Alzheimer's Disease
Conditions
Brief summary
This randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The primary efficacy assessment will be performed at 105 weeks. The participants who do not enter open-label extension will enter for a long term follow-up period for up to 52 weeks after the last crenezumab dose (Week 153).
Interventions
DRUGCrenezumab
Crenezumab was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.
DRUGPlacebo
Placebo was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Weight between 40 and 120 kilograms (Kg) inclusive * Availability of a person (referred to as the caregiver) who in the investigator's judgment: * Has frequent and sufficient contact with the participant to be able to provide accurate information regarding the participant's cognitive and functional abilities, agrees to provide information at clinic visits (which require partner input for scale completion), signs the necessary consent form, and has sufficient cognitive capacity to accurately report upon the participant's behavior and cognitive and functional abilities * Fluency in the language of the tests used at the study site * Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted) * Evidence of the AD pathological process, by a positive amyloid assessment either on cerebrospinal fluid (CSF) amyloid beta 1-42 levels as measured on the Elecsys beta-amyloid(1-42) test system or amyloid PET scan by qualitative read by the core/central PET laboratory * Demonstrated abnormal memory function at screening (up to 4 weeks before screening begins) or screening (FCSRT cueing index =\<0.67 AND free recall =\<27) * Screening mini mental state examination (MMSE) score of greater than or equal to (\>=) 22 points and Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1.0 * Meets National Institute on Aging/Alzheimer's Association (NIAAA) core clinical criteria for probable AD dementia or prodromal AD (consistent with the NIAAA diagnostic criteria and guidelines for mild cognitive impairment (MCI) * If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening * Participant must have completed at least 6 years of formal education after the age of 5 years
Exclusion criteria
* Any evidence of a condition other than AD that may affect cognition such as other dementias, stroke, brain damage, autoimmune disorders (e.g. multiple sclerosis) or infections with neurological sequelae. * History of major psychiatric illness such as schizophrenia or major depression (if not considered in remission) * At risk of suicide in the opinion of the investigator * Any abnormal MRI findings, such as presence of cerebral vascular pathology, cortical stroke, etc or inability to tolerate MRI procedures or contraindication to MRI * Unstable or clinically significant cardiovascular (e.g., myocardial infarction), kidney or liver disease * Uncontrolled hypertension * Screening hemoglobin A1c (HbA1C) \>8% * Poor peripheral venous access * History of cancer except: If considered to be cured or If not being actively treated with anti-cancer therapy or radiotherapy \- Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale Score | Baseline, Week 77 | The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline for this primary endpoint. Data after 29 January 2019 are censored for the primary and secondary efficacy analyses to avoid potential biases due to investigators, participants, raters, etc. being potentially influenced by early closure of the study due to lack of efficacy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score | Baseline, Week 77 | The ADAS-Cog-11 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The score range for ADAS-Cog-11 is from 0 to 70 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS) | Baseline, Week 77 | The CDR-GS represents a semi-structured interview which rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care) on a 5-point scale in which CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE) | Baseline, Week 77 | The MMSE is a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target 6 areas: orientation, registration, attention, short-term recall, language and constructional praxis/visuospatial abilities. The scores on the MMSE range from 0 to 30, with higher scores indicating better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 77 on Function as Assessed by (ADCS-ADL) Total Score | Baseline, Week 77 | The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 77 on Function as Assessed by (ADCS-iADL) Instrumental Score | Baseline, Week 77 | The ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) measures activities such as using the telephone, managing finances and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 77 on Function as Assessed by the Functional Activities Questionnaire (FAQ) Total Score | Baseline, Week 77 | The Functional Activities Questionnaire (FAQ) is an instrument consisting of 10 items and assesses instrumental, social and cognitive functioning. The score range is from 0 to 30 with higher scores representing higher impairment. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 77 on a Measure of Dependence Level Assessed From the ADCS-ADL Score | Baseline, Week 77 | The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score | Baseline, Week 53 | The NPI-Q evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavioral disturbances and appetite/eating abnormalities. The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, moderate and marked). The total severity score range is from 0 to 36 with higher scores representing higher severity. Difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures adjusting for disease severity, APOEe4 status, geographic region and the use/non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score | Baseline, Week 77 | The QoL-AD (Quality of Life - Alzheimer's Disease) scale assesses QoL in participants who have dementia. The QoL-AD consists of 13 items covering aspects of participants' relationships with friends and family, physical condition, mood, concerns about finances and overall assessment of QoL. Items are rated on 4-point Likert-type scales ranging from 1 \[poor\] to 4 \[excellent\]. The score range is from 13 to 52, with higher scores indicating a better QoL. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score | Baseline, Week 53 | The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally designed to reflect the stresses experienced by caregivers of people with dementia. This modified version includes slight modifications in item and title wording (e.g., removal of your relative to refer directly to the patient, removal of burden from title) and the use of 11-point numerical rating scales. The ZCI-AD scale consists of a total of 30 items. Total scores will be calculated with a total score range from 0 to 300 (higher scores indicate a higher burden on the caregiver). The difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score | Baseline, Week 77 | The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Caregivers | Baseline, Week 77 | The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs) | Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks). | An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Percentage of Participants With Anti-Crenezumab Antibodies | Baseline up to Week 105 | Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Crenezumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis. |
| Serum Concentration of Crenezumab | Pre-infusion (0 hour), 60-90 minutes post-infusion on Day 1 Week 1 and on Week 25; Weeks 13 (Pre-dose), 37 (Pre-dose), 53 (Pre-dose) and 77 (Pre-dose) (infusion length = as per the Pharmacy Manual) | Serum concentration data for Crenezumab will be tabulated and summarized. Descriptive summary statistics will include the arithmetic mean and SD. Since a sparse PK sampling design is being used, population (non-linear mixed-effects) modeling will be used to analyze the dose concentration-time data of crenezumab. Information from other clinical studies may be incorporated to establish the PK model. Please note that Post-dose samples were not collected at Weeks 5, 13, 37, 53 and 77. |
| Plasma Amyloid Beta (Abeta) 40 Concentrations | Week 1 Day 1; Weeks 53 | Plasma Abeta 40 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53. |
| Plasma Amyloid Beta (Abeta) 42 Concentrations | Week 1 Day 1; Weeks 53 | Plasma Abeta 42 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53. |
| Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI) | Baseline, Week 105 | Percentage Change in Whole Brain Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI) | Baseline, Week 105 | Percentage Change in Ventricle Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI) | Baseline, Week 105 | Percentage Change in Hippocampal Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
| European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Participants | Baseline, Week 77 | The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Denmark, Estonia, France, Germany, Israel, Italy, Japan, Norway, Peru, Poland, Portugal, Russia, Serbia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 209 centers in 27 countries.
Pre-assignment details
A total of 806 participants were enrolled at 209 centers. 4 participants did not receive any study treatment meaning that the modified intent-to-treat and safety populations consisted of 802 participants.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks. | 399 |
| Crenezumab Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks. | 407 |
| Total | 806 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 6 |
| Overall Study | Death | 4 | 0 |
| Overall Study | Multiple Reasons | 1 | 2 |
| Overall Study | Physician Decision | 2 | 2 |
| Overall Study | Study Terminated By Sponsor | 355 | 374 |
| Overall Study | Symptomatic Deterioration | 0 | 1 |
| Overall Study | Withdrawal by Subject | 28 | 22 |
Baseline characteristics
| Characteristic | Total | Placebo | Crenezumab |
|---|---|---|---|
| Age, Continuous | 70.9 Years STANDARD_DEVIATION 7.7 | 70.7 Years STANDARD_DEVIATION 7.9 | 71.1 Years STANDARD_DEVIATION 7.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 13 Participants | 8 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 92 Participants | 45 Participants | 47 Participants |
| Race/Ethnicity, Customized Black or African American | 7 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 77 Participants | 42 Participants | 35 Participants |
| Race/Ethnicity, Customized Multiple | 7 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 682 Participants | 334 Participants | 348 Participants |
| Race/Ethnicity, Customized Not Stated | 34 Participants | 15 Participants | 19 Participants |
| Race/Ethnicity, Customized Unknown | 12 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 675 Participants | 333 Participants | 342 Participants |
| Sex: Female, Male Female | 456 Participants | 225 Participants | 231 Participants |
| Sex: Female, Male Male | 350 Participants | 174 Participants | 176 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 398 | 0 / 404 |
| other Total, other adverse events | 77 / 398 | 85 / 404 |
| serious Total, serious adverse events | 42 / 398 | 33 / 404 |
Outcome results
Primary
Change From Baseline to Week 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale Score
The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline for this primary endpoint. Data after 29 January 2019 are censored for the primary and secondary efficacy analyses to avoid potential biases due to investigators, participants, raters, etc. being potentially influenced by early closure of the study due to lack of efficacy.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale Score | 3.19 Units on a Scale | Standard Error 0.434 |
| Crenezumab | Change From Baseline to Week 77 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Scale Score | 1.89 Units on a Scale | Standard Error 0.471 |
95% CI: [0, 2.6]
Secondary
Change From Baseline to Week 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score
The NPI-Q evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavioral disturbances and appetite/eating abnormalities. The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, moderate and marked). The total severity score range is from 0 to 36 with higher scores representing higher severity. Difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures adjusting for disease severity, APOEe4 status, geographic region and the use/non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 53
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score | -0.00 Units on a Scale | Standard Error 0.852 |
| Crenezumab | Change From Baseline to Week 53 on Behavior in Neuropsychiatric Inventory Questionnaire (NPI-Q) Total Score | 0.76 Units on a Scale | Standard Error 0.886 |
95% CI: [-1.75, 0.23]
Secondary
Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score
The ADAS-Cog-11 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The score range for ADAS-Cog-11 is from 0 to 70 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score | 7.16 Units on a Scale | Standard Error 1.452 |
| Crenezumab | Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 11 (ADAS-Cog-11) Subscale Score | 6.84 Units on a Scale | Standard Error 1.592 |
95% CI: [-4.03, 4.68]
Secondary
Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score
The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score | 8.90 Units on a Scale | Standard Error 1.382 |
| Crenezumab | Change From Baseline to Week 77 in Alzheimer's Disease Assessment Scale-Cognition 13 (ADAS-Cog-13) Subscale Score | 7.16 Units on a Scale | Standard Error 1.526 |
95% CI: [-2.4, 5.89]
Secondary
Change From Baseline to Week 77 on a Measure of Dependence Level Assessed From the ADCS-ADL Score
The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: Please note that for this Outcome Measure, no participants were evaluated at all as the derivation of this endpoint was not pre-specified before the Sponsor terminated the study and therefore it was not reported.
Secondary
Change From Baseline to Week 77 on Function as Assessed by (ADCS-ADL) Total Score
The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 on Function as Assessed by (ADCS-ADL) Total Score | -8.83 Units on a Scale | Standard Error 2.064 |
| Crenezumab | Change From Baseline to Week 77 on Function as Assessed by (ADCS-ADL) Total Score | -6.31 Units on a Scale | Standard Error 2.278 |
95% CI: [-8.74, 3.7]
Secondary
Change From Baseline to Week 77 on Function as Assessed by (ADCS-iADL) Instrumental Score
The ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) measures activities such as using the telephone, managing finances and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 on Function as Assessed by (ADCS-iADL) Instrumental Score | -6.69 Units on a Scale | Standard Error 1.692 |
| Crenezumab | Change From Baseline to Week 77 on Function as Assessed by (ADCS-iADL) Instrumental Score | -5.51 Units on a Scale | Standard Error 1.872 |
95% CI: [-6.29, 3.92]
Secondary
Change From Baseline to Week 77 on Function as Assessed by the Functional Activities Questionnaire (FAQ) Total Score
The Functional Activities Questionnaire (FAQ) is an instrument consisting of 10 items and assesses instrumental, social and cognitive functioning. The score range is from 0 to 30 with higher scores representing higher impairment. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 on Function as Assessed by the Functional Activities Questionnaire (FAQ) Total Score | 5.00 Units on a Scale | Standard Error 0.991 |
| Crenezumab | Change From Baseline to Week 77 on Function as Assessed by the Functional Activities Questionnaire (FAQ) Total Score | 4.37 Units on a Scale | Standard Error 1.059 |
95% CI: [-2.25, 3.51]
Secondary
Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS)
The CDR-GS represents a semi-structured interview which rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care) on a 5-point scale in which CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS) | 0.39 Units on a Scale | Standard Error 0.096 |
| Crenezumab | Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS) | 0.29 Units on a Scale | Standard Error 0.102 |
95% CI: [-0.2, 0.39]
Secondary
Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE)
The MMSE is a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target 6 areas: orientation, registration, attention, short-term recall, language and constructional praxis/visuospatial abilities. The scores on the MMSE range from 0 to 30, with higher scores indicating better function. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE) | -3.63 Units on a Scale | Standard Error 0.672 |
| Crenezumab | Change From Baseline to Week 77 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE) | -3.21 Units on a Scale | Standard Error 0.74 |
95% CI: [-2.42, 1.6]
Secondary
European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Caregivers
The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Caregivers | -4.07 Units on a Scale | Standard Error 2.724 |
| Crenezumab | European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Caregivers | -0.68 Units on a Scale | Standard Error 3.031 |
95% CI: [-11.5, 4.73]
Secondary
European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Participants
The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Participants | -3.69 Units on a Scale | Standard Error 3.961 |
| Crenezumab | European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Domain Scores for Participants | -3.39 Units on a Scale | Standard Error 4.392 |
95% CI: [-12.31, 11.71]
Secondary
Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI)
Percentage Change in Hippocampal Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 105
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI) | -6.34 Percentage | Standard Error 0.338 |
| Crenezumab | Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI) | -5.98 Percentage | Standard Error 0.29 |
95% CI: [-1.13, 0.41]
Secondary
Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI)
Percentage Change in Ventricle Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 105
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI) | 18.78 Percentage | Standard Error 1.343 |
| Crenezumab | Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI) | 17.18 Percentage | Standard Error 1.145 |
95% CI: [-1.7, 4.9]
Secondary
Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI)
Percentage Change in Whole Brain Volume will be measured over time and descriptive summary statistics will include the arithmetic mean, median, range, SD, and coefficient of variation, as appropriate. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 105
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI) | -2.71 Percentage | Standard Error 0.444 |
| Crenezumab | Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI) | -2.15 Percentage | Standard Error 0.345 |
95% CI: [-2.01, 0.89]
Secondary
Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs)
An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time frame: Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).
Population: The Safety analysis population included all randomized participants who received at least 1 dose of study drug with participants grouped according to actual treatment received. If a participant received at least 2 vials of crenezumab, then they were placed in the crenezumab arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs) | AEs | 73.1 Percentage |
| Placebo | Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs) | SAEs | 10.6 Percentage |
| Crenezumab | Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs) | AEs | 73.5 Percentage |
| Crenezumab | Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs) | SAEs | 8.2 Percentage |
Secondary
Percentage of Participants With Anti-Crenezumab Antibodies
Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Crenezumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.
Time frame: Baseline up to Week 105
Population: Please note that for this Outcome Measure, no Participants were evaluated at all as the existing immunogenicity data from an identical study (Study BN29552) showed a low potential of Crenezumab to induce Anti-Drug Antibodies (ADAs).
Secondary
Plasma Amyloid Beta (Abeta) 40 Concentrations
Plasma Abeta 40 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53.
Time frame: Week 1 Day 1; Weeks 53
Population: The PD Analysis population was defined as all participants who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Amyloid Beta (Abeta) 40 Concentrations | Week 1 Day 1 Predose | 0.415 ng/mL | Standard Deviation 0.0687 |
| Placebo | Plasma Amyloid Beta (Abeta) 40 Concentrations | Week 53 Predose | 46.6 ng/mL | Standard Deviation 6.91 |
Secondary
Plasma Amyloid Beta (Abeta) 42 Concentrations
Plasma Abeta 42 concentrations will be measured over time and descriptive summary statistics will include the arithmetic mean and SD. Please note that Pre-dose samples were only collected at Weeks 1 and 53.
Time frame: Week 1 Day 1; Weeks 53
Population: The PD Analysis population was defined as all participants who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Amyloid Beta (Abeta) 42 Concentrations | Week 1 Day 1 Predose | 0.0331 ng/mL | Standard Deviation 0.00463 |
| Placebo | Plasma Amyloid Beta (Abeta) 42 Concentrations | Week 53 Predose | 2.94 ng/mL | Standard Deviation 0.473 |
Secondary
Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score
The QoL-AD (Quality of Life - Alzheimer's Disease) scale assesses QoL in participants who have dementia. The QoL-AD consists of 13 items covering aspects of participants' relationships with friends and family, physical condition, mood, concerns about finances and overall assessment of QoL. Items are rated on 4-point Likert-type scales ranging from 1 \[poor\] to 4 \[excellent\]. The score range is from 13 to 52, with higher scores indicating a better QoL. The difference in mean change from Baseline to Week 77 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 77
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score | -1.61 Units on a Scale | Standard Error 1.31 |
| Crenezumab | Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score | -1.16 Units on a Scale | Standard Error 1.432 |
95% CI: [-3.3, 2.39]
Secondary
Serum Concentration of Crenezumab
Serum concentration data for Crenezumab will be tabulated and summarized. Descriptive summary statistics will include the arithmetic mean and SD. Since a sparse PK sampling design is being used, population (non-linear mixed-effects) modeling will be used to analyze the dose concentration-time data of crenezumab. Information from other clinical studies may be incorporated to establish the PK model. Please note that Post-dose samples were not collected at Weeks 5, 13, 37, 53 and 77.
Time frame: Pre-infusion (0 hour), 60-90 minutes post-infusion on Day 1 Week 1 and on Week 25; Weeks 13 (Pre-dose), 37 (Pre-dose), 53 (Pre-dose) and 77 (Pre-dose) (infusion length = as per the Pharmacy Manual)
Population: The PK Analysis population was defined as all participants who have received at least one dose of crenezumab and with at least one evaluable post-dose PK sample. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Serum Concentration of Crenezumab | Week 1 Day 1 Predose | NA ug/mL | — |
| Placebo | Serum Concentration of Crenezumab | Week 1 Day 1 Postdose | 1260 ug/mL | Standard Deviation 437 |
| Placebo | Serum Concentration of Crenezumab | Week 5 Predose | 246 ug/mL | Standard Deviation 128 |
| Placebo | Serum Concentration of Crenezumab | Week 13 Predose | 360 ug/mL | Standard Deviation 162 |
| Placebo | Serum Concentration of Crenezumab | Week 25 Predose | 401 ug/mL | Standard Deviation 196 |
| Placebo | Serum Concentration of Crenezumab | Week 25 Postdose | 1650 ug/mL | Standard Deviation 443 |
| Placebo | Serum Concentration of Crenezumab | Week 37 Predose | 456 ug/mL | Standard Deviation 351 |
| Placebo | Serum Concentration of Crenezumab | Week 53 Predose | 401 ug/mL | Standard Deviation 130 |
| Placebo | Serum Concentration of Crenezumab | Week 77 Predose | 357 ug/mL | Standard Deviation 94.2 |
Secondary
Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score
The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally designed to reflect the stresses experienced by caregivers of people with dementia. This modified version includes slight modifications in item and title wording (e.g., removal of your relative to refer directly to the patient, removal of burden from title) and the use of 11-point numerical rating scales. The ZCI-AD scale consists of a total of 30 items. Total scores will be calculated with a total score range from 0 to 300 (higher scores indicate a higher burden on the caregiver). The difference in mean change from Baseline to Week 53 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline.
Time frame: Baseline, Week 53
Population: The Modified Intent-To-Treat population (Placebo (n = 398); Cren (n = 404)) was defined as all randomized participants who received at least 1 dose of study drug, with participants grouped according to the treatment assigned at randomization. Data presented below is only for participants that were included in the actual analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score | 9.20 Units on a Scale | Standard Error 9.292 |
| Crenezumab | Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score | 2.65 Units on a Scale | Standard Error 9.643 |
95% CI: [-4.35, 17.44]