Trial Outcomes & Findings for A Study of CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (NCT NCT03131453)

Last Updated: 2021-08-05

Results Overview

Event was defined as the first confirmed diagnosis of MCI due to Alzheimer's disease (AD) or dementia due to AD (whichever occurred first) after adjudication by the progression adjudication committee (PAC) as triggered either by an investigator diagnosis or an increase in the Clinical Dementia Rating (CDR) global score. An event had to be confirmed by the PAC at two consecutive visits. In case no confirmed event was observed for a participant, the observation was censored, and the censoring date was defined as the last date where the diagnostic classification was assessed. The Study was terminated and only confirmed events collected up to the data cut-off point were counted. Due to the early termination of the study only a small number of events were observed and time-to-event could not be analyzed. Kaplan-Meyer (KM) estimates were provided to estimate probability that a subject would have an event prior to the specified visit.

Recruitment status

TERMINATED

Study phase

PHASE2/PHASE3

Target enrollment

1145 participants

Primary outcome timeframe

Baseline to last cognitive assessment performed (up to day 648)

Results posted on

2021-08-05

Participant Flow

8970 participants were screened

Participant milestones

Participant milestones
Measure	CNP520 50 mg 50 mg capsule taken orally once daily	CNP520 15 mg 15 mg capsule taken orally once daily	Placebo Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Study STARTED	456	233	456
Overall Study Patient Misrandomized	1	0	0
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	456	233	456

Reasons for withdrawal

Reasons for withdrawal
Measure	CNP520 50 mg 50 mg capsule taken orally once daily	CNP520 15 mg 15 mg capsule taken orally once daily	Placebo Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Study Study terminated by Sponsor	424	222	438
Overall Study Withdrawal by Subject	18	7	13
Overall Study Adverse Event	10	3	3
Overall Study Lost to Follow-up	1	0	1
Overall Study Physician Decision	1	0	1
Overall Study Non-compliance with study treatment	1	0	0
Overall Study Technical problems	1	0	0
Overall Study Protocol deviation	0	1	0

Baseline Characteristics

A Study of CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CNP520 50 mg n=455 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=233 Participants 15 mg capsule taken orally once daily	Placebo n=456 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily	Total n=1144 Participants Total of all reporting groups
Age, Customized <=64	76 participants n=5 Participants	45 participants n=7 Participants	80 participants n=5 Participants	201 participants n=4 Participants
Age, Customized 65-69	181 participants n=5 Participants	82 participants n=7 Participants	162 participants n=5 Participants	425 participants n=4 Participants
Age, Customized >70	198 participants n=5 Participants	106 participants n=7 Participants	214 participants n=5 Participants	518 participants n=4 Participants
Sex: Female, Male Female	284 Participants n=5 Participants	148 Participants n=7 Participants	288 Participants n=5 Participants	720 Participants n=4 Participants
Sex: Female, Male Male	171 Participants n=5 Participants	85 Participants n=7 Participants	168 Participants n=5 Participants	424 Participants n=4 Participants
Race/Ethnicity, Customized Caucasian	416 participants n=5 Participants	213 participants n=7 Participants	422 participants n=5 Participants	1051 participants n=4 Participants
Race/Ethnicity, Customized Black	7 participants n=5 Participants	1 participants n=7 Participants	5 participants n=5 Participants	13 participants n=4 Participants
Race/Ethnicity, Customized Asian	18 participants n=5 Participants	12 participants n=7 Participants	22 participants n=5 Participants	52 participants n=4 Participants
Race/Ethnicity, Customized Native American	3 participants n=5 Participants	2 participants n=7 Participants	1 participants n=5 Participants	6 participants n=4 Participants
Race/Ethnicity, Customized Pacific Islander	2 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	3 participants n=4 Participants
Race/Ethnicity, Customized Other	4 participants n=5 Participants	2 participants n=7 Participants	0 participants n=5 Participants	6 participants n=4 Participants
Race/Ethnicity, Customized Unknown	5 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants	13 participants n=4 Participants
Baseline cognitive scale assessment APCC score	74.6 scores on a scale STANDARD_DEVIATION 6.68 • n=5 Participants	75.8 scores on a scale STANDARD_DEVIATION 6.81 • n=7 Participants	74.9 scores on a scale STANDARD_DEVIATION 7.16 • n=5 Participants	75.0 scores on a scale STANDARD_DEVIATION 6.91 • n=4 Participants
Baseline cognitive scale assessment RBANS Total	100.5 scores on a scale STANDARD_DEVIATION 11.96 • n=5 Participants	102.0 scores on a scale STANDARD_DEVIATION 12.09 • n=7 Participants	100.7 scores on a scale STANDARD_DEVIATION 12.42 • n=5 Participants	100.9 scores on a scale STANDARD_DEVIATION 12.18 • n=4 Participants
Baseline cognitive scale assessment CDR-SOB	0.19 scores on a scale STANDARD_DEVIATION 0.389 • n=5 Participants	0.16 scores on a scale STANDARD_DEVIATION 0.358 • n=7 Participants	0.14 scores on a scale STANDARD_DEVIATION 0.358 • n=5 Participants	0.16 scores on a scale STANDARD_DEVIATION 0.371 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline to last cognitive assessment performed (up to day 648)

Population: Safety analysis set; n=number of participants at risk to experience an event at the time-point

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=455 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=233 Participants 15 mg capsule taken orally once daily	Placebo n=456 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) Week 26 n=232,123,250	0.99 probability of an event Interval 0.96 to 1.0	1.00 probability of an event Interval 1.0 to 1.0	1.00 probability of an event Interval 0.97 to 1.0
Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) Week 52 n=52,24,57	0.97 probability of an event Interval 0.94 to 0.99	0.99 probability of an event Interval 0.92 to 1.0	0.99 probability of an event Interval 0.96 to 1.0
Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) Week 78 n=6,2,2	0.97 probability of an event Interval 0.94 to 0.99	0.99 probability of an event Interval 0.92 to 1.0	0.97 probability of an event Interval 0.88 to 0.99

PRIMARY outcome

Timeframe: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Population: Safety analysis set - only participants with a value at both Baseline and that visit are included. Last on-treatment is the last assessment before or at last day on study drug + 31 days. Last off-treatment is the last assessment after last day on study drug + 31 days.

APCC is a composite score derived from the specific scores from the Repeatable Battery for the Assessment of Neurological Status (RBANS), Mini-Mental State Examination (MMSE) and the Raven's Progressive Matrices. The APCC score is a weighted score with ranges from from 0 to 100 where higher scores correspond to better cognitive performance.

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=269 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=144 Participants 15 mg capsule taken orally once daily	Placebo n=275 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score Week 26 n=160,79,162	-3.1 Total scores Standard Deviation 5.20	-2.9 Total scores Standard Deviation 5.00	-1.7 Total scores Standard Deviation 4.44
Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score Last on-treatment n=269,144,275	-2.2 Total scores Standard Deviation 4.88	-0.8 Total scores Standard Deviation 4.67	-1.3 Total scores Standard Deviation 5.21
Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score Last off-treatment n=255,124,260	-0.8 Total scores Standard Deviation 4.56	-0.8 Total scores Standard Deviation 4.38	-0.8 Total scores Standard Deviation 4.64

SECONDARY outcome

Timeframe: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

The CDR was obtained through semi-structured interviews of participants and informants, and cognitive functioning was rated on a 5-point scale of functioning in six domains: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. The CDR global score ranged from zero to three, while the CDR-SOB was the sum of the ratings from the six domains, ranging from 0 to 18 with a minimum increment of 0.5. Higher scores indicated greater disease severity

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=265 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=144 Participants 15 mg capsule taken orally once daily	Placebo n=267 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score Week 26 n=160,78,160	0.17 Scores on a scale Standard Deviation 0.606	0.20 Scores on a scale Standard Deviation 0.451	0.08 Scores on a scale Standard Deviation 0.385
Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score Last on-treatment n=265,144,267	0.15 Scores on a scale Standard Deviation 0.557	0.08 Scores on a scale Standard Deviation 0.449	0.10 Scores on a scale Standard Deviation 0.468
Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score Last off-treatment n=254,117,256	0.09 Scores on a scale Standard Deviation 0.525	0.07 Scores on a scale Standard Deviation 0.401	0.10 Scores on a scale Standard Deviation 0.565

SECONDARY outcome

Timeframe: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Repeatable Battery for the Assessment of Neurological Status (RBANS) is a clinical tool designed to detect and characterize the earliest neurocognitive changes associated with dementia. The RBANS generates age-adjusted index scores for five neurocognitive domains: Immediate Memory, Visuospatial/Constructional, Language, Attention and Delayed Memory, which are used to calculate a Total Scale Index score. Index scores and total score range from 40 to 160 and a higher score indicates better cognitive functioning.

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=356 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=183 Participants 15 mg capsule taken orally once daily	Placebo n=353 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Visuospatial Week 26 n=162,81,162	-5.6 scores Standard Deviation 15.11	-5.4 scores Standard Deviation 15.51	-2.6 scores Standard Deviation 15.26
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Language Last off-treatment n=259,125,265	-1.0 scores Standard Deviation 10.93	-2.0 scores Standard Deviation 12.68	-3.4 scores Standard Deviation 11.47
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Attention Week 26 n=162,81,162	0.1 scores Standard Deviation 11.19	-0.1 scores Standard Deviation 10.37	0.1 scores Standard Deviation 10.56
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Visuospatial Last on-treatment n=347,183,353	-3.7 scores Standard Deviation 14.90	-3.8 scores Standard Deviation 15.14	-1.2 scores Standard Deviation 13.95
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Visuospatial Last off-treatment n=259,125,266	-1.5 scores Standard Deviation 14.87	-0.7 scores Standard Deviation 14.37	-1.2 scores Standard Deviation 14.56
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Language Week 26 n=162,81,162	-0.8 scores Standard Deviation 11.48	-1.8 scores Standard Deviation 11.05	-3.1 scores Standard Deviation 11.07
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Language Last on-treatment n=347,183,353	-0.3 scores Standard Deviation 11.95	-1.7 scores Standard Deviation 11.69	-1.3 scores Standard Deviation 12.58
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Immediate memory - Last on-treatment n=347,183,353	-5.9 scores Standard Deviation 13.01	-4.0 scores Standard Deviation 13.54	-1.1 scores Standard Deviation 13.04
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Immediate memory - Last off-treatment n=259,125,266	-3.1 scores Standard Deviation 12.50	-4.8 scores Standard Deviation 13.52	-3.0 scores Standard Deviation 13.00
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed memory - Last off-treatment n=259,125,265	-1.0 scores Standard Deviation 10.91	-2.5 scores Standard Deviation 10.34	-0.5 scores Standard Deviation 10.57
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Attention Last on-treatment n=347,183,353	0.0 scores Standard Deviation 11.30	0.0 scores Standard Deviation 10.68	0.7 scores Standard Deviation 10.99
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Week 26 n=162,81,162	-5.8 scores Standard Deviation 8.54	-6.3 scores Standard Deviation 8.58	-3.4 scores Standard Deviation 8.35
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Last on-treatment n=356,183,353	-3.4 scores Standard Deviation 8.66	-3.5 scores Standard Deviation 8.87	-0.5 scores Standard Deviation 8.88
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Total Last off-treatment n=259,125,265	-1.3 scores Standard Deviation 8.12	-2.4 scores Standard Deviation 9.55	-1.9 scores Standard Deviation 8.56
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Immediate memory - Week 26 n=162,81,162	-9.8 scores Standard Deviation 11.85	-9.7 scores Standard Deviation 12.10	-5.2 scores Standard Deviation 11.26
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Attention Last off-treatment n=259,125,265	1.6 scores Standard Deviation 11.59	1.7 scores Standard Deviation 10.65	1.1 scores Standard Deviation 9.81
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed memory - Week 26 n=162,81,162	-5.5 scores Standard Deviation 11.54	-5.0 scores Standard Deviation 11.68	-2.1 scores Standard Deviation 11.69
Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Delayed memory - Last on-treatment n=346,183,353	-3.0 scores Standard Deviation 11.58	-2.8 scores Standard Deviation 10.56	0.8 scores Standard Deviation 11.43

SECONDARY outcome

Timeframe: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Everyday Cognition Scale (ECog) measures cognitively-relevant everyday abilities comprised of 39 items covering 6 cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention. The questionnaire is a self-reported measure completed by both participant and study partner (informant). The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse daily function.

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=266 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=143 Participants 15 mg capsule taken orally once daily	Placebo n=268 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in the Everyday Cognition Scale (ECog-Subject) Total Scores Week 26 n=155,78,157	0.9 Total scores Standard Deviation 7.90	0.2 Total scores Standard Deviation 5.52	0.5 Total scores Standard Deviation 6.76
Change in the Everyday Cognition Scale (ECog-Subject) Total Scores Last on-treatment n=266,143,268	1.6 Total scores Standard Deviation 8.03	0.4 Total scores Standard Deviation 5.62	0.7 Total scores Standard Deviation 8.25
Change in the Everyday Cognition Scale (ECog-Subject) Total Scores Last off-treatment n=249,122,255	-0.1 Total scores Standard Deviation 6.49	0.0 Total scores Standard Deviation 7.02	0.1 Total scores Standard Deviation 7.47

SECONDARY outcome

Timeframe: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=252 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=138 Participants 15 mg capsule taken orally once daily	Placebo n=255 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in the Everyday Cognition Scale (ECog-Informant) Total Scores Week 26 n=153,76,153	-0.3 Total scores Standard Deviation 7.55	1.7 Total scores Standard Deviation 7.77	-1.2 Total scores Standard Deviation 6.10
Change in the Everyday Cognition Scale (ECog-Informant) Total Scores Last on-treatment n=252,138,255	0.5 Total scores Standard Deviation 7.58	0.7 Total scores Standard Deviation 8.49	0.2 Total scores Standard Deviation 7.00
Change in the Everyday Cognition Scale (ECog-Informant) Total Scores Last off-treatment n=223,113,239	0.5 Total scores Standard Deviation 6.97	0.0 Total scores Standard Deviation 6.74	1.2 Total scores Standard Deviation 9.36

SECONDARY outcome

Timeframe: Baseline up to study termination approximately 617 days

Safety MRI included sequences necessary for ascertainment of possible ARIA-E (Amyloid Related Imaging Abnormality-Edema), ARIA-H (Amyloid Related Imaging Abnormality- Hemorrhage, including superficial siderosis and microhemorrhages), assessment of recent infarcts and white matter integrity examination (White matter disease worsening) and a general assessment of brain abnormalities.

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=455 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=233 Participants 15 mg capsule taken orally once daily	Placebo n=456 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) Presence of ARIA-H	0 Participants	0 Participants	0 Participants
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) Questionable presence of ARIA-E	1 Participants	0 Participants	2 Participants
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) White matter disease worsening: 1-3 increase	4 Participants	2 Participants	3 Participants
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) White matter disease worsening: 4- - >8 increase	0 Participants	0 Participants	0 Participants
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) White matter disease worsening >8	0 Participants	0 Participants	0 Participants
Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) Any other MRI abnormalities	1 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Annualized % change from baseline in volume of specific brain regions of interest (ROIs): whole brain (WB), hippocampus (Hip), and lateral ventricles (LV). Annualized percentage change was calculated as (percentage per participant / time interval (in days)) x 365.25. Time interval (in days) was derived as date of current MRI assessment on study drug - date of baseline MRI assessment + 1.

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=179 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=85 Participants 15 mg capsule taken orally once daily	Placebo n=182 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Annualized Percent Change on Volume of Brain Regions WB Week 26 n=169,83,169	-1.1016 Percentage of volume change Standard Deviation 1.03196	-0.9348 Percentage of volume change Standard Deviation 0.85477	-0.5552 Percentage of volume change Standard Deviation 1.21385
Annualized Percent Change on Volume of Brain Regions WB Last on-treatment n=179,85,182	-1.0427 Percentage of volume change Standard Deviation 0.93751	-0.9205 Percentage of volume change Standard Deviation 0.75633	-0.5378 Percentage of volume change Standard Deviation 1.09542
Annualized Percent Change on Volume of Brain Regions WB Last off-treatment n=72,44,81	-0.6984 Percentage of volume change Standard Deviation 0.73644	-0.9188 Percentage of volume change Standard Deviation 0.94516	-0.5811 Percentage of volume change Standard Deviation 0.75412
Annualized Percent Change on Volume of Brain Regions Hip Week 26 n=169,83,169	-2.0993 Percentage of volume change Standard Deviation 2.77159	-1.9100 Percentage of volume change Standard Deviation 2.31406	-1.2113 Percentage of volume change Standard Deviation 2.71764
Annualized Percent Change on Volume of Brain Regions Hip Last on-treatment n=179,85,182	-2.0052 Percentage of volume change Standard Deviation 2.65898	-1.7909 Percentage of volume change Standard Deviation 2.06883	-1.1628 Percentage of volume change Standard Deviation 2.56183
Annualized Percent Change on Volume of Brain Regions Hip Last off-treatment n=72,44,81	-1.3755 Percentage of volume change Standard Deviation 1.90613	-1.2522 Percentage of volume change Standard Deviation 2.23213	-1.1929 Percentage of volume change Standard Deviation 1.81333
Annualized Percent Change on Volume of Brain Regions LV Week 26 n=169,83,169	5.4388 Percentage of volume change Standard Deviation 5.91870	5.3457 Percentage of volume change Standard Deviation 4.67788	3.5415 Percentage of volume change Standard Deviation 4.75268
Annualized Percent Change on Volume of Brain Regions LV Last on-treatment n=179,85,182	5.0974 Percentage of volume change Standard Deviation 5.31542	5.0822 Percentage of volume change Standard Deviation 3.88165	3.4582 Percentage of volume change Standard Deviation 4.35888
Annualized Percent Change on Volume of Brain Regions LV Last off-treatment n=72,44,81	4.0014 Percentage of volume change Standard Deviation 4.29087	3.9355 Percentage of volume change Standard Deviation 5.17657	3.3851 Percentage of volume change Standard Deviation 3.38576

SECONDARY outcome

Timeframe: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40)

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=16 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=5 Participants 15 mg capsule taken orally once daily	Placebo n=14 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in CSF Levels of Amyloid Beta 40 (Aβ40) AB40 Last on-treatment n=1,0,1	-7.320 ng/mL	—	-0.760 ng/mL
Change in CSF Levels of Amyloid Beta 40 (Aβ40) AB40 Last off-treatment n=16,5,13	-1.492 ng/mL Standard Deviation 1.9263	0.804 ng/mL Standard Deviation 1.9220	-1.172 ng/mL Standard Deviation 1.7408

SECONDARY outcome

Timeframe: Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42).

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=16 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=5 Participants 15 mg capsule taken orally once daily	Placebo n=13 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in CSF Levels of Amyloid Beta 42 (Aβ42) AB42 Last on-treatment n=1,0,1	-366.200 pg/mL	—	-61.300 pg/mL
Change in CSF Levels of Amyloid Beta 42 (Aβ42) AB42 Last off-treatment n=16,5,13	20.431 pg/mL Standard Deviation 74.5595	-68.660 pg/mL Standard Deviation 62.8505	21.246 pg/mL Standard Deviation 104.3395

SECONDARY outcome

Timeframe: Baseline to Months 24 and 60

Population: No available data since no post-baseline (month 24 and 60) PET scan could be obtained due to the early termination of the trial.

To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to Months 24 and 60

Population: No available data since no post-baseline (month 24 and 60) PET scan could be obtained due to the early termination of the trial.

To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)

Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=16 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=5 Participants 15 mg capsule taken orally once daily	Placebo n=13 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in CSF Levels of Total Tau and Phosphorylated Tau Total tau - Last on-treatment n=1,0,1	40.000 pg/mL	—	-12.600 pg/mL
Change in CSF Levels of Total Tau and Phosphorylated Tau Total tau - Last off-treatment n=16,5,13	-22.119 pg/mL Standard Deviation 28.6218	-3.320 pg/mL Standard Deviation 21.1548	-3.238 pg/mL Standard Deviation 23.4442
Change in CSF Levels of Total Tau and Phosphorylated Tau Phosphorylated tau - Last on-treatment n=1,0,1	-2.360 pg/mL	—	-0.550 pg/mL
Change in CSF Levels of Total Tau and Phosphorylated Tau Phosphorylated tau - Last off-treatment n=16,5,13	-1.849 pg/mL Standard Deviation 2.3397	-0.852 pg/mL Standard Deviation 2.7005	0.065 pg/mL Standard Deviation 1.3032

SECONDARY outcome

Timeframe: Baseline to Week 26, baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)

Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=33 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=17 Participants 15 mg capsule taken orally once daily	Placebo n=40 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Change in Serum Neurofilaments Week 26 n=33,17,38	0.622 pg/mL Standard Deviation 4.5576	0.901 pg/mL Standard Deviation 4.6732	-5.731 pg/mL Standard Deviation 40.9042
Change in Serum Neurofilaments Last on-treatment n=33,15,40	0.932 pg/mL Standard Deviation 4.2494	0.041 pg/mL Standard Deviation 3.4144	-5.771 pg/mL Standard Deviation 39.8254
Change in Serum Neurofilaments Last off-treatment n=5,2,1	-2.764 pg/mL Standard Deviation 3.0981	7.350 pg/mL Standard Deviation 9.5884	3.880 pg/mL

SECONDARY outcome

Timeframe: Baseline up to study termination approximately 617 days

Population: Safety analysis set which includes only participants with events

Prospective suicidality assessment was performed with the use of Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire using a detailed branched logic algorithm evaluating participant's suicidality ideation and behavior. Answer "yes" on item 4 or 5 of the Suicidal Ideation section or "yes" on any item of the Suicidal Behavior section was considered positive.

Outcome measures

Outcome measures
Measure	CNP520 50 mg n=455 Participants 50 mg capsule taken orally once daily	CNP520 15 mg n=233 Participants 15 mg capsule taken orally once daily	Placebo n=456 Participants Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Number of Suicidal Ideation or Behavior Events Any suicidal ideation n=13,3,9	25 events	6 events	12 events
Number of Suicidal Ideation or Behavior Events Any suicidal behavior n=1,0,1	1 events	—	1 events

Adverse Events

CNP520 50 mg

Serious events: 15 serious events

Other events: 137 other events

Deaths: 0 deaths

CNP520 15 mg

Serious events: 9 serious events

Other events: 62 other events

Deaths: 0 deaths

Placebo

Serious events: 15 serious events

Other events: 89 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	CNP520 50 mg n=455 participants at risk 50 mg capsule taken orally once daily	CNP520 15 mg n=233 participants at risk 15 mg capsule taken orally once daily	Placebo n=456 participants at risk Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Infections and infestations Bronchitis	1.3% 6/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.0% 7/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	0.88% 4/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Infections and infestations Nasopharyngitis	4.8% 22/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.9% 9/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	2.4% 11/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Infections and infestations Upper respiratory tract infection	4.0% 18/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	2.1% 5/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.5% 16/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Infections and infestations Urinary tract infection	1.8% 8/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.4% 8/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	1.5% 7/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Injury, poisoning and procedural complications Fall	2.4% 11/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.0% 7/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	1.1% 5/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Investigations Weight decreased	4.2% 19/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	1.3% 3/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	1.5% 7/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Musculoskeletal and connective tissue disorders Arthralgia	2.4% 11/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	2.6% 6/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	2.4% 11/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Musculoskeletal and connective tissue disorders Back pain	3.1% 14/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	0.86% 2/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	0.88% 4/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Nervous system disorders Dizziness	3.1% 14/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.0% 7/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	1.8% 8/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Nervous system disorders Headache	2.6% 12/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.4% 8/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.3% 15/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Psychiatric disorders Abnormal dreams	4.0% 18/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.0% 7/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	0.66% 3/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Psychiatric disorders Anxiety	4.6% 21/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	1.7% 4/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	1.8% 8/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.
Skin and subcutaneous tissue disorders Pruritus	7.0% 32/455 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	5.2% 12/233 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.	3.5% 16/456 • Adverse events were reported from first dose of study treatment until end of study treatment plus 31 days of washout period for a maximum duration of 617 days.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: + 1 862 778 8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER