A Study of CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (GS2)

• ClinicalTrials.gov Identifier: NCT03131453
• Recruitment Status: Terminated
• First Posted: April 27, 2017
• Results First Posted: August 5, 2021
• Last Update Posted: August 5, 2021
• Sponsor: Novartis Pharmaceuticals
• Collaborators: Amgen; Banner Alzheimer's Institute
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimers Disease
• Interventions: Drug: CNP520 50mg; Drug: CNP520 15mg; Other: Matching placebo
• Enrollment: 1145

Participant Flow

Recruitment Details
Pre-assignment Details	8970 participants were screened

Arm/Group Title	CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description	50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Period Title: Overall Study
Started	456	233	456
Patient Misrandomized	1	0	0
Completed	0	0	0
Not Completed	456	233	456
Reason Not Completed
Study terminated by Sponsor	424	222	438
Withdrawal by Subject	18	7	13
Adverse Event	10	3	3
Lost to Follow-up	1	0	1
Physician Decision	1	0	1
Non-compliance with study treatment	1	0	0
Technical problems	1	0	0
Protocol deviation	0	1	0

Baseline Characteristics

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo	Total
Arm/Group Description		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily	Total of all reporting groups
Overall Number of Baseline Participants		455	233	456	1144
Baseline Analysis Population Description		One patient was misrandomized and not included in the CNP520 50mg arm
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	455 participants	233 participants	456 participants	1144 participants
<=64		76	45	80	201
65-69		181	82	162	425
>70		198	106	214	518
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	455 participants	233 participants	456 participants	1144 participants
	Female	284 62.4%	148 63.5%	288 63.2%	720 62.9%
	Male	171 37.6%	85 36.5%	168 36.8%	424 37.1%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	455 participants	233 participants	456 participants	1144 participants
Caucasian		416	213	422	1051
Black		7	1	5	13
Asian		18	12	22	52
Native American		3	2	1	6
Pacific Islander		2	1	0	3
Other		4	2	0	6
Unknown		5	2	6	13
Baseline cognitive scale assessment [1]; Mean (Standard Deviation); Unit of measure: Scores on a scale	Number Analyzed	455 participants	233 participants	456 participants	1144 participants
APCC score		74.6 (6.68)	75.8 (6.81)	74.9 (7.16)	75.0 (6.91)
RBANS Total		100.5 (11.96)	102.0 (12.09)	100.7 (12.42)	100.9 (12.18)
CDR-SOB		0.19 (0.389)	0.16 (0.358)	0.14 (0.358)	0.16 (0.371)
		[1] Measure Description: APCC(API Preclinical Composite Cognitive Battery) is a composite score derived from RBANS(Repeatable Battery for Assessment of Neurological Status), MMSE(Mini-Mental State Examination) and the Raven's Progressive Matrices; scores: 0-100/higher scores=better cognitive performance. RBANS is a tool to detect/characterize neurocognitive dementia changes in 5 neurocognitive domains; scores: 40-160/higher scores=better cognitive functioning. Clinical Dementia Rating Sum of Boxes(CDR-SOB) measures cognition+functioning in 6 domains; scores: 0-18/higher scores indicate greater disease severity

Outcome Measures

1. Primary Outcome

Title	Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD))
Description	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.
Time Frame	Baseline to last cognitive assessment performed (up to day 648)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		455	233	456
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: probability of an event
Week 26 n=232,123,250	Number Analyzed	232 participants	123 participants	250 participants
		0.99; (0.96 to 1.00)	1.00; (1.00 to 1.00)	1.00; (0.97 to 1.00)
Week 52 n=52,24,57	Number Analyzed	52 participants	24 participants	57 participants
		0.97; (0.94 to 0.99)	0.99; (0.92 to 1.00)	0.99; (0.96 to 1.00)
Week 78 n=6,2,2	Number Analyzed	6 participants	2 participants	2 participants
		0.97; (0.94 to 0.99)	0.99; (0.92 to 1.00)	0.97; (0.88 to 0.99)

2. Primary Outcome

Title	Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score
Description	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.
Time Frame	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		269	144	275
Mean (Standard Deviation); Unit of Measure: Total scores
Week 26 n=160,79,162	Number Analyzed	160 participants	79 participants	162 participants
		-3.1 (5.20)	-2.9 (5.00)	-1.7 (4.44)
Last on-treatment n=269,144,275	Number Analyzed	269 participants	144 participants	275 participants
		-2.2 (4.88)	-0.8 (4.67)	-1.3 (5.21)
Last off-treatment n=255,124,260	Number Analyzed	255 participants	124 participants	260 participants
		-0.8 (4.56)	-0.8 (4.38)	-0.8 (4.64)

3. Secondary Outcome

Title	Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score
Description	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
Time Frame	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		265	144	267
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Week 26 n=160,78,160	Number Analyzed	160 participants	78 participants	160 participants
		0.17 (0.606)	0.20 (0.451)	0.08 (0.385)
Last on-treatment n=265,144,267	Number Analyzed	265 participants	144 participants	267 participants
		0.15 (0.557)	0.08 (0.449)	0.10 (0.468)
Last off-treatment n=254,117,256	Number Analyzed	254 participants	117 participants	256 participants
		0.09 (0.525)	0.07 (0.401)	0.10 (0.565)

4. Secondary Outcome

Title	Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Description	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.
Time Frame	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

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

5. Secondary Outcome

Title	Change in the Everyday Cognition Scale (ECog-Subject) Total Scores
Description	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.
Time Frame	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		266	143	268
Mean (Standard Deviation); Unit of Measure: Total scores
Week 26 n=155,78,157	Number Analyzed	155 participants	78 participants	157 participants
		0.9 (7.90)	0.2 (5.52)	0.5 (6.76)
Last on-treatment n=266,143,268	Number Analyzed	266 participants	143 participants	268 participants
		1.6 (8.03)	0.4 (5.62)	0.7 (8.25)
Last off-treatment n=249,122,255	Number Analyzed	249 participants	122 participants	255 participants
		-0.1 (6.49)	0.0 (7.02)	0.1 (7.47)

6. Secondary Outcome

Title	Change in the Everyday Cognition Scale (ECog-Informant) Total Scores
Description	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.
Time Frame	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		252	138	255
Mean (Standard Deviation); Unit of Measure: Total scores
Week 26 n=153,76,153	Number Analyzed	153 participants	76 participants	153 participants
		-0.3 (7.55)	1.7 (7.77)	-1.2 (6.10)
Last on-treatment n=252,138,255	Number Analyzed	252 participants	138 participants	255 participants
		0.5 (7.58)	0.7 (8.49)	0.2 (7.00)
Last off-treatment n=223,113,239	Number Analyzed	223 participants	113 participants	239 participants
		0.5 (6.97)	0.0 (6.74)	1.2 (9.36)

7. Secondary Outcome

Title	Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities)
Description	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.
Time Frame	Baseline up to study termination approximately 617 days

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:	50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed	455	233	456
Measure Type: Count of Participants; Unit of Measure: Participants
Presence of ARIA-H	0 0.0%	0 0.0%	0 0.0%
Questionable presence of ARIA-E	1 0.2%	0 0.0%	2 0.4%
White matter disease worsening: 1-3 increase	4 0.9%	2 0.9%	3 0.7%
White matter disease worsening: 4- - >8 increase	0 0.0%	0 0.0%	0 0.0%
White matter disease worsening >8	0 0.0%	0 0.0%	0 0.0%
Any other MRI abnormalities	1 0.2%	0 0.0%	1 0.2%

8. Secondary Outcome

Title	Annualized Percent Change on Volume of Brain Regions
Description	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.
Time Frame	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

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

9. Secondary Outcome

Title	Change in CSF Levels of Amyloid Beta 40 (Aβ40)
Description	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aβ40)
Time Frame	Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		16	5	14
Mean (Standard Deviation); Unit of Measure: ng/mL
AB40 Last on-treatment n=1,0,1	Number Analyzed	1 participants	0 participants	1 participants
		-7.320		-0.760
AB40 Last off-treatment n=16,5,13	Number Analyzed	16 participants	5 participants	13 participants
		-1.492 (1.9263)	0.804 (1.9220)	-1.172 (1.7408)

10. Secondary Outcome

Title	Change in CSF Levels of Amyloid Beta 42 (Aβ42)
Description	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aβ42).
Time Frame	Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		16	5	13
Mean (Standard Deviation); Unit of Measure: pg/mL
AB42 Last on-treatment n=1,0,1	Number Analyzed	1 participants	0 participants	1 participants
		-366.200		-61.300
AB42 Last off-treatment n=16,5,13	Number Analyzed	16 participants	5 participants	13 participants
		20.431 (74.5595)	-68.660 (62.8505)	21.246 (104.3395)

11. Secondary Outcome

Title	Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available)
Description	To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
Time Frame	Baseline to Months 24 and 60

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:	50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

12. Secondary Outcome

Title	Change in Amyloid Deposition as Measured by Standardized Uptake Ratio (SUVR) of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer
Description	To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
Time Frame	Baseline to Months 24 and 60

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:	50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

13. Secondary Outcome

Title	Change in CSF Levels of Total Tau and Phosphorylated Tau
Description	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels
Time Frame	Baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		16	5	13
Mean (Standard Deviation); Unit of Measure: pg/mL
Total tau - Last on-treatment n=1,0,1	Number Analyzed	1 participants	0 participants	1 participants
		40.000		-12.600
Total tau - Last off-treatment n=16,5,13	Number Analyzed	16 participants	5 participants	13 participants
		-22.119 (28.6218)	-3.320 (21.1548)	-3.238 (23.4442)
Phosphorylated tau - Last on-treatment n=1,0,1	Number Analyzed	1 participants	0 participants	1 participants
		-2.360		-0.550
Phosphorylated tau - Last off-treatment n=16,5,13	Number Analyzed	16 participants	5 participants	13 participants
		-1.849 (2.3397)	-0.852 (2.7005)	0.065 (1.3032)

14. Secondary Outcome

Title	Change in Serum Neurofilaments
Description	Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)
Time Frame	Baseline to Week 26, baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		33	17	40
Mean (Standard Deviation); Unit of Measure: pg/mL
Week 26 n=33,17,38	Number Analyzed	33 participants	17 participants	38 participants
		0.622 (4.5576)	0.901 (4.6732)	-5.731 (40.9042)
Last on-treatment n=33,15,40	Number Analyzed	33 participants	15 participants	40 participants
		0.932 (4.2494)	0.041 (3.4144)	-5.771 (39.8254)
Last off-treatment n=5,2,1	Number Analyzed	5 participants	2 participants	1 participants
		-2.764 (3.0981)	7.350 (9.5884)	3.880

15. Secondary Outcome

Title	Number of Suicidal Ideation or Behavior Events
Description	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.
Time Frame	Baseline up to study termination approximately 617 days

Outcome Measure Data

Analysis Population Description

Safety analysis set which includes only participants with events

Arm/Group Title		CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description:		50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
Overall Number of Participants Analyzed		455	233	456
Measure Type: Number; Unit of Measure: events
Any suicidal ideation n=13,3,9	Number Analyzed	13 participants	3 participants	9 participants
		25	6	12
Any suicidal behavior n=1,0,1	Number Analyzed	1 participants	0 participants	1 participants
		1		1

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	CNP520 50 mg	CNP520 15 mg	Placebo
Arm/Group Description	50 mg capsule taken orally once daily	15 mg capsule taken orally once daily	Matching placebo to 15 and 50 mg CNP520 taken orally once daily
All-Cause Mortality
	CNP520 50 mg	CNP520 15 mg	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/455 (0.00%)	0/233 (0.00%)	0/456 (0.00%)
Serious Adverse Events
	CNP520 50 mg	CNP520 15 mg	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	15/455 (3.30%)	9/233 (3.86%)	15/456 (3.29%)
Cardiac disorders
Aortic valve incompetence † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Coronary artery disease † 1	2/455 (0.44%)	1/233 (0.43%)	0/456 (0.00%)
Mitral valve incompetence † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Supraventricular tachycardia † 1	0/455 (0.00%)	1/233 (0.43%)	1/456 (0.22%)
Gastrointestinal disorders
Colitis ulcerative † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Nausea † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Pancreatitis † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
General disorders
Non-cardiac chest pain † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Hepatobiliary disorders
Drug-induced liver injury † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Hepatic cirrhosis † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Infections and infestations
Pneumonia † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Pneumonia influenzal † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Injury, poisoning and procedural complications
Femur fracture † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Fibula fracture † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Radius fracture † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Subdural haematoma † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Traumatic lung injury † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Investigations
Haemoglobin decreased † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Hepatic enzyme increased † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Serum ferritin decreased † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Osteoarthritis † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Bladder transitional cell carcinoma † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Breast cancer † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Chordoma † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Endometrial cancer † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Intraductal proliferative breast lesion † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Malignant melanoma † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Squamous cell carcinoma † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Squamous cell carcinoma of skin † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Nervous system disorders
Cerebellar infarction † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Cerebrovascular accident † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Dizziness † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Generalised tonic-clonic seizure † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Headache † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Ischaemic stroke † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Parkinson's disease † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Seizure † 1	1/455 (0.22%)	1/233 (0.43%)	0/456 (0.00%)
Transient ischaemic attack † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Psychiatric disorders
Major depression † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Mania † 1	1/455 (0.22%)	0/233 (0.00%)	0/456 (0.00%)
Suicidal ideation † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Renal and urinary disorders
Acute kidney injury † 1	0/455 (0.00%)	0/233 (0.00%)	1/456 (0.22%)
Vascular disorders
Aortic aneurysm † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
Hypertension † 1	0/455 (0.00%)	1/233 (0.43%)	0/456 (0.00%)
1 Term from vocabulary, MedDRA (23.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2.5%
	CNP520 50 mg	CNP520 15 mg	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	137/455 (30.11%)	62/233 (26.61%)	89/456 (19.52%)
Infections and infestations
Bronchitis † 1	6/455 (1.32%)	7/233 (3.00%)	4/456 (0.88%)
Nasopharyngitis † 1	22/455 (4.84%)	9/233 (3.86%)	11/456 (2.41%)
Upper respiratory tract infection † 1	18/455 (3.96%)	5/233 (2.15%)	16/456 (3.51%)
Urinary tract infection † 1	8/455 (1.76%)	8/233 (3.43%)	7/456 (1.54%)
Injury, poisoning and procedural complications
Fall † 1	11/455 (2.42%)	7/233 (3.00%)	5/456 (1.10%)
Investigations
Weight decreased † 1	19/455 (4.18%)	3/233 (1.29%)	7/456 (1.54%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	11/455 (2.42%)	6/233 (2.58%)	11/456 (2.41%)
Back pain † 1	14/455 (3.08%)	2/233 (0.86%)	4/456 (0.88%)
Nervous system disorders
Dizziness † 1	14/455 (3.08%)	7/233 (3.00%)	8/456 (1.75%)
Headache † 1	12/455 (2.64%)	8/233 (3.43%)	15/456 (3.29%)
Psychiatric disorders
Abnormal dreams † 1	18/455 (3.96%)	7/233 (3.00%)	3/456 (0.66%)
Anxiety † 1	21/455 (4.62%)	4/233 (1.72%)	8/456 (1.75%)
Skin and subcutaneous tissue disorders
Pruritus † 1	32/455 (7.03%)	12/233 (5.15%)	16/456 (3.51%)
1 Term from vocabulary, MedDRA (23.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

The study was terminated due to safety issues.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: + 1 862 778 8300
• EMail: Novartis.email@Novartis.com

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT03131453
• Other Study ID Numbers: CCNP520A2202J; 2016-002976-28 ( EudraCT Number )
• First Submitted: April 5, 2017
• First Posted: April 27, 2017
• Results First Submitted: March 25, 2021
• Results First Posted: August 5, 2021
• Last Update Posted: August 5, 2021