Alzheimer's Disease
Conditions
Keywords
Alzheimer's Disease
Brief summary
Alzheimer's disease (AD) is a fatal degenerative disease of the brain for which there is no cure. AD causes brain cells to die. AD is thought to be caused by an excess of beta amyloid (β-amyloid), a sticky protein in the brain that forms amyloid plaques. At autopsy, AD patients are required to have these amyloid plaques in the brain in order to have a definitive diagnosis of AD. Inhibiting the enzyme gamma-secretase (γ-secretase) lowers the production of β-amyloid. Semagacestat (LY450139) is a functional γ-secretase inhibitor and was shown to lower β-amyloid in blood and spinal fluid in humans tested thus far and in blood, spinal fluid and brain in animals tested thus far. This study used several different tests to measure the effect of semagacestat on both β-amyloid and amyloid plaques for some patients. The buildup of amyloid plaques was measured by a brain scan that takes a picture of amyloid plaques in the brain. Other tests measured the overall function of the brain and brain size in some patients. In this trial, patients who initially received placebo (inactive sugar pill) were, at a certain point in the study, switched over to active drug, semagacestat. In other words, all patients could eventually receive active drug. Each patient's participation could last approximately 2 years. Patients taking approved AD medications were permitted to participate in this study and continue taking these medications during the study. All patients who completed this study had the option to continue receiving semagacestat by participating in an open label study. Preliminary results from this study (LFBC) (and another similar study LFAN \[NCT00594568\]) showed semagacestat did not slow disease progression and was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Study drug was stopped in all studies. LFBC, LFAN and open label LFBF (NCT01035138) have been amended to continue collecting safety data, including cognitive scores, for at least seven months. The CT-Registry will reflect results of analyses from the original protocol in addition to those from the amended protocol.
Interventions
DRUGLY450139
Administered orally once daily.
DRUGPlacebo
Administered orally once daily.
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meets criteria for mild to moderate Alzheimer's disease (AD) with Mini-Mental State Examination score of 16 through 26 at visit 1 * Modified Hachinski Ischemia Scale score of less than or equal to 4 * Geriatric Depression Scale score of less than or equal to 6 * A magnetic resonance imaging (MRI) or computerized tomography (CT) scan in the last 2 years with no findings inconsistent with a diagnosis of AD * If female, must be without menstruation for a least 12 consecutive months or have had both ovaries removed.
Exclusion criteria
* Is not capable of swallowing whole oral medication * Has serious or unstable illnesses * Does not have a reliable caregiver * Chronic alcohol and/or drug abuse within the past 5 years * Has ever had a active vaccination for AD
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 76 Weeks | Baseline (randomization), 76 weeks | The cognitive subscale of the ADAS (ADAS Cog11) was used as a primary efficacy measure and consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 16 Weeks After Cessation of Study Drug | Baseline (randomization), 16 weeks following treatment cessation | The cognitive subscale of ADAS (ADAS Cog11) consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 76 Weeks | Baseline (randomization), 76 weeks | The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 16 Weeks After Cessation of Study Drug | Baseline (randomization), 16 weeks following treatment cessation | The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) at 76 Weeks | Baseline (randomization), 76 weeks | Assess QoL for AD: participant rates mood, relationships, memory, finances, physical condition, and overall QoL assessment. Each of 13 items, rated on a 4-point scale. Sum of items=total score (range: 13 to 52). Higher scores indicate greater QoL. Participant's primary caregiver asked to complete same measure. Least Squares (LS) Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Mini Mental State Examination (MMSE) at 76 Weeks | Baseline (randomization), 76 weeks | MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures) in elderly participants. Total score ranges from 0 to 30; lower score indicates greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication |
| Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks | Baseline (randomization), 52 weeks | Concentration of amino acid peptide known as Aβ 1-42 in plasma. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. |
| Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks | Baseline (randomization), 76 weeks | Measurement of local cerebral glucose metabolism by PET using the radioactive tracer 18F-FDG. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the Pons. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. |
| Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Baseline (randomization), up to 76 weeks | The vMRI assessment of right and left hippocampal volume is reported. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. |
| Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks | Baseline (randomization), up to 76 weeks | A radioactive tracer for PET that is a ligand for amyloid called \[18F\]-AV-45. This permits the visualization of amyloid in the brains of Alzheimer's participants. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the cerebellar gray matter. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. |
| Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks | Baseline (randomization), up to 76 weeks | Concentration of total tau in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. |
| LY450139 Population Pharmacokinetics: Clearance of LY450139 | 6 weeks, 12 weeks, and 52 weeks | Model estimated apparent oral clearance. Clearance is defined as the volume of plasma which is completely cleared of drug (LY450139) per unit time. |
| LY450139 Population Pharmacokinetics: Volume of Distribution of LY450139 | 6 weeks, 12 weeks, and 52 weeks | Model-estimated apparent volume of distribution. Volume of distribution is a measure of the extent to which drug distributes in the body. |
| Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) at 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | Semi-structured interview. Participant's cognitive status rated across 6 domains of functioning: memory, orientation, judgment/problem solving, community affairs, home/hobbies, personal care. Severity score assigned for each of 6 domains; total score (SB) ranges: 0 to 18. Higher scores=greater disease severity. Least Squares Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care medication. LY450139 dosing stopped due to evidence of dose-dependent cognitive/functional worsening. Participants followed off-dose for 32 weeks, but CDR-SB not assessed. |
| Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) at 76 Weeks | Baseline (randomization), 76 weeks | CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) at 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | Assesses healthcare resource utilization (formal and informal care). Information gathered on both care-giving time, work status) and participants (accommodation, healthcare resource utilization) is collected. Reported number of participant hospitalizations. Least Squares (LS) Mean value controlled for age and investigator. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but RUD-Lite was not assessed. |
| Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) at 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. VAS assesses caregiver's impression of participant's health state; score ranges: 0 to 100. Lower scores=greater disease severity. Least Squares (LS) Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but EQ-5D VAS was not assessed. |
| Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) at 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | Assess QoL for AD; participant rates mood, relationships, memory, finances, physical condition, and overall QoL assessment. Each of 13 items rated on a 4-point scale. Sum of items=total score (range: 13-52). Higher scores=greater QoL. Participant's primary caregiver asked to complete same measure. Least Squares Mean value controlled for baseline, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but QoL-AD not assessed. |
| Change From Baseline in Mini Mental State Examination (MMSE) 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | Used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures) in elderly participants. Total score ranges: 0 to 30. Lower score indicates greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but MMSE was not assessed. |
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 76 Weeks | Baseline (randomization), 76 weeks | ADAS-Cog12 is ADAS-Cog11 augmented with delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 76 Weeks | Baseline (randomization), 76 weeks | ADAS-Cog14 is ADAS-Cog11 augmented with delayed free recall, digit cancellation, and maze completion measures. A score of 0 to 10 for delayed free recall and a conversion code of 0 to 5 for digit cancellation and maze completion provide total score ranges for this extended ADAS-Cog14 of 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Phosphorylated-Tau (P-tau) Concentration in Spinal Fluid up to 76 Weeks | Baseline (randomization), up to 76 weeks | Concentration of p-tau in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. |
| Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | Baseline (randomization), up to 76 weeks | Concentration of an amino acid peptide known as Aβ 1-42 in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. |
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 16 Weeks After Cessation of Study Drug | Baseline (randomization), 16 weeks following treatment cessation | ADAS-Cog12 is ADAS-Cog11 augmented with delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 16 Weeks After Cessation of Study Drug | Baseline (randomization), 16 weeks following treatment cessation | ADAS-Cog14 is ADAS-Cog11 augmented with delayed free recall, digit cancellation, and maze completion measures. A score of 0 to 10 for delayed free recall and a conversion code of 0 to 5 for digit cancellation and maze completion provide total score ranges for this extended ADAS-Cog14 of 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, concomitant standard of care (SOC) medication. |
| Change From Baseline in Neuropsychiatric Inventory (NPI) at 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with participant's behavior. Total score ranges from 12 to 144; higher scores indicate greater disease severity. The Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but NPI was not assessed. |
| Change From Baseline in Neuropsychiatric Inventory (NPI) at 76 Weeks | Baseline (randomization), 76 weeks | NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 12 to 144; higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
| Change From Baseline in the Resource Utilization in Dementia-Lite (RUD-Lite) up to 76 Weeks | Baseline (randomization), up to 76 weeks | Assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (care-giving time, work status) and participants (accommodation and healthcare resource utilization) was gathered from baseline and follow-up interviews. Reported number of hospitalizations per participant up to 76 weeks. Least Squares (LS) Mean value was controlled for age and investigator. |
| Change From Baseline in the EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) at 76 Weeks | Baseline (randomization), 76 weeks | EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression; each has 3 severity levels (no, some, severe problems) coded to a 1-digit number (1-3). Digits are combined into 5-digit number describing health state. Numerals 1-3 are not added for total score. VAS assesses caregiver's impression of participant's overall health state; scores range: 0 to 100. Lower scores indicate greater disease severity. Least Squares (LS) Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. |
Countries
Brazil, Bulgaria, Canada, China, France, Germany, Hungary, Italy, Japan, Mexico, Romania, Russia, Serbia, South Korea, Taiwan, Turkey (Türkiye), Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 140 mg LY450139 Participants received 60 mg LY450139 orally once daily for 2 weeks followed by 100 mg LY450139 orally once daily for 2 weeks, then 140 mg LY450139 orally once daily until Week 88. | 555 |
| Placebo Participants received placebo orally once daily for the first 76 weeks. At the end of 76 weeks, participants in the placebo arm received LY450139 titrated up to 140 mg orally once daily until Week 88. | 553 |
| Total | 1,108 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Delayed Start | Adverse Event | 0 | 4 |
| Delayed Start | Caregiver Decision | 1 | 1 |
| Delayed Start | Protocol Violation | 0 | 1 |
| Delayed Start | Sponsor Decision | 16 | 20 |
| Initial Treatment | Abnormal Lab/ECG Result | 6 | 4 |
| Initial Treatment | Adverse Event | 132 | 40 |
| Initial Treatment | Caregiver Decision | 21 | 16 |
| Initial Treatment | Death | 7 | 6 |
| Initial Treatment | Entry Criteria Exclusion | 0 | 1 |
| Initial Treatment | Lost to Follow-up | 5 | 0 |
| Initial Treatment | Physician Decision | 1 | 0 |
| Initial Treatment | Protocol Violation | 4 | 1 |
| Initial Treatment | Sponsor Decision | 293 | 401 |
| Initial Treatment | Withdrawal by Subject | 65 | 52 |
| Safety Follow Up (SFU)-Optional | Adverse Event | 0 | 1 |
| Safety Follow Up (SFU)-Optional | Caregiver Decision | 8 | 8 |
| Safety Follow Up (SFU)-Optional | Death | 1 | 8 |
| Safety Follow Up (SFU)-Optional | Lost to Follow-up | 6 | 1 |
| Safety Follow Up (SFU)-Optional | No safety visit or SFU | 48 | 54 |
| Safety Follow Up (SFU)-Optional | Withdrawal by Subject | 21 | 46 |
Baseline characteristics
| Characteristic | Placebo | Total | 140 mg LY450139 |
|---|---|---|---|
| Age, Continuous | 73.0 years STANDARD_DEVIATION 8 | 73.2 years STANDARD_DEVIATION 8 | 73.4 years STANDARD_DEVIATION 8 |
| Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score (n=507, 533) | 24.2 units on a scale STANDARD_DEVIATION 9.1 | 24.3 units on a scale STANDARD_DEVIATION 9.1 | 24.5 units on a scale STANDARD_DEVIATION 9.1 |
| Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory Score (n=505, 529) | 59.1 units on a scale STANDARD_DEVIATION 13.8 | 58.9 units on a scale STANDARD_DEVIATION 13.5 | 58.8 units on a scale STANDARD_DEVIATION 13.3 |
| Race/Ethnicity, Customized African | 8 participants | 19 participants | 11 participants |
| Race/Ethnicity, Customized Caucasian | 354 participants | 712 participants | 358 participants |
| Race/Ethnicity, Customized East Asian | 160 participants | 310 participants | 150 participants |
| Race/Ethnicity, Customized Hispanic | 29 participants | 62 participants | 33 participants |
| Race/Ethnicity, Customized West Asian | 2 participants | 5 participants | 3 participants |
| Region of Enrollment Brazil | 21 participants | 39 participants | 18 participants |
| Region of Enrollment Bulgaria | 18 participants | 38 participants | 20 participants |
| Region of Enrollment Canada | 49 participants | 99 participants | 50 participants |
| Region of Enrollment China | 22 participants | 44 participants | 22 participants |
| Region of Enrollment France | 29 participants | 57 participants | 28 participants |
| Region of Enrollment Germany | 20 participants | 44 participants | 24 participants |
| Region of Enrollment Hungary | 16 participants | 35 participants | 19 participants |
| Region of Enrollment Italy | 11 participants | 25 participants | 14 participants |
| Region of Enrollment Japan | 69 participants | 133 participants | 64 participants |
| Region of Enrollment Korea, Republic of | 43 participants | 81 participants | 38 participants |
| Region of Enrollment Mexico | 24 participants | 50 participants | 26 participants |
| Region of Enrollment Romania | 17 participants | 37 participants | 20 participants |
| Region of Enrollment Russian Federation | 19 participants | 34 participants | 15 participants |
| Region of Enrollment Serbia | 8 participants | 13 participants | 5 participants |
| Region of Enrollment Taiwan | 24 participants | 49 participants | 25 participants |
| Region of Enrollment Turkey | 23 participants | 48 participants | 25 participants |
| Region of Enrollment Ukraine | 20 participants | 39 participants | 19 participants |
| Region of Enrollment United States | 120 participants | 243 participants | 123 participants |
| Sex: Female, Male Female | 327 Participants | 643 Participants | 316 Participants |
| Sex: Female, Male Male | 226 Participants | 465 Participants | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 130 / 555 | 258 / 556 | 6 / 34 | 0 / 22 | 0 / 430 | 0 / 312 |
| serious Total, serious adverse events | 60 / 555 | 92 / 556 | 7 / 34 | 1 / 22 | 22 / 430 | 20 / 312 |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 16 Weeks After Cessation of Study Drug
The cognitive subscale of ADAS (ADAS Cog11) consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 16 weeks following treatment cessation
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication and had both baseline and post-baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 16 Weeks After Cessation of Study Drug | 4.81 units on a scale | Standard Error 0.7 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 16 Weeks After Cessation of Study Drug | 4.85 units on a scale | Standard Error 0.63 |
p-value: 0.959Mixed Models Analysis
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 76 Weeks
The cognitive subscale of the ADAS (ADAS Cog11) was used as a primary efficacy measure and consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 76 Weeks | 7.37 units on a scale | Standard Error 0.79 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog11) at 76 Weeks | 6.77 units on a scale | Standard Error 0.72 |
p-value: 0.56Mixed Models Analysis
Primary
Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 16 Weeks After Cessation of Study Drug
The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 16 weeks following treatment cessation
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication and had both baseline and post-baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 16 Weeks After Cessation of Study Drug | -8.88 units on a scale | Standard Error 0.93 |
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 16 Weeks After Cessation of Study Drug | -7.68 units on a scale | Standard Error 0.84 |
p-value: 0.199Mixed Models Analysis
Primary
Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 76 Weeks
The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 76 Weeks | -10.49 units on a scale | Standard Error 0.98 |
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at 76 Weeks | -9.77 units on a scale | Standard Error 0.9 |
p-value: 0.567Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 16 Weeks After Cessation of Study Drug
ADAS-Cog14 is ADAS-Cog11 augmented with delayed free recall, digit cancellation, and maze completion measures. A score of 0 to 10 for delayed free recall and a conversion code of 0 to 5 for digit cancellation and maze completion provide total score ranges for this extended ADAS-Cog14 of 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 16 weeks following treatment cessation
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication and had both baseline and post-baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 16 Weeks After Cessation of Study Drug | 6.00 units on a scale | Standard Error 0.82 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 16 Weeks After Cessation of Study Drug | 5.89 units on a scale | Standard Error 0.73 |
p-value: 0.893Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 76 Weeks
ADAS-Cog14 is ADAS-Cog11 augmented with delayed free recall, digit cancellation, and maze completion measures. A score of 0 to 10 for delayed free recall and a conversion code of 0 to 5 for digit cancellation and maze completion provide total score ranges for this extended ADAS-Cog14 of 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 76 Weeks | 9.23 units on a scale | Standard Error 0.9 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale (ADAS-Cog14) at 76 Weeks | 8.32 units on a scale | Standard Error 0.82 |
p-value: 0.437Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 16 Weeks After Cessation of Study Drug
ADAS-Cog12 is ADAS-Cog11 augmented with delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 16 weeks following treatment cessation
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication and had both baseline and post-baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 16 Weeks After Cessation of Study Drug | 5.33 units on a scale | Standard Error 0.74 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 16 Weeks After Cessation of Study Drug | 5.14 units on a scale | Standard Error 0.67 |
p-value: 0.805Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 76 Weeks
ADAS-Cog12 is ADAS-Cog11 augmented with delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication and had both baseline and post-baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 76 Weeks | 10.09 units on a scale | Standard Error 3.29 |
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) at 76 Weeks | 10.34 units on a scale | Standard Error 2.67 |
p-value: 0.929Mixed Models Analysis
Secondary
Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks
Concentration of an amino acid peptide known as Aβ 1-42 in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator.
Time frame: Baseline (randomization), up to 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication, last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | 19.20 picogram per milliliter (pg/mL) | Standard Error 26.03 |
| Placebo | Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | -21.39 picogram per milliliter (pg/mL) | Standard Error 35.35 |
p-value: 0.417ANCOVA
Secondary
Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks
A radioactive tracer for PET that is a ligand for amyloid called \[18F\]-AV-45. This permits the visualization of amyloid in the brains of Alzheimer's participants. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the cerebellar gray matter. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator.
Time frame: Baseline (randomization), up to 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication, last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks | -0.36 ratio | Standard Error 0.23 |
| Placebo | Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks | 0.16 ratio | Standard Error 0.11 |
p-value: 0.326ANCOVA
Secondary
Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) at 4 Weeks After Cessation of Study Drug
Semi-structured interview. Participant's cognitive status rated across 6 domains of functioning: memory, orientation, judgment/problem solving, community affairs, home/hobbies, personal care. Severity score assigned for each of 6 domains; total score (SB) ranges: 0 to 18. Higher scores=greater disease severity. Least Squares Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care medication. LY450139 dosing stopped due to evidence of dose-dependent cognitive/functional worsening. Participants followed off-dose for 32 weeks, but CDR-SB not assessed.
Time frame: Baseline (randomization), 4 weeks following treatment cessation
Population: August 2010: all dosing was stopped after protocol-specified interim review showed dose-dependent cognitive/functional worsening of LY450139-treated participants. Participants were followed off-dose for 32 weeks. No analysis was performed at 4 weeks after cessation of drug since this outcome measure was not assessed during the follow-up period.
Secondary
Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) at 76 Weeks
CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication and had both baseline and post-baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) at 76 Weeks | 3.05 units on a scale | Standard Error 1.1 |
| Placebo | Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) at 76 Weeks | 4.00 units on a scale | Standard Error 0.92 |
p-value: 0.294Mixed Models Analysis
Secondary
Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) at 4 Weeks After Cessation of Study Drug
EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. VAS assesses caregiver's impression of participant's health state; score ranges: 0 to 100. Lower scores=greater disease severity. Least Squares (LS) Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but EQ-5D VAS was not assessed.
Time frame: Baseline (randomization), 4 weeks following treatment cessation
Population: August 2010: all dosing was stopped after protocol-specified interim review showed dose-dependent cognitive/functional worsening of LY450139-treated participants. Participants were followed off-dose for 32 weeks. No analysis was performed at 4 weeks after cessation of drug since this outcome measure was not assessed during the follow-up period.
Secondary
Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks
The vMRI assessment of right and left hippocampal volume is reported. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator.
Time frame: Baseline (randomization), up to 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication, last observation carried forward (LOCF).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Right Hippocampal Volume | -158.50 cubic millimeter (mm^3) | Standard Error 29.44 |
| 140 mg LY450139 | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Left Hippocampal Volume | -84.41 cubic millimeter (mm^3) | Standard Error 61.96 |
| Placebo | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Right Hippocampal Volume | -73.60 cubic millimeter (mm^3) | Standard Error 24.18 |
| Placebo | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Left Hippocampal Volume | -111.27 cubic millimeter (mm^3) | Standard Error 49.22 |
p-value: 0.101ANCOVA
p-value: 0.772ANCOVA
Secondary
Change From Baseline in Mini Mental State Examination (MMSE) 4 Weeks After Cessation of Study Drug
Used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures) in elderly participants. Total score ranges: 0 to 30. Lower score indicates greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but MMSE was not assessed.
Time frame: Baseline (randomization), 4 weeks following treatment cessation
Population: August 2010: all dosing was stopped after protocol-specified interim review showed dose-dependent cognitive/functional worsening of LY450139-treated participants. Participants were followed off-dose for 32 weeks. No analysis was performed at 4 weeks after cessation of drug since this outcome measure was not assessed during the follow-up period.
Secondary
Change From Baseline in Mini Mental State Examination (MMSE) at 76 Weeks
MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures) in elderly participants. Total score ranges from 0 to 30; lower score indicates greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Mini Mental State Examination (MMSE) at 76 Weeks | -3.56 units on a scale | Standard Error 0.38 |
| Placebo | Change From Baseline in Mini Mental State Examination (MMSE) at 76 Weeks | -3.35 units on a scale | Standard Error 0.35 |
p-value: 0.632Mixed Models Analysis
Secondary
Change From Baseline in Neuropsychiatric Inventory (NPI) at 4 Weeks After Cessation of Study Drug
NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with participant's behavior. Total score ranges from 12 to 144; higher scores indicate greater disease severity. The Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but NPI was not assessed.
Time frame: Baseline (randomization), 4 weeks following treatment cessation
Population: August 2010: all dosing was stopped after protocol-specified interim review showed dose-dependent cognitive/functional worsening of LY450139-treated participants. Participants were followed off-dose for 32 weeks. No analysis was performed at 4 weeks after cessation of drug since this outcome measure was not assessed during the follow-up period.
Secondary
Change From Baseline in Neuropsychiatric Inventory (NPI) at 76 Weeks
NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 12 to 144; higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Neuropsychiatric Inventory (NPI) at 76 Weeks | 2.94 units on a scale | Standard Error 1.04 |
| Placebo | Change From Baseline in Neuropsychiatric Inventory (NPI) at 76 Weeks | 3.84 units on a scale | Standard Error 0.95 |
p-value: 0.477Mixed Models Analysis
Secondary
Change From Baseline in Phosphorylated-Tau (P-tau) Concentration in Spinal Fluid up to 76 Weeks
Concentration of p-tau in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator.
Time frame: Baseline (randomization), up to 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication, last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Phosphorylated-Tau (P-tau) Concentration in Spinal Fluid up to 76 Weeks | 7.94 picogram per milliliter (pg/mL) | Standard Error 3.06 |
| Placebo | Change From Baseline in Phosphorylated-Tau (P-tau) Concentration in Spinal Fluid up to 76 Weeks | 14.75 picogram per milliliter (pg/mL) | Standard Error 4.68 |
p-value: 0.318ANCOVA
Secondary
Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks
Measurement of local cerebral glucose metabolism by PET using the radioactive tracer 18F-FDG. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the Pons. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication and had both baseline and post-baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks | -0.13 ratio | Standard Error 0.05 |
| Placebo | Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks | -0.08 ratio | Standard Error 0.03 |
p-value: 0.426ANCOVA
Secondary
Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) at 4 Weeks After Cessation of Study Drug
Assess QoL for AD; participant rates mood, relationships, memory, finances, physical condition, and overall QoL assessment. Each of 13 items rated on a 4-point scale. Sum of items=total score (range: 13-52). Higher scores=greater QoL. Participant's primary caregiver asked to complete same measure. Least Squares Mean value controlled for baseline, age, investigator, visit, and concomitant standard of care (SOC) medication. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but QoL-AD not assessed.
Time frame: Baseline (randomization), 4 weeks following treatment cessation
Population: August 2010: all dosing was stopped after protocol-specified interim review showed dose-dependent cognitive/functional worsening of LY450139-treated participants. Participants were followed off-dose for 32 weeks. No analysis was performed at 4 weeks after cessation of drug since this outcome measure was not assessed during the follow-up period.
Secondary
Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) at 76 Weeks
Assess QoL for AD: participant rates mood, relationships, memory, finances, physical condition, and overall QoL assessment. Each of 13 items, rated on a 4-point scale. Sum of items=total score (range: 13 to 52). Higher scores indicate greater QoL. Participant's primary caregiver asked to complete same measure. Least Squares (LS) Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) at 76 Weeks | -1.83 units on a scale | Standard Error 0.47 |
| Placebo | Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) at 76 Weeks | -1.05 units on a scale | Standard Error 0.43 |
p-value: 0.178Mixed Models Analysis
Secondary
Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) at 4 Weeks After Cessation of Study Drug
Assesses healthcare resource utilization (formal and informal care). Information gathered on both care-giving time, work status) and participants (accommodation, healthcare resource utilization) is collected. Reported number of participant hospitalizations. Least Squares (LS) Mean value controlled for age and investigator. All LY450139 dosing was stopped due to evidence of dose-dependent cognitive/functional worsening. Participants were followed off-dose for 32 weeks, but RUD-Lite was not assessed.
Time frame: Baseline (randomization), 4 weeks following treatment cessation
Population: August 2010: all dosing was stopped after protocol-specified interim review showed dose-dependent cognitive/functional worsening of LY450139-treated participants. Participants were followed off-dose for 32 weeks. No analysis was performed at 4 weeks after cessation of drug since this outcome measure was not assessed during the follow-up period.
Secondary
Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks
Concentration of total tau in spinal fluid. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator.
Time frame: Baseline (randomization), up to 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication, last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks | -11.60 picogram per milliliter (pg/mL) | Standard Error 39.39 |
| Placebo | Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks | 117.88 picogram per milliliter (pg/mL) | Standard Error 53.58 |
p-value: 0.117ANCOVA
Secondary
Change From Baseline in the EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) at 76 Weeks
EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression; each has 3 severity levels (no, some, severe problems) coded to a 1-digit number (1-3). Digits are combined into 5-digit number describing health state. Numerals 1-3 are not added for total score. VAS assesses caregiver's impression of participant's overall health state; scores range: 0 to 100. Lower scores indicate greater disease severity. Least Squares (LS) Mean value controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in the EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) at 76 Weeks | -4.46 units on a scale | Standard Error 1.78 |
| Placebo | Change From Baseline in the EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) at 76 Weeks | -3.38 units on a scale | Standard Error 1.64 |
p-value: 0.622Mixed Models Analysis
Secondary
Change From Baseline in the Resource Utilization in Dementia-Lite (RUD-Lite) up to 76 Weeks
Assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (care-giving time, work status) and participants (accommodation and healthcare resource utilization) was gathered from baseline and follow-up interviews. Reported number of hospitalizations per participant up to 76 weeks. Least Squares (LS) Mean value was controlled for age and investigator.
Time frame: Baseline (randomization), up to 76 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication, last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Change From Baseline in the Resource Utilization in Dementia-Lite (RUD-Lite) up to 76 Weeks | 0.72 number of hospitalizations | Standard Error 0.14 |
| Placebo | Change From Baseline in the Resource Utilization in Dementia-Lite (RUD-Lite) up to 76 Weeks | 0.82 number of hospitalizations | Standard Error 0.16 |
p-value: 0.673ANCOVA
Secondary
LY450139 Population Pharmacokinetics: Clearance of LY450139
Model estimated apparent oral clearance. Clearance is defined as the volume of plasma which is completely cleared of drug (LY450139) per unit time.
Time frame: 6 weeks, 12 weeks, and 52 weeks
Population: All participants randomized to LY450139 with sufficient dosing information and concentration data to allow estimation of pharmacokinetic parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | LY450139 Population Pharmacokinetics: Clearance of LY450139 | 18.9 liters per hour (L/h) | Geometric Coefficient of Variation 26.6 |
Secondary
LY450139 Population Pharmacokinetics: Volume of Distribution of LY450139
Model-estimated apparent volume of distribution. Volume of distribution is a measure of the extent to which drug distributes in the body.
Time frame: 6 weeks, 12 weeks, and 52 weeks
Population: All participants randomized to LY450139 with sufficient dosing information and concentration data to allow estimation of pharmacokinetic parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | LY450139 Population Pharmacokinetics: Volume of Distribution of LY450139 | 66.1 liters (L) | Geometric Coefficient of Variation 26.2 |
Secondary
Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks
Concentration of amino acid peptide known as Aβ 1-42 in plasma. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator.
Time frame: Baseline (randomization), 52 weeks
Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 140 mg LY450139 | Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks | -16.03 picogram per milliliter (pg/mL) | Standard Error 28.33 |
| Placebo | Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks | 76.37 picogram per milliliter (pg/mL) | Standard Error 24.73 |
p-value: 0.009ANCOVA