Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo (EXPEDITION 3)

• ClinicalTrials.gov Identifier: NCT01900665
• Recruitment Status: Terminated
• First Posted: July 16, 2013
• Results First Posted: March 14, 2018
• Last Update Posted: October 9, 2019
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: July 12, 2013
• First Posted Date: July 16, 2013
• Results First Submitted Date: February 16, 2018
• Results First Posted Date: March 14, 2018
• Last Update Posted Date: October 9, 2019
• Study Start Date: July 2013
• Actual Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 16, 2018)

Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 14 Item Subscore (ADAS-Cog14) [ Time Frame: Baseline, Week 80 ]

The ADAS is a rater administered instrument that was designed to assess the severity of the dysfunction in the cognitive and noncognitive behaviors characteristic of persons with AD. The cognitive subscale of the ADAS that was used as the primary efficacy measure consists of 14 items assessing areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation, and maze completion measures. The ADAS-Cog14 scale ranges from 0 to 90. Higher scores indicate greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.

Original Primary Outcome Measures (submitted: July 12, 2013)

• Change from Baseline in Alzheimer's Disease Assessment Scale-Cognitive 14 Item Subscore (ADAS-Cog14) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Alzheimer's Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL) [ Time Frame: Baseline, Week 80 ]

Current Secondary Outcome Measures (submitted: April 2, 2018)

• Change From Baseline in Alzheimer's Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL) [ Time Frame: Baseline, Week 80 ]
  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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 11 Item Subscore (ADAS-Cog11) [ Time Frame: Baseline, Week 80 ]
  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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Mini-Mental State Examination (MMSE) [ Time Frame: Baseline, Week 80 ]
  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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) [ Time Frame: Baseline, Week 80 ]
  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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Functional Activities Questionnaire (FAQ) [ Time Frame: Baseline, Week 80 ]
  FAQ is a 10-item, caregiver-based questionnaire and was administered to the study partner who was asked to rate the participant's ability to perform a variety of activities ranging from financial management, shopping, playing games, food preparation, traveling, keeping appointments, keeping track of current events, and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. A negative change indicated an improvement from baseline. FAQ Total Score is the sum of 10 items, ranging from 0 (best possible outcome) to 100 (worst possible outcome). LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) [ Time Frame: Baseline, Week 80 ]
  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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Neuropsychiatric Inventory (NPI) [ Time Frame: Baseline, Week 80 ]
  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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) [ Time Frame: Baseline, Week 80 ]
  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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) [ Time Frame: Baseline, Week 80 ]
  Assesses 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. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in 5-Dimensional EuroQol Quality of Life Scale Proxy Version (EQ-5D Proxy) [ Time Frame: Baseline, Week 80 ]
  EQ-5D (proxy version) measures mobility, self-care, usual activities, pain/discomfort, anxiety/depression. 3 severity levels: no, some, severe problems. Visual analog scale (VAS) assesses caregiver's impression of participant's health state; score ranges: 0 to 100 millimeter (mm). Lower scores=greater disease severity LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS) [ Time Frame: Baseline, Week 80 ]
  Integrated Alzheimer's Disease Rating Scale is used to assess that solanezumab slows down the cognitive and functional decline associated with AD compared with placebo. iADRS is a simple linear combination of ADAS-Cog 13 or 14 and the ADCS-iADL. The scale ranges from 0 to 146, where lower scores indicate worse performance. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Percentage of Participants of Cognitive and Functional Responders [ Time Frame: Baseline through Week 80 ]
  Assess the proportion of participants who reach certain levels of cognitive and functional decline. Decline in cognition was defined as worsening from baseline by at least 6 or 9 points on the ADAS Cog14. If there is a cognitive decline of a specified cut-off or more at any time then the participant is considered a nonresponder. Functional nonresponders are participants who have not had any of the following at any time point: Clinically evident decline in ability to perform one or more basic ADL present at baseline; A clinically evident decline in ability to perform 20% or more of the instrumental ADL present at baseline; An increase in global CDR score of 1 point or more compared with baseline. A decline from no impairment to mild impairment (bADL, iADL is not considered clinically significant, but other declines of 1 or more points and any participant discontinuation within the first 6 months will be considered a non-responder.
• Change From Baseline in Plasma Amyloid-Beta (Aβ) Species [ Time Frame: Baseline, Week 80 ]
  Concentration of amino acid peptide known as Aβ 1-42 in plasma. The change in plasma Aβ analytes after treatment were assessed separately for each plasma Aβ parameter. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) [ Time Frame: Baseline, Week 80 ]
  The vMRI assessment of right and left hippocampal atrophy, is reported. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.
• Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of Solanezumab (LY2062430) [ Time Frame: Visit 2 (Post-dose), Visit 5, 9, 15 (Pre-dose, Post-dose) and Visit 22 (Pre-dose): Pre-dose before the infusion, Post-dose 30 minutes End of Infusion ]
  Area Under the Concentration versus Time Curve was evaluated for Solanezumab.
• Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan [ Time Frame: Baseline, Week 80 ]
  Florbetapir PET imaging was used to confirm the presence of amyloid pathology consistent with AD. Change from baseline was done to test the hypothesis that amyloid burden was reduced in participants in the treatment group. The change from baseline to the postbaseline visit of the composite summary standard uptake value ratio of florbetapir F18 was calculated. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit. The composite summary measure is an unweighted average of the 6 smaller regions (anterior cingulate, frontal medial orbital, parietal, posterior cingulate, precuneus, and temporal) normalized to whole cerebellum or subject-specific white matter.
• Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels [ Time Frame: Baseline, Week 80 ]
  Concentration of CSF parameters includes amino acid peptide known as Aβ 1-42 and Aβ 1-42. Analyses of these CSF biomarkers was conducted in a subset of participants (as an addendum to the protocol). The dependent variable for each CSF parameter was its change from baseline to endpoint. LS Mean value was controlled for baseline value, baseline age, pooled investigator, treatment and visit.

Original Secondary Outcome Measures (submitted: July 12, 2013)

• Change from Baseline in Alzheimer's Disease Assessment Scale-Cognitive 11 Item Subscore (ADAS-Cog11) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Mini-Mental State Examination (MMSE) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Functional Activities Questionnaire (FAQ) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Neuropsychiatric Inventory (NPI) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Quality of Life in Alzheimer's Disease (QoL-AD) [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in 5-Dimensional EuroQol Quality of Life Scale Proxy Version (EQ-5D Proxy) [ Time Frame: Baseline, Week 80 ]
• Proportion of Cognitive and Functional Responders [ Time Frame: Baseline through Week 80 ]
• Change from Baseline in Plasma Amyloid-Beta (Aβ) Species [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in volumetric Magnetic Resonance Imaging (vMRI) [ Time Frame: Baseline, Week 80 ]
• Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of Solanezumab (LY2062430) [ Time Frame: Baseline through Week 80 ]
• Change from Baseline in Florbetapir Positron Emission Tomography (PET) Scan [ Time Frame: Baseline, Week 80 ]
• Change from Baseline in Cerebrospinal Fluid (CSF) Aβ Levels [ Time Frame: Baseline, Week 80 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo
• Official Title: Effect of Passive Immunization on the Progression of Mild Alzheimer's Disease: Solanezumab (LY2062430) Versus Placebo
• Brief Summary: To test the idea that solanezumab will slow the cognitive decline of Alzheimer's Disease (AD) as compared with placebo in participants with mild AD.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimer's Disease

Intervention

• Drug: Solanezumab
  Administered Intravenously (IV)
  Other Names:

  • LY2062430
  • A Beta Antibody
• Drug: Placebo
  Administered IV

Study Arms

• Experimental: Solanezumab
  Solanezumab 400 milligrams (mg) every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who complete the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.
  Intervention: Drug: Solanezumab
• Placebo Comparator: Placebo
  Placebo every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who complete the full 80 weeks of treatment/assessment and decide to continue will switch to solanezumab 400 mg every 4 weeks for up to an additional 208 weeks.
  Intervention: Drug: Placebo

• Publications *: Honig LS, Vellas B, Woodward M, Boada M, Bullock R, Borrie M, Hager K, Andreasen N, Scarpini E, Liu-Seifert H, Case M, Dean RA, Hake A, Sundell K, Poole Hoffmann V, Carlson C, Khanna R, Mintun M, DeMattos R, Selzler KJ, Siemers E. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018 Jan 25;378(4):321-330. doi: 10.1056/NEJMoa1705971.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: February 16, 2018): 2129
• Original Estimated Enrollment (submitted: July 12, 2013): 2100
• Actual Study Completion Date: February 2017
• Actual Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Meets National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable AD
• Has a Modified Hachinski Ischemia Scale score of less than or equal to 4
• Has a Mini-Mental State Examination (MMSE) score of 20 through 26 at Screening visit
• Has a Geriatric Depression Scale score of less than or equal to 6 (on the staff-administered short form)
• Has had a magnetic resonance imaging (MRI) or computerized tomography (CT) scan performed within the past 2 years that has confirmed no findings inconsistent with a diagnosis of AD
• Has a florbetapir positron emission tomography (PET) scan or cerebrospinal fluid (CSF) result consistent with the presence of amyloid pathology at screening

Exclusion Criteria:

• Does not have a reliable caregiver who is in frequent contact with the participant (defined as at least 10 hours per week), will accompany the participant to the office and/or be available by telephone at designated times, and will monitor administration of prescribed medications
• Meets National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS/AIREN) criteria for vascular dementia
• Has current serious or unstable illnesses including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic (other than AD), psychiatric, immunologic, or hematologic disease and other conditions that, in the investigator's opinion, could interfere with the analyses of safety and efficacy in this study; or has a life expectancy of <2 years
• Has had a history within the last 5 years of a serious infectious disease affecting the brain or head trauma resulting in protracted loss of consciousness
• Has a history within the last 5 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen posttreatment
• Has a known history of human immunodeficiency virus (HIV), clinically significant multiple or severe drug allergies, or severe posttreatment hypersensitivity reactions
• Has received acetylcholinesterase inhibitor (AChEIs), memantine and/or other AD therapy for less than 4 months or has less than 2 months of stable therapy on these treatments
• Has received medications that affect the central nervous system (CNS), except treatments for AD, for less than 4 weeks
• Has a history of chronic alcohol or drug abuse/dependence within the past 5 years
• Has a Visit 1 MRI with results showing >4 Amyloid-related Imaging Abnormality (ARIA), -hemorrhage /hemosiderin deposition (ARIA-H) or presence of ARIA-E (edema/effusions)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Germany, Italy, Japan, Poland, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT01900665
• Other Study ID Numbers: 15136; H8A-MC-LZAX ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: September 2019