Trial Outcomes & Findings for Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo (NCT NCT01900665)

NCT ID: NCT01900665

Last Updated: 2019-10-09

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

2129 participants

Primary outcome timeframe

Baseline, Week 80

Results posted on

2019-10-09

Participant Flow

Participants were excluded after study enrollment,if PET imaging or CSF results did not show evidence of brain amyloid pathology,a screening MRI with results \>4 ARIA-H(amyloid-related imaging abnormality-hemorrhage/hemosiderin deposition) or presence of ARIA-E(amyloid-related imaging abnormality-edema/effusions) and abnormal lab results were found.

Participant milestones

Participant milestones
Measure	Solanezumab Participants received Solanezumab 400 milligrams (mg)Intravenously (IV) every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo Participants received Placebo IV 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.
Placebo Controlled Period STARTED	1057	1072
Placebo Controlled Period Received at Least 1 Dose of Study Drug	1054	1067
Placebo Controlled Period COMPLETED	914	908
Placebo Controlled Period NOT COMPLETED	143	164
Open Label Period STARTED	881	859
Open Label Period COMPLETED	0	0
Open Label Period NOT COMPLETED	881	859

Reasons for withdrawal

Reasons for withdrawal
Measure	Solanezumab Participants received Solanezumab 400 milligrams (mg)Intravenously (IV) every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo Participants received Placebo IV 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.
Placebo Controlled Period Death	9	16
Placebo Controlled Period Adverse Event	48	39
Placebo Controlled Period Protocol Violation	1	7
Placebo Controlled Period Withdrawal by Subject	33	45
Placebo Controlled Period Physician Decision	11	7
Placebo Controlled Period Lost to Follow-up	3	0
Placebo Controlled Period Caregiver Decision	33	41
Placebo Controlled Period Entry Criteria Not Met	5	9
Open Label Period Adverse Event	16	20
Open Label Period Death	5	6
Open Label Period Lost to Follow-up	1	1
Open Label Period Parent/Caregiver Decision	33	34
Open Label Period Physician Decision	4	4
Open Label Period Protocol Violation	0	1
Open Label Period Sponsor Decision	802	765
Open Label Period Withdrawal by Subject	20	28

Baseline Characteristics

All randomized participants who had baseline ethnicity data.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Solanezumab n=1057 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=1072 Participants 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. Placebo: Administered IV	Total n=2129 Participants Total of all reporting groups
Region of Enrollment Poland	52 Participants n=1057 Participants	50 Participants n=1072 Participants	102 Participants n=2129 Participants
Region of Enrollment Italy	46 Participants n=1057 Participants	52 Participants n=1072 Participants	98 Participants n=2129 Participants
Region of Enrollment United Kingdom	45 Participants n=1057 Participants	44 Participants n=1072 Participants	89 Participants n=2129 Participants
Region of Enrollment Australia	32 Participants n=1057 Participants	36 Participants n=1072 Participants	68 Participants n=2129 Participants
Region of Enrollment France	87 Participants n=1057 Participants	86 Participants n=1072 Participants	173 Participants n=2129 Participants
Region of Enrollment Germany	48 Participants n=1057 Participants	48 Participants n=1072 Participants	96 Participants n=2129 Participants
Region of Enrollment Spain	56 Participants n=1057 Participants	58 Participants n=1072 Participants	114 Participants n=2129 Participants
Age, Continuous	72.69 years STANDARD_DEVIATION 7.814 • n=1057 Participants	73.26 years STANDARD_DEVIATION 7.966 • n=1072 Participants	72.98 years STANDARD_DEVIATION 7.894 • n=2129 Participants
Sex: Female, Male Female	600 Participants n=1057 Participants	631 Participants n=1072 Participants	1231 Participants n=2129 Participants
Sex: Female, Male Male	457 Participants n=1057 Participants	441 Participants n=1072 Participants	898 Participants n=2129 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	49 Participants n=970 Participants • All randomized participants who had baseline ethnicity data.	49 Participants n=986 Participants • All randomized participants who had baseline ethnicity data.	98 Participants n=1956 Participants • All randomized participants who had baseline ethnicity data.
Ethnicity (NIH/OMB) Not Hispanic or Latino	921 Participants n=970 Participants • All randomized participants who had baseline ethnicity data.	937 Participants n=986 Participants • All randomized participants who had baseline ethnicity data.	1858 Participants n=1956 Participants • All randomized participants who had baseline ethnicity data.
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=970 Participants • All randomized participants who had baseline ethnicity data.	0 Participants n=986 Participants • All randomized participants who had baseline ethnicity data.	0 Participants n=1956 Participants • All randomized participants who had baseline ethnicity data.
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=970 Participants • All randomized participants who had baseline race data.	0 Participants n=986 Participants • All randomized participants who had baseline race data.	0 Participants n=1956 Participants • All randomized participants who had baseline race data.
Race (NIH/OMB) Asian	75 Participants n=970 Participants • All randomized participants who had baseline race data.	71 Participants n=986 Participants • All randomized participants who had baseline race data.	146 Participants n=1956 Participants • All randomized participants who had baseline race data.
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=970 Participants • All randomized participants who had baseline race data.	0 Participants n=986 Participants • All randomized participants who had baseline race data.	1 Participants n=1956 Participants • All randomized participants who had baseline race data.
Race (NIH/OMB) Black or African American	14 Participants n=970 Participants • All randomized participants who had baseline race data.	19 Participants n=986 Participants • All randomized participants who had baseline race data.	33 Participants n=1956 Participants • All randomized participants who had baseline race data.
Race (NIH/OMB) White	878 Participants n=970 Participants • All randomized participants who had baseline race data.	894 Participants n=986 Participants • All randomized participants who had baseline race data.	1772 Participants n=1956 Participants • All randomized participants who had baseline race data.
Race (NIH/OMB) More than one race	2 Participants n=970 Participants • All randomized participants who had baseline race data.	2 Participants n=986 Participants • All randomized participants who had baseline race data.	4 Participants n=1956 Participants • All randomized participants who had baseline race data.
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=970 Participants • All randomized participants who had baseline race data.	0 Participants n=986 Participants • All randomized participants who had baseline race data.	0 Participants n=1956 Participants • All randomized participants who had baseline race data.
Region of Enrollment Canada	61 Participants n=1057 Participants	66 Participants n=1072 Participants	127 Participants n=2129 Participants
Region of Enrollment Sweden	26 Participants n=1057 Participants	26 Participants n=1072 Participants	52 Participants n=2129 Participants
Region of Enrollment United States	537 Participants n=1057 Participants	541 Participants n=1072 Participants	1078 Participants n=2129 Participants
Region of Enrollment Japan	67 Participants n=1057 Participants	65 Participants n=1072 Participants	132 Participants n=2129 Participants

PRIMARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

Outcome measures

Outcome measures
Measure	Solanezumab n=1053 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=1067 Participants Participants received Placebo IV 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.
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 14 Item Subscore (ADAS-Cog14)	6.65 Units on a scale Standard Error 0.355	7.44 Units on a scale Standard Error 0.356

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=908 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=896 Participants Participants received Placebo IV 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.
Change From Baseline in Alzheimer's Disease Cooperative Study- Instrumental Activities of Daily Living (ADCS-iADL)	-6.17 Units on a scale Standard Error 0.318	-7.17 Units on a scale Standard Error 0.320

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=1053 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=1067 Participants Participants received Placebo IV 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.
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive 11 Item Subscore (ADAS-Cog11)	5.22 Units on a scale Standard Error 0.284	5.90 Units on a scale Standard Error 0.285

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=893 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=876 Participants Participants received Placebo IV 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.
Change From Baseline in Mini-Mental State Examination (MMSE)	-3.17 Units on a scale Standard Error 0.154	-3.66 Units on a scale Standard Error 0.156

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

Outcome measures

Outcome measures
Measure	Solanezumab n=908 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=897 Participants Participants received Placebo IV 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.
Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL)	-7.42 Units on a scale Standard Error 0.386	-8.77 Units on a scale Standard Error 0.387

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=907 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=892 Participants Participants received Placebo IV 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.
Change From Baseline in Functional Activities Questionnaire (FAQ)	5.17 Units on a scale Standard Error 0.212	5.57 Units on a scale Standard Error 0.213

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=903 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=895 Participants Participants received Placebo IV 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.
Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB)	1.91 Units on a scale Standard Deviation 2.442	2.23 Units on a scale Standard Deviation 2.692

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=909 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=891 Participants Participants received Placebo IV 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.
Change From Baseline in Neuropsychiatric Inventory (NPI)	2.26 Units on a scale Standard Error 3.11	0.382 Units on a scale Standard Error 0.387

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=909 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=891 Participants Participants received Placebo IV 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.
Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Basic ADL	0.34 Number of hospitalizations Standard Error 0.058	0.35 Number of hospitalizations Standard Error 0.058
Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Instrumental ADL	0.55 Number of hospitalizations Standard Error 0.099	0.50 Number of hospitalizations Standard Error 0.100
Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Sum of Basic and Instrumental ADL	0.91 Number of hospitalizations Standard Error 0.132	0.86 Number of hospitalizations Standard Error 0.134
Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Supervision	0.72 Number of hospitalizations Standard Error 0.125	0.88 Number of hospitalizations Standard Error 0.127

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=853 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=812 Participants Participants received Placebo IV 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.
Change From Baseline in Quality of Life in Alzheimer's Disease (QoL-AD)	-0.55 Units on a scale Standard Error 0.158	-0.72 Units on a scale Standard Error 0.161

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=904 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=892 Participants Participants received Placebo IV 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.
Change From Baseline in 5-Dimensional EuroQol Quality of Life Scale Proxy Version (EQ-5D Proxy)	-1.10 mm Standard Error 0.556	-2.61 mm Standard Error 0.562

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=903 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=883 Participants Participants received Placebo IV 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.
Change From Baseline in Integrated Alzheimer's Disease Rating Scale (iADRS)	-12.92 units on a scale Standard Error 0.533	-14.59 units on a scale Standard Error 0.537

SECONDARY outcome

Timeframe: Baseline through Week 80

Population: All randomized participants.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=1057 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=1072 Participants Participants received Placebo IV 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.
Percentage of Participants of Cognitive and Functional Responders Cognitive Responders: Cut-off 6	35.7 percentage of participants	35.3 percentage of participants
Percentage of Participants of Cognitive and Functional Responders Cognitive Responders: Cut-off 9	55.2 percentage of participants	52.3 percentage of participants
Percentage of Participants of Cognitive and Functional Responders Functional Responders	38.0 percentage of participants	36.8 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=1057 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=1072 Participants Participants received Placebo IV 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.
Change From Baseline in Plasma Amyloid-Beta (Aβ) Species Modified amyloid beta 1-40	172754.36 Picogram/milliliter Standard Error 1613.534	262.98 Picogram/milliliter Standard Error 1609.006
Change From Baseline in Plasma Amyloid-Beta (Aβ) Species Modified amyloid beta1-42	18485.26 Picogram/milliliter Standard Error 104.913	15.75 Picogram/milliliter Standard Error 105.237

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=1057 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=1072 Participants Participants received Placebo IV 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.
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Right hippocampal atrophy	-145.7 Cubic millimeter (mm^3) Standard Deviation 75.42	-154.1 Cubic millimeter (mm^3) Standard Deviation 81.06
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Left hippocampal atrophy	-142.3 Cubic millimeter (mm^3) Standard Deviation 74.27	-146.3 Cubic millimeter (mm^3) Standard Deviation 78.04
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Right hippocampal atrophy+Left hippocampal atrophy	-288.0 Cubic millimeter (mm^3) Standard Deviation 135.19	-300.4 Cubic millimeter (mm^3) Standard Deviation 138.52
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Right entorhinal cortex atrophy	-77.3 Cubic millimeter (mm^3) Standard Deviation 45.18	-80.8 Cubic millimeter (mm^3) Standard Deviation 45.16
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Left entorhinal cortex atrophy	-91.6 Cubic millimeter (mm^3) Standard Deviation 47.60	-95.2 Cubic millimeter (mm^3) Standard Deviation 53.46
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Right+Left entorhinal cortex atrophy	-169.0 Cubic millimeter (mm^3) Standard Deviation 79.65	-176.0 Cubic millimeter (mm^3) Standard Deviation 86.11
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Atrophy of whole brain volume	-22725.6 Cubic millimeter (mm^3) Standard Deviation 11920.78	-23500.5 Cubic millimeter (mm^3) Standard Deviation 12000.09
Change From Baseline in Volumetric Magnetic Resonance Imaging (vMRI) Enlargement of Ventricular volume	7055.4 Cubic millimeter (mm^3) Standard Deviation 4580.36	7226.6 Cubic millimeter (mm^3) Standard Deviation 4545.73

SECONDARY outcome

Timeframe: 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

Population: All randomized participants who received at least 1 dose of study medication (Solanezumab) with evaluable Solanezumab PK data.

Area Under the Concentration versus Time Curve was evaluated for Solanezumab.

Outcome measures

Outcome measures
Measure	Solanezumab n=1044 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo Participants received Placebo IV 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.
Pharmacokinetics (PK): Area Under the Concentration Time Curve (AUC) of Solanezumab (LY2062430)	43.2 milligramhour per milliliter (mgh/mL) Geometric Coefficient of Variation 24.3	—

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=915 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=924 Participants Participants received Placebo IV 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.
Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan Subject specific white matter corrected	0.02 standard uptake value ratio Standard Error 0.002	0.02 standard uptake value ratio Standard Error 0.002
Change From Baseline in Florbetapir Positron Emission Tomography (PET) Scan Mean whole cerebellum corrected	-0.01 standard uptake value ratio Standard Error 0.005	0.00 standard uptake value ratio Standard Error 0.005

SECONDARY outcome

Timeframe: Baseline, Week 80

Population: All randomized participants who received at least 1 dose of study drug and had baseline and post baseline data.

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.

Outcome measures

Outcome measures
Measure	Solanezumab n=1057 Participants Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo n=1072 Participants Participants received Placebo IV 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.
Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels Free amyloid beta 1-42, CSF	-37.33 picogram/milliliter Standard Error 7.507	-9.27 picogram/milliliter Standard Error 8.175
Change From Baseline in Cerebrospinal Fluid (CSF) Aβ Levels Modified amyloid beta 1-42, CSF	315.69 picogram/milliliter Standard Error 42.620	-107.91 picogram/milliliter Standard Error 42.907

Adverse Events

Solanezumab: Double-Blind Phase

Serious events: 175 serious events

Other events: 536 other events

Deaths: 0 deaths

Placebo: Double-Blind Phase

Serious events: 203 serious events

Other events: 530 other events

Deaths: 0 deaths

Solanezumab: Open Label

Serious events: 102 serious events

Other events: 255 other events

Deaths: 0 deaths

Placebo: Open Label

Serious events: 114 serious events

Other events: 260 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Solanezumab: Double-Blind Phase n=1054 participants at risk Participants received Solanezumab 400 mg IV every 4 weeks for 76 weeks with an additional 4 weeks of assessments. Participants who completed the full 80 weeks of treatment/assessment and decide to continue will take this regimen for up to an additional 208 weeks.	Placebo: Double-Blind Phase n=1067 participants at risk Participants received Placebo IV 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.	Solanezumab: Open Label n=879 participants at risk Participants who complete 80 weeks treatment/assessment of the double-blind period were entered into open-label period. Participants received Solanezumab 400 mg IV every 4 weeks for 180 weeks with an additional 4 weeks of assessments.	Placebo: Open Label n=856 participants at risk Participants who complete 80 weeks treatment/assessment of the double-blind period were entered into open-label period. Participants received Placebo IV every 4 weeks for 180 weeks with an additional 4 weeks of assessments.
Gastrointestinal disorders Diarrhoea	7.2% 76/1054 • Number of events 86 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	8.2% 87/1067 • Number of events 109 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.6% 23/879 • Number of events 24 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.0% 17/856 • Number of events 18 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	5.1% 54/1054 • Number of events 69 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	4.3% 46/1067 • Number of events 63 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.6% 23/879 • Number of events 32 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	1.8% 15/856 • Number of events 18 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Infections and infestations Nasopharyngitis	8.4% 89/1054 • Number of events 114 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	7.5% 80/1067 • Number of events 99 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	3.3% 29/879 • Number of events 31 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	3.7% 32/856 • Number of events 36 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Infections and infestations Upper respiratory tract infection	6.1% 64/1054 • Number of events 74 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	5.1% 54/1067 • Number of events 61 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.6% 23/879 • Number of events 25 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.5% 21/856 • Number of events 23 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	5.5% 58/1054 • Number of events 79 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	6.7% 72/1067 • Number of events 103 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	4.3% 38/879 • Number of events 47 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	4.2% 36/856 • Number of events 46 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Fall	13.9% 146/1054 • Number of events 195 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	13.5% 144/1067 • Number of events 207 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	7.6% 67/879 • Number of events 97 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	9.3% 80/856 • Number of events 109 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	4.2% 44/1054 • Number of events 51 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	5.2% 56/1067 • Number of events 62 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.4% 21/879 • Number of events 23 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.6% 22/856 • Number of events 22 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	6.0% 63/1054 • Number of events 70 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	5.6% 60/1067 • Number of events 67 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	3.0% 26/879 • Number of events 26 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.7% 23/856 • Number of events 23 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Nervous system disorders Dizziness	5.8% 61/1054 • Number of events 66 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	5.3% 57/1067 • Number of events 65 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.6% 23/879 • Number of events 24 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	3.4% 29/856 • Number of events 31 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Nervous system disorders Headache	8.2% 86/1054 • Number of events 96 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	8.1% 86/1067 • Number of events 151 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	3.2% 28/879 • Number of events 34 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	3.4% 29/856 • Number of events 42 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Psychiatric disorders Anxiety	5.1% 54/1054 • Number of events 57 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	5.4% 58/1067 • Number of events 59 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	1.7% 15/879 • Number of events 18 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.0% 17/856 • Number of events 17 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Psychiatric disorders Depression	5.7% 60/1054 • Number of events 62 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	5.3% 57/1067 • Number of events 57 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.0% 18/879 • Number of events 18 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.3% 20/856 • Number of events 20 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	4.2% 44/1054 • Number of events 53 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	5.4% 58/1067 • Number of events 69 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.8% 25/879 • Number of events 27 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.	2.1% 18/856 • Number of events 22 • Up To 80 Weeks All randomized participants who received at least 1 dose of study drug.

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
Publication restrictions are in place

Restriction type: OTHER