Alzheimer's Disease
Conditions
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 participants. The build-up 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 participants. In this trial, participants 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 participants could eventually receive active drug. Participation could last approximately 2 years. Participants taking approved AD medications were permitted to participate in this study and continue taking these medications during the study. All participants who completed this study had the option to continue receiving semagacestat by participating in an open-label study. Preliminary results from this study (H6L-MC-LFAN \[LFAN\]) and another similar study (H6L-MC-LFBC \[LFBC; NCT00762411\]) 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. Studies LFAN, LFBC, and open-label H6L-MC-LFBF (LFBF; NCT01035138) were amended to continue collecting safety data, including cognitive scores, for at least 7 months. The Clinical Trial Registry (CTR) will reflect results of analyses from the original LFAN protocol in addition to those from the amended LFAN 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 (MMSE) score of 16-26 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 at 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 or drug abuse within the past 5 years * Has ever had active vaccination for AD
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks | Baseline (randomization), 76 weeks | ADAS-Cog11 was used as a primary efficacy measure. It 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) Score at 16 Weeks After Cessation of Study Drug | Baseline (randomization), 16 weeks following treatment cessation | 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 (ADCS-ADL) Inventory Score at 76 Weeks | Baseline (randomization), 76 weeks | ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of 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 (ADCS-ADL) Inventory Score at 16 Weeks After Cessation of Study Drug | Baseline (randomization), 16 weeks following treatment cessation | ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of 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 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 that 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 the drug distributes in the body. |
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score 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-Cognitive Subscale (ADAS-Cog14) Score 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, concomitant standard of care (SOC) medication. |
| Change From Baseline in Mini Mental State Examination (MMSE) Score at 76 Weeks | Baseline (randomization), 76 weeks | MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, and ability to name objects, follow verbal and written commands, write a sentence, and copy figures) in elderly participants. The 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. |
| Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score 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 Neuropsychiatric Inventory (NPI) Score 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 EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score 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 from 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. |
| 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 Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score 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-Cognitive Subscale (ADAS-Cog14) Score 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 Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score 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. LS Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) 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 Neuropsychiatric Inventory (NPI) Score 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. 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 Mini Mental State Examination (MMSE) Score at 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | 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, copy figures) in elderly participants. Total score ranges from 0 to 30; Lower score indicates greater disease severity. 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 EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score 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 from 0 to 100; Lower score indicates greater disease severity. 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 Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) at 4 Weeks After Cessation of Study Drug | Baseline (randomization), 4 weeks following treatment cessation | RUD-Lite assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (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 Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | Baseline (randomization), up to 76 weeks | Concentration of an amino 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 Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid | 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 Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks | Baseline (randomization), up to 76 weeks | Assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (caregiving time, work status) and participants (accommodation and healthcare resource utilization) was collected 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 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 left and right 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 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. |
Countries
Argentina, Australia, Belgium, Canada, Chile, Denmark, Finland, France, Germany, India, Israel, Italy, Japan, Poland, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo orally once daily for the first 76 weeks. At the end of 76 weeks, placebo arm participants received LY450139 titrated up to 140 mg orally once daily until Week 88. | 501 |
| 100 mg LY450139 Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily until Week 88. | 506 |
| 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. | 527 |
| Total | 1,534 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Delayed Start | Adverse Event | 12 | 2 | 2 |
| Delayed Start | Caregiver Decision | 5 | 6 | 2 |
| Delayed Start | Death | 0 | 0 | 1 |
| Delayed Start | Lost to Follow-up | 0 | 0 | 1 |
| Delayed Start | Physician Decision | 0 | 0 | 1 |
| Delayed Start | Sponsor Decision | 77 | 66 | 59 |
| Delayed Start | Withdrawal by Subject | 4 | 3 | 0 |
| Initial Treatment | Abnormal lab/electrocardiogram (ECG) | 7 | 7 | 6 |
| Initial Treatment | Adverse Event | 51 | 121 | 144 |
| Initial Treatment | Caregiver decision | 21 | 36 | 36 |
| Initial Treatment | Death | 6 | 11 | 15 |
| Initial Treatment | Entry criteria exclusion | 0 | 1 | 1 |
| Initial Treatment | Lost to Follow-up | 4 | 1 | 4 |
| Initial Treatment | Physician Decision | 3 | 2 | 4 |
| Initial Treatment | Protocol Violation | 2 | 2 | 5 |
| Initial Treatment | Sponsor decision | 193 | 142 | 147 |
| Initial Treatment | Withdrawal by Subject | 25 | 31 | 46 |
| Safety Follow Up (SFU)-Optional | Adverse Event | 5 | 0 | 0 |
| Safety Follow Up (SFU)-Optional | Caregiver Decision | 17 | 16 | 9 |
| Safety Follow Up (SFU)-Optional | Death | 0 | 1 | 0 |
| Safety Follow Up (SFU)-Optional | Lost to Follow-up | 2 | 1 | 2 |
| Safety Follow Up (SFU)-Optional | No safety visit or follow up | 25 | 22 | 18 |
| Safety Follow Up (SFU)-Optional | Withdrawal by Subject | 12 | 15 | 13 |
Baseline characteristics
| Characteristic | Placebo | 100 mg LY450139 | 140 mg LY450139 | Total |
|---|---|---|---|---|
| Age, Continuous | 73.9 years STANDARD_DEVIATION 8.1 | 73.6 years STANDARD_DEVIATION 8 | 73.9 years STANDARD_DEVIATION 8.5 | 73.8 years STANDARD_DEVIATION 8.2 |
| Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog11) Score | 22.8 units on a scale STANDARD_DEVIATION 9.1 | 22.5 units on a scale STANDARD_DEVIATION 8.9 | 23.1 units on a scale STANDARD_DEVIATION 8.8 | 22.8 units on a scale STANDARD_DEVIATION 8.9 |
| Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score | 60.5 units on a scale STANDARD_DEVIATION 13 | 62.3 units on a scale STANDARD_DEVIATION 11.6 | 60.5 units on a scale STANDARD_DEVIATION 12.4 | 61.1 units on a scale STANDARD_DEVIATION 12.4 |
| Race/Ethnicity, Customized African | 3 participants | 6 participants | 3 participants | 12 participants |
| Race/Ethnicity, Customized Caucasian | 413 participants | 428 participants | 441 participants | 1282 participants |
| Race/Ethnicity, Customized East Asian | 47 participants | 45 participants | 51 participants | 143 participants |
| Race/Ethnicity, Customized Hispanic | 33 participants | 22 participants | 24 participants | 79 participants |
| Race/Ethnicity, Customized Native American | 0 participants | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized West Asian | 5 participants | 5 participants | 6 participants | 16 participants |
| Region of Enrollment Argentina | 24 participants | 23 participants | 26 participants | 73 participants |
| Region of Enrollment Australia | 20 participants | 25 participants | 24 participants | 69 participants |
| Region of Enrollment Belgium | 8 participants | 5 participants | 5 participants | 18 participants |
| Region of Enrollment Canada | 20 participants | 21 participants | 18 participants | 59 participants |
| Region of Enrollment Chile | 17 participants | 14 participants | 12 participants | 43 participants |
| Region of Enrollment Denmark | 5 participants | 5 participants | 4 participants | 14 participants |
| Region of Enrollment Finland | 6 participants | 8 participants | 8 participants | 22 participants |
| Region of Enrollment France | 15 participants | 14 participants | 14 participants | 43 participants |
| Region of Enrollment Germany | 29 participants | 21 participants | 27 participants | 77 participants |
| Region of Enrollment India | 10 participants | 9 participants | 11 participants | 30 participants |
| Region of Enrollment Israel | 22 participants | 21 participants | 21 participants | 64 participants |
| Region of Enrollment Italy | 6 participants | 5 participants | 6 participants | 17 participants |
| Region of Enrollment Japan | 41 participants | 37 participants | 43 participants | 121 participants |
| Region of Enrollment Poland | 12 participants | 15 participants | 18 participants | 45 participants |
| Region of Enrollment South Africa | 26 participants | 28 participants | 30 participants | 84 participants |
| Region of Enrollment Spain | 24 participants | 24 participants | 25 participants | 73 participants |
| Region of Enrollment Sweden | 10 participants | 17 participants | 15 participants | 42 participants |
| Region of Enrollment United Kingdom | 14 participants | 20 participants | 21 participants | 55 participants |
| Region of Enrollment United States | 192 participants | 194 participants | 199 participants | 585 participants |
| Sex: Female, Male Female | 278 Participants | 279 Participants | 263 Participants | 820 Participants |
| Sex: Female, Male Male | 223 Participants | 227 Participants | 264 Participants | 714 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 262 / 501 | 310 / 507 | 385 / 529 | 0 / 192 | 0 / 153 | 0 / 124 | 0 / 290 | 0 / 223 | 0 / 214 |
| serious Total, serious adverse events | 72 / 501 | 123 / 507 | 132 / 529 | 10 / 192 | 9 / 153 | 5 / 124 | 12 / 290 | 22 / 223 | 5 / 214 |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 16 Weeks After Cessation of Study Drug
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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 16 Weeks After Cessation of Study Drug | 6.59 units on a scale | Standard Error 0.8 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 16 Weeks After Cessation of Study Drug | 7.57 units on a scale | Standard Error 0.91 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 16 Weeks After Cessation of Study Drug | 7.90 units on a scale | Standard Error 0.9 |
p-value: 0.296Mixed Models Analysis
p-value: 0.172Mixed Models Analysis
p-value: 0.746Mixed Models Analysis
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks
ADAS-Cog11 was used as a primary efficacy measure. It 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks | 6.19 units on a scale | Standard Error 0.54 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks | 7.29 units on a scale | Standard Error 0.57 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks | 7.68 units on a scale | Standard Error 0.59 |
p-value: 0.134Mixed Models Analysis
p-value: 0.045Mixed Models Analysis
p-value: 0.61Mixed Models Analysis
Primary
Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 16 Weeks After Cessation of Study Drug
ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 16 Weeks After Cessation of Study Drug | -9.26 units on a scale | Standard Error 1.14 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 16 Weeks After Cessation of Study Drug | -9.15 units on a scale | Standard Error 1.28 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 16 Weeks After Cessation of Study Drug | -11.73 units on a scale | Standard Error 1.26 |
p-value: 0.935Mixed Models Analysis
p-value: 0.068Mixed Models Analysis
p-value: 0.07Mixed Models Analysis
Primary
Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 76 Weeks
ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 76 Weeks | -8.76 units on a scale | Standard Error 0.72 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 76 Weeks | -10.13 units on a scale | Standard Error 0.77 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 76 Weeks | -12.70 units on a scale | Standard Error 0.79 |
p-value: 0.166Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
p-value: 0.014Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 16 Weeks After Cessation of Study Drug | 6.97 units on a scale | Standard Error 0.84 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 16 Weeks After Cessation of Study Drug | 8.27 units on a scale | Standard Error 0.95 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 16 Weeks After Cessation of Study Drug | 8.41 units on a scale | Standard Error 0.94 |
p-value: 0.186Mixed Models Analysis
p-value: 0.149Mixed Models Analysis
p-value: 0.889Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 76 Weeks | 6.52 units on a scale | Standard Error 0.58 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 76 Weeks | 7.98 units on a scale | Standard Error 0.61 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 76 Weeks | 8.33 units on a scale | Standard Error 0.63 |
p-value: 0.062Mixed Models Analysis
p-value: 0.022Mixed Models Analysis
p-value: 0.669Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 16 Weeks After Cessation of Study Drug | 7.90 units on a scale | Standard Error 0.93 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 16 Weeks After Cessation of Study Drug | 9.30 units on a scale | Standard Error 1.06 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 16 Weeks After Cessation of Study Drug | 9.89 units on a scale | Standard Error 1.04 |
p-value: 0.202Mixed Models Analysis
p-value: 0.075Mixed Models Analysis
p-value: 0.616Mixed Models Analysis
Secondary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score 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, concomitant standard of care (SOC) medication.
Time frame: Baseline (randomization), 76 weeks
Population: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 76 Weeks | 7.42 units on a scale | Standard Error 0.63 |
| 100 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 76 Weeks | 8.97 units on a scale | Standard Error 0.67 |
| 140 mg LY450139 | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 76 Weeks | 9.48 units on a scale | Standard Error 0.69 |
p-value: 0.071Mixed Models Analysis
p-value: 0.018Mixed Models Analysis
p-value: 0.571Mixed Models Analysis
Secondary
Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks
Concentration of an amino 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | -86.16 picogram per milliliter (pg/mL) | Standard Error 50.89 |
| 100 mg LY450139 | Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | 23.27 picogram per milliliter (pg/mL) | Standard Error 34.55 |
| 140 mg LY450139 | Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks | -40.51 picogram per milliliter (pg/mL) | Standard Error 31.68 |
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 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks | 0.08 ratio | Standard Error 0.06 |
| 100 mg LY450139 | Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks | 0.06 ratio | Standard Error 0.06 |
| 140 mg LY450139 | Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks | 0.09 ratio | Standard Error 0.07 |
p-value: 0.784ANCOVA
p-value: 0.931ANCOVA
p-value: 0.718ANCOVA
Secondary
Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score 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. LS Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) 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) Score 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 76 Weeks | 2.31 units on a scale | Standard Error 0.17 |
| 100 mg LY450139 | Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 76 Weeks | 2.73 units on a scale | Standard Error 0.18 |
| 140 mg LY450139 | Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 76 Weeks | 3.04 units on a scale | Standard Error 0.18 |
p-value: 0.069Mixed Models Analysis
p-value: 0.002Mixed Models Analysis
p-value: 0.198Mixed 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) Score 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 from 0 to 100; Lower score indicates greater disease severity. 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 EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score 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 from 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score at 76 Weeks | -1.41 units on a scale | Standard Error 1.11 |
| 100 mg LY450139 | Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score at 76 Weeks | -7.49 units on a scale | Standard Error 1.2 |
| 140 mg LY450139 | Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score at 76 Weeks | -5.33 units on a scale | Standard Error 1.22 |
p-value: <0.001Mixed Models Analysis
p-value: 0.005Mixed Models Analysis
p-value: 0.141Mixed Models Analysis
Secondary
Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks
The vMRI assessment of left and right 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Left Hippocampal Volume | -96.54 cubic millimeter (mm^3) | Standard Error 10.73 |
| Placebo | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Right Hippocampal Volume | -108.69 cubic millimeter (mm^3) | Standard Error 11.56 |
| 100 mg LY450139 | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Left Hippocampal Volume | -75.34 cubic millimeter (mm^3) | Standard Error 11.06 |
| 100 mg LY450139 | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Right Hippocampal Volume | -93.89 cubic millimeter (mm^3) | Standard Error 12.19 |
| 140 mg LY450139 | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Left Hippocampal Volume | -107.62 cubic millimeter (mm^3) | Standard Error 11.38 |
| 140 mg LY450139 | Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks | Right Hippocampal Volume | -112.40 cubic millimeter (mm^3) | Standard Error 12.52 |
p-value: 0.143ANCOVA
p-value: 0.464ANCOVA
p-value: 0.025ANCOVA
p-value: 0.347ANCOVA
p-value: 0.82ANCOVA
p-value: 0.243ANCOVA
Secondary
Change From Baseline in Mini Mental State Examination (MMSE) Score at 4 Weeks After Cessation of Study Drug
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, copy figures) in elderly participants. Total score ranges from 0 to 30; Lower score indicates greater disease severity. 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) Score at 76 Weeks
MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, attention, and ability to name objects, follow verbal and written commands, write a sentence, and copy figures) in elderly participants. The 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mini Mental State Examination (MMSE) Score at 76 Weeks | -2.95 units on a scale | Standard Error 0.26 |
| 100 mg LY450139 | Change From Baseline in Mini Mental State Examination (MMSE) Score at 76 Weeks | -3.14 units on a scale | Standard Error 0.27 |
| 140 mg LY450139 | Change From Baseline in Mini Mental State Examination (MMSE) Score at 76 Weeks | -3.71 units on a scale | Standard Error 0.27 |
p-value: 0.518Mixed Models Analysis
p-value: 0.013Mixed Models Analysis
p-value: 0.072Mixed Models Analysis
Secondary
Change From Baseline in Neuropsychiatric Inventory (NPI) Score 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. 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) Score 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 76 Weeks | 1.92 units on a scale | Standard Error 0.75 |
| 100 mg LY450139 | Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 76 Weeks | 3.31 units on a scale | Standard Error 0.79 |
| 140 mg LY450139 | Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 76 Weeks | 4.15 units on a scale | Standard Error 0.81 |
p-value: 0.127Mixed Models Analysis
p-value: 0.016Mixed Models Analysis
p-value: 0.381Mixed Models Analysis
Secondary
Change From Baseline in Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid
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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid | 9.75 picogram per milliliter (pg/mL) | Standard Error 7.67 |
| 100 mg LY450139 | Change From Baseline in Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid | -6.26 picogram per milliliter (pg/mL) | Standard Error 5.46 |
| 140 mg LY450139 | Change From Baseline in Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid | -5.13 picogram per milliliter (pg/mL) | Standard Error 5.04 |
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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks | -0.08 ratio | Standard Error 0.01 |
| 100 mg LY450139 | Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks | -0.12 ratio | Standard Error 0.01 |
| 140 mg LY450139 | Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks | -0.11 ratio | Standard Error 0.02 |
p-value: 0.038ANCOVA
p-value: 0.147ANCOVA
p-value: 0.604ANCOVA
Secondary
Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) at 4 Weeks After Cessation of Study Drug
RUD-Lite assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (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 Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks
Assesses healthcare resource utilization (formal and informal care). Information gathered on both caregivers (caregiving time, work status) and participants (accommodation and healthcare resource utilization) was collected 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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks | 0.55 hospitalizations/participant | Standard Error 0.09 |
| 100 mg LY450139 | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks | 0.66 hospitalizations/participant | Standard Error 0.07 |
| 140 mg LY450139 | Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks | 0.83 hospitalizations/participant | Standard Error 0.08 |
p-value: 0.337ANCOVA
p-value: 0.018ANCOVA
p-value: 0.157ANCOVA
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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks | 75.11 picogram per milliliter (pg/mL) | Standard Error 92.02 |
| 100 mg LY450139 | Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks | 20.50 picogram per milliliter (pg/mL) | Standard Error 69.54 |
| 140 mg LY450139 | Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks | 61.00 picogram per milliliter (pg/mL) | Standard Error 59.07 |
p-value: 0.634ANCOVA
p-value: 0.901ANCOVA
p-value: 0.659ANCOVA
Secondary
LY450139 Population Pharmacokinetics: Clearance of LY450139
Model estimated apparent oral clearance. Clearance is defined as the volume of plasma that is completely cleared of drug (LY450139) per unit time.
Time frame: 6 weeks, 12 weeks, and 52 weeks
Population: The analysis population (N=974) included all participants randomized to LY450139 with sufficient drug concentration and dosing information to allow estimation of clearance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | LY450139 Population Pharmacokinetics: Clearance of LY450139 | 18.8 liter per hour (L/h) | Geometric Coefficient of Variation 26.8 |
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 the drug distributes in the body.
Time frame: 6 weeks, 12 weeks, and 52 weeks
Population: The analysis population (N=974) included all participants randomized to LY450139 with sufficient drug concentration and dosing information to allow estimation of volume of distribution.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | LY450139 Population Pharmacokinetics: Volume of Distribution of LY450139 | 66.8 liter (L) | Geometric Coefficient of Variation 26.1 |
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: The analysis population included all randomized participants who received at least 1 dose of study medication with baseline and at least 1 post baseline evaluable data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks | 3.86 picogram per milliliter (pg/mL) | Standard Error 2.32 |
| 100 mg LY450139 | Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks | -5.97 picogram per milliliter (pg/mL) | Standard Error 2.5 |
| 140 mg LY450139 | Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks | -19.95 picogram per milliliter (pg/mL) | Standard Error 2.58 |
p-value: 0.002ANCOVA
p-value: <0.001ANCOVA
p-value: <0.001ANCOVA