versus placebo in individuals 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 randomized 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. The switch to the intravenous (IV) dose will be optional (as per participant decision). The study will also include a cohort of PSEN1 E280A mutation non-carriers who will be dosed with placebo only.

NCT01998841 Alzheimer's Disease
MeSH: Alzheimer Disease
HPO: Alzheimer disease

2 Interventions

Name: Crenezumab

Description: Crenezumab will be administered subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks.

Type: Drug

Mutation Carriers: Crenezumab

Name: Placebo

Description: Placebo matched to crenezumab will be administered subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks.

Type: Drug

Mutation Carriers: Placebo Non-carriers of Mutation: Placebo


Primary Outcomes

Measure: Change From Baseline in Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Composite Cognitive Test Total Score at Week 260

Time: Baseline and Week 260

Secondary Outcomes

Measure: Time to Progression to Mild Cognitive Impairment (MCI) due to AD or to Dementia due to AD

Time: Baseline up to 260 weeks

Measure: Time to Clinical Dementia Rating (CDR) Scale Global Score of Greater Than (>) Zero

Time: Baseline up to 260 weeks

Measure: Change From Baseline in CDR Scale - Sum of Boxes at Week 260

Time: Baseline and Week 260

Measure: Change From Baseline in Episodic Memory Measure: Free and Cued Selective Reminding Task (FCSRT) at Week 260

Time: Baseline and Week 260

Measure: Change From Baseline in Measure of Overall Neurocognitive Functioning: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) at Week 260

Time: Baseline and Week 260

Measure: Change From Baseline in Mean Cerebral Fibrillar Amyloid Accumulation Standard Uptake Value Ratio (SUVR) as Assessed by Positron Emission Tomography (PET) at Week 260

Time: Baseline and Week 260

Measure: Change From Baseline in Regional Cerebral Metabolic Rate of Glucose (CMRgI) Using Fluorine-18-Labeled 2-Deoxyglucose (FDG)-PET at Week 260

Time: Baseline and Week 260

Measure: Change From Baseline in Brain Atrophy Measured by Volumetric Measurements Using Magnetic Resonance Imaging (MRI) at Week 260

Time: Baseline and Week 260

Measure: Change From Baseline in a tau-Based Cerebral Spinal Fluid (CSF) Biomarker at Week 260

Time: Baseline and Week 260

Measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: Day 1 up to 16 weeks following the last administration of study drug or study discontinuation/termination, whichever is later (up to approximately 432 weeks)

Measure: Number of Participants With Anti-Crenezumab Antibodies

Time: Day 1 up to 16 weeks following the last administration of study drug or study discontinuation/termination, whichever is later (up to approximately 432 weeks)

Measure: CSF Crenezumab Concentration

Time: Baseline (at least 72 hours prior to the first study drug administration); Weeks 104 and 260; at study completion/early discontinuation (up to approximately 416 weeks)

Measure: Serum Crenezumab Concentration

Time: Predose (Hour 0) at Baseline, Weeks 4, 12, 16, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, 260, 284, 312, 336, 364, 388, 416, and 16 weeks after last dose/early discontinuation (up to approximately 432 weeks)

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 E280A

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. --- E280A ---

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 This randomized, double-blind, placebo-controlled, parallel group, adaptive study will evaluate the efficacy and safety of crenezumab versus placebo in individuals 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. --- E280A ---

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 This randomized, double-blind, placebo-controlled, parallel group, adaptive study will evaluate the efficacy and safety of crenezumab versus placebo in individuals 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. --- E280A --- --- E280A ---

The study will also include a cohort of PSEN1 E280A mutation non-carriers who will be dosed with placebo only. --- E280A ---

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. --- E280A ---

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. --- E280A --- --- E280A ---

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. --- E280A --- --- E280A --- --- E280A ---

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 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. --- E280A ---

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 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. --- E280A --- --- E280A ---

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 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. --- E280A --- --- E280A --- --- E280A ---



HPO Nodes


HPO:
Alzheimer disease
Genes 13
MPO HFE ABCA7 PSEN1 APOE APP A2M CACNA1G PSEN2 APOE PLAU GATA1 NOS3