A Study of Semagacestat for Alzheimer's Patients

Study Overview
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Brief Summary
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The primary objective of the original study was to assess the safety of semagacestat in Alzheimer's disease (AD) patients during 24 months of open-label treatment. Baseline for the efficacy measures is defined as the baseline for feeder studies LFAN (NCT00594568) and LFBC (NCT00762411). For all safety analyses (adverse events), baseline for patients will be week 0 of this study (LFBF). Preliminary results from LFAN and LFBC 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 LFBF 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. Very few participants from LFBC rolled over into LFBF (N = 9). Due to insufficient sample size, the data for LFBC participants who rolled into LFBF were not analyzed.

Official Title
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Open-Label Extension for Alzheimer's Disease Patients Who Complete One of Two Semagacestat Phase 3 Double-Blind Studies (H6L-MC-LFAN or H6L-MC-LFBC)

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: semagacestat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable Alzheimer's Disease Completed semagacestat study LFAN or study LFBC through 88 weeks Must continue to have a reliable caregiver Capable of swallowing whole oral medication Agrees not to participate in other investigational compounds for the duration of study Exclusion Criteria: Meets LFAN or LFBC study discontinuation criteria at the last visit of the LFAN or LFBC study

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug: semagacestat<br> | Drug: semagacestat<br>* 140mg administered orally, once daily for 24 months; dose reduction to 100mg or 60 mg possible due to intolerability<br>* Other names: LY450139;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog11) at Week 16 After Cessation of Study Drug | The cognitive subscale of the 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. | Baseline (LFAN randomization), 16 weeks (LFBF) after cessation of study drug | 
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at Week 16 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. It measures both basic and instrumental activities of daily living. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. | Baseline (LFAN randomization), 16 weeks (LFBF) after cessation of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at Week 12 | Concentration of amino acid peptide known as Aβ 1-42 in plasma. Least Square (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (LFAN Randomization ), 6 hours pose-dose at Week 12 (LFBF) | 
| Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) at Week 12 | The vMRI assessment of right hippocampal and left hippocampal volume is reported. Least Square (LS) Mean value was controlled for baseline value, age, and investigator. | Baseline (LFAN Randomization), 12 weeks (LFBF) | 
| Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45-PET) at Week 12 | 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 for the cerebellar gray matter. Least Squares (LS) Mean value was controlled for baseline value, age, and investigator. Due to insufficient sample size, this analysis was not done. | Baseline (LFAN Randomization), 12 weeks (LFBF) | 
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog11) at Week 12 | The cognitive subscale of the 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 Square (LS) Mean value was controlled for baseline value, age, investigator, and concomitant standard of care (SOC) medication. | Baseline (LFAN Randomization), 12 weeks (LFBF) | 
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) at Week 12 | ADAS-Cog12 is the ADAS-Cog11 augmented with the delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. Least Square (LS) Mean value was controlled for baseline value, age, investigator, and concomitant standard of care (SOC) medication. | Baseline (LFAN Randomization), 12 weeks (LFBF) | 
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog14) at Week 12 | The ADAS-Cog14 is the 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 Square (LS) Mean value was controlled for the baseline value, age, investigator, and concomitant standard of care (SOC) medication. | Baseline (LFAN Randomization), 12 weeks (LFBF) | 
| Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) at Week 12 | The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. It measures both basic and instrumental activities of daily living. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Square (LS) Mean value was controlled for baseline value, age, investigator, and concomitant standard of care (SOC) medication. | Baseline (LFAN Randomization), 12 weeks (LFBF) | 
| Mean Concentration of LY450139 |  | 3 months (pre-dose, 2, 4, and 6 hours after dosing )(LFBF) | 
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) at Week 16 After Cessation of Study Drug | ADAS-Cog12 is the ADAS-Cog11 augmented with the delayed free recall measure, resulting in a total score ranging from 0 to 80. Higher scores indicate greater disease severity. | Baseline (LFAN Randomization), 16 weeks (LFBF) after cessation of study drug | 
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog14) at Week 16 After Cessation of Study Drug | The ADAS-Cog14 is the 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. | Baseline (LFAN Randomization), 16 weeks (LFBF) after cessation of study drug | 
| Change From Baseline in Clinical Dementia Rating Scale (Sum of Boxes) (CDR-SB) at Week 24 | The CDR-SB is a semi-structured interview of participants and their caregivers. The participant's cognitive status is rated in 6 domains of functioning, including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. A severity score is assigned for each of the 6 domains with total score ranging from 0 to 18. Higher scores indicate greater disease severity. Least Square (LS) Mean value was controlled for baseline value, age, investigator, and concomitant standard of care (SOC) medication. | Baseline (LFAN Randomization), 24 weeks (LFBF) | 
| Change From Baseline in Mini-Mental State Examination (MMSE) at Week 24 | The MMSE is a brief screening instrument used to assess cognitive function in elderly participants. It assesses orientation, memory, attention, and ability to name objects, follow verbal and written commands, write a sentence, and copy figures. The total score ranges from 0 to 30, with a lower score indicating greater disease severity. Least Square (LS) Mean value was controlled for baseline value, age, investigator, and concomitant standard of care (SOC) medication. | Baseline (LFAN Randomization), 24 weeks (LFBF) | 
| Change From Baseline in Neuropsychiatric Inventory (NPI) at Week 24 | The NPI is a tool for assessing psychopathology in patients with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the patient's behavior. The score ranges from 12 to 144, with higher scores indicating greater disease severity. Least Square (LS) Mean value was controlled for the baseline value, age, investigator, concomitant standard of care medication. | Baseline (LFAN Randomization), 24 weeks (LFBF) | 
| Change From Baseline in EuroQol-5D (EQ-5D) at Week 24 | 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. Numbers 1-3 are not added for total score. Visual Analog Scale (VAS) assesses caregiver's impression of participant's overall health state; VAS scores range=0-100, with lower scores indicating greater disease severity. LS Mean value was controlled for baseline value, age, investigator, and concomitant standard of care (SOC) medication. | Baseline (LFAN Randomization), 24 weeks (LFBF) | 
| Change From Baseline in Resource Utilization in Dementia-Lite Questionnaire (RUD-Lite) at Week 12 | RUD-Lite assesses the healthcare resource utilization of participants and their caregivers to determine the level of formal and informal care attributable to Alzheimer's Disease (AD). Information on both caregivers (caregiving time, work status) and participants (accommodation and healthcare resource utilization) is collected from the baseline and follow-up interviews. Reported the change in number of hospitalizations per participant to week 12. | Baseline (LFAN Randomization), 12 weeks (LFBF) |