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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03131453
• Collaborator: Amgen (Industry), Banner Alzheimer's Institute (Other)
• Enrollment: 1,145
• Locations: 194
• Arms: 3
• Actual Duration (Months): 31.7
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effects of CNP520 on cognition, global clinical status, and underlying AD pathology, as well as the safety of CNP520, in people at risk for the onset of clinical symptoms of AD based on their age, APOE genotype and elevated amyloid.

Condition or Disease	Intervention/Treatment	Phase
Alzheimers Disease	Drug: CNP520 50mg; Drug: CNP520 15mg; Other: Matching placebo	Phase 2/Phase 3

Detailed Description

This trial was a randomized, double-blind, placebo-controlled, parallel group, adaptive design with variable treatment duration planned in cognitively unimpaired participants aged 60 to 75 years, with at least one apolipoprotein E allele (APOE4), (homozygotes (HMs) or heterozygotes (HTs)) and, if HTs, with evidence of elevated brain amyloid. The participants were randomized to either CNP520 50 mg, CNP520 15 mg or placebo a 2:1:2 ratio and was stratified based on amyloid status. The planned treatment period of 5 to 8 years was not achieved due to early study termination.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1145 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of CNP520 in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (AD).
• Actual Study Start Date: Aug 3, 2017
• Actual Primary Completion Date: Mar 26, 2020
• Actual Study Completion Date: Mar 26, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CNP520 50 mg 50 mg capsule taken orally once daily	Drug: CNP520 50mg; 50 mg capsule
Experimental: CNP520 15 mg 15 mg capsule taken orally once daily	Drug: CNP520 15mg; 15 mg capsule
Placebo Comparator: Placebo Matching placebo to 15 and 50 mg CNP520 taken orally once daily	Other: Matching placebo; Matching placebo for 15 and 50 mg capsules

Outcome Measures

Primary Outcome Measures

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

   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.

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

   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.

Secondary Outcome Measures

1. Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score [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

2. Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [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.

3. Change in the Everyday Cognition Scale (ECog-Subject) Total Scores [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.

4. Change in the Everyday Cognition Scale (ECog-Informant) Total Scores [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.

5. Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) [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.

6. Annualized Percent Change on Volume of Brain Regions [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.

7. Change in CSF Levels of Amyloid Beta 40 (Aβ40) [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)

8. Change in CSF Levels of Amyloid Beta 42 (Aβ42) [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).

9. Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available) [Baseline to Months 24 and 60]

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

10. Change in Amyloid Deposition as Measured by Standardized Uptake Ratio (SUVR) of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer [Baseline to Months 24 and 60]

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

11. Change in CSF Levels of Total Tau and Phosphorylated Tau [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

12. Change in Serum Neurofilaments [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)

13. Number of Suicidal Ideation or Behavior Events [Baseline up to study termination approximately 617 days]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• consent to receive disclosure of their risk estimates to develop clinical symptoms of AD based on their APOE genotype and, if Heterozygotes, evidence of elevated brain amyloid.

• Male or female, age 60 to 75 years inclusive. Females must be considered post-menopausal and not of child bearing potential

• Cognitively unimpaired as evaluated by memory tests performed at screening.

• Participant's willingness to have a study partner.

• Carrier of at least one APOE4 gene if Heterozygotes, elevated brain amyloid (as measured by CSF Abeta or amyloid PET imaging).

Exclusion Criteria:

• Any disability that could have prevented the participants from completing all study requirements. -

• Current medical or neurological condition that could have impacted cognition or performance on cognitive assessments.

• Advanced, severe progressive or unstable disease that could have interfered with the safety, tolerability and study assessments, or put the participant at special risk.

• History of malignancy of any organ system, treated or untreated, within the past 60 months.

• Indication for, or current treatment with ChEIs and/or another AD treatment (e.g. memantine).

• Contraindication or intolerance to MRI.

• Brain MRI results showing findings unrelated to AD that, in the opinion of the Investigator might be a leading cause to future cognitive decline, could have posed a risk to the participant, or could have prevented a satisfactory MRI assessment for safety monitoring.

• Suicidal Ideation in the past six months, or Suicidal Behavior in the past two years.

• A positive drug screen at Screening, if, in the Investigator's opinion, was is due to drug abuse.

• Significantly abnormal laboratory results at Screening, not as a result of a temporary condition.

• Current clinically significant ECG findings.

• Clinically relevant depigmenting or hypopigmenting conditions (e.g. albinism, vitiligo) or active / history of chronic urticaria in the past year.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Alzheimer's Institute, 901 East Willetta Street	Phoenix	Arizona	United States	85006
2	Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Building B	Sun City	Arizona	United States	85351
3	Novartis Investigative Site	Tucson	Arizona	United States	85724
4	ATP Clinical Research Inc, 3151 Airway Avenue T 3	Costa Mesa	California	United States	92626
5	Irvine Center for Clinical Res, 2515 McCabe Way	Irvine	California	United States	92618
6	Torrance Clinical Research Institute, 25043 Narbonne Avenue	Lomita	California	United States	90717
7	Novartis Investigative Site	Oxnard	California	United States	93030
8	Novartis Investigative Site	Palo Alto	California	United States	94304
9	Novartis Investigative Site	San Diego	California	United States	92103
10	Syrentis Clinical Research, 1401 N Tustin Ave, Suite 130	Santa Ana	California	United States	92705
11	Novartis Investigative Site	Sebastopol	California	United States	95472
12	Novartis Investigative Site	Sherman Oaks	California	United States	91403
13	Mountain Neurological Research, 350 Market Street, Suite 316	Basalt	Colorado	United States	81621
14	Colorado Springs Neurological, 2312 North Nevada Avenue, Suite 100	Colorado Springs	Colorado	United States	80907
15	Denver Neurological Clinic, 950 E Harvard Ave	Denver	Colorado	United States	80210
16	Yale University, One Church Street, Suite 600	New Haven	Connecticut	United States	06519
17	Novartis Investigative Site	Stamford	Connecticut	United States	06905
18	Novartis Investigative Site	Washington	District of Columbia	United States	20057
19	Novartis Investigative Site	Atlantis	Florida	United States	33462-6608
20	Quantum Laboratories	Deerfield Beach	Florida	United States	33064
21	Brain Matters Research, Inc., 800 NW 17th Avenue	Delray Beach	Florida	United States	33445
22	Infinity Clinical Research LLC, 4925 Sheridan Street, Suite 200	Hollywood	Florida	United States	33021
23	Alzheimer's Research and Treatment Center, 5065 State Road 7, Suite 102	Lake Worth	Florida	United States	33449
24	Meridien Research, 2300 Maitland center, Pkwy Ste 230	Maitland	Florida	United States	32751
25	Novartis Investigative Site	Melbourne	Florida	United States	32940
26	Novartis Investigative Site	Merritt Island	Florida	United States	32952
27	Novartis Investigative Site	Miami Beach	Florida	United States	33140
28	Novartis Investigative Site	Miami	Florida	United States	33032
29	Novartis Investigative Site	Miami	Florida	United States	33136
30	New Horizon Research Center, 11880 SW 40 St., Suite 405	Miami	Florida	United States	33175
31	Miami-Dade Medical Research, 8955 SW 87 CT, Suite 112	Miami	Florida	United States	33176
32	Compass Research, LLC,100 West Gore Street, Suite 202	Orlando	Florida	United States	32806
33	Novartis Investigative Site	Orlando	Florida	United States	32806
34	Novartis Investigative Site	Ormond Beach	Florida	United States	32174
35	Novartis Investigative Site	Palm Beach Gardens	Florida	United States	33410
36	Novartis Investigative Site	Port Orange	Florida	United States	32127
37	Roskamp Institute, Inc., 2040 Whitfield Avenue	Sarasota	Florida	United States	34243
38	Novartis Investigative Site	Tallahassee	Florida	United States	32308
39	Novartis Investigative Site	Tampa	Florida	United States	33613
40	Novartis Investigative Site	West Palm Beach	Florida	United States	33407
41	Novartis Investigative Site	Atlanta	Georgia	United States	30322
42	Novartis Investigative Site	Columbus	Georgia	United States	31909
43	Novartis Investigative Site	Decatur	Georgia	United States	30033
44	Hawaii Pacific Neuroscience, 2230 Liliha st 104	Honolulu	Hawaii	United States	96817
45	Advanced Clinical Research, 2950 E Magic View Dr, Suite 182	Meridian	Idaho	United States	83642
46	Novartis Investigative Site	Chicago	Illinois	United States	60612
47	Novartis Investigative Site	Chicago	Illinois	United States	60640
48	Alexian Brothers Neuroscience, 800 Biesterfield Rd, Neuroscience Institute Brock	Elk Grove Village	Illinois	United States	60007
49	Novartis Investigative Site	Indianapolis	Indiana	United States	46202
50	Novartis Investigative Site	Fairway	Kansas	United States	66205
51	Novartis Investigative Site	Wichita	Kansas	United States	67206
52	Novartis Investigative Site	Wichita	Kansas	United States	67214
53	Novartis Investigative Site	Lexington	Kentucky	United States	40536-0284
54	Novartis Investigative Site	Bangor	Maine	United States	04401
55	Novartis Investigative Site	Boston	Massachusetts	United States	02118
56	Novartis Investigative Site	Boston	Massachusetts	United States	02215
57	QUEST Research Institute, 28595 Orchard Lake Road, Suite 301	Farmington Hills	Michigan	United States	48334
58	Novartis Investigative Site	Kalamazoo	Michigan	United States	49008
59	Novartis Investigative Site	Rochester	Minnesota	United States	55905
60	Hattiesburg Clinic, 415 South 28th Avenue	Hattiesburg	Mississippi	United States	39401
61	Novartis Investigative Site	Saint Louis	Missouri	United States	63104
62	Novartis Investigative Site	Omaha	Nebraska	United States	68198 7680
63	Novartis Investigative Site	West Long Branch	New Jersey	United States	07764
64	Albuquerque Neuroscience, 101 Hospital Loop ne, 209 209	Albuquerque	New Mexico	United States	87109
65	Novartis Investigative Site	Brooklyn	New York	United States	11235
66	Novartis Investigative Site	East Syracuse	New York	United States	13057
67	Novartis Investigative Site	Latham	New York	United States	12110
68	NYU Langone Medical Center, 145 East 32nd Street, 2nd Floor, Room 226	New York	New York	United States	10016
69	Novartis Investigative Site	Orangeburg	New York	United States	10962
70	Novartis Investigative Site	Rochester	New York	United States	14642
71	ANI Neurology, PLLC dba Alzhe, 7809 Sardis Road	Charlotte	North Carolina	United States	28270
72	Novartis Investigative Site	Durham	North Carolina	United States	27710
73	Novartis Investigative Site	Greensboro	North Carolina	United States	27410
74	Novartis Investigative Site	Cincinnati	Ohio	United States	45242
75	Novartis Investigative Site	Oklahoma City	Oklahoma	United States	73112
76	Tulsa Clinical Research LLC, 1705 E 19th ST., STE 406/408	Tulsa	Oklahoma	United States	74104
77	Summit Research Network, 2701 NW Vaughn St, Suite 350	Portland	Oregon	United States	97210
78	Novartis Investigative Site	Portland	Oregon	United States	97239
79	Novartis Investigative Site	Jenkintown	Pennsylvania	United States	19046
80	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19104
81	Abington Neurological Associate Ltd., 2325 Maryland Road, Suite 100	Willow Grove	Pennsylvania	United States	19090
82	Rhode Island Hospital and Memory Research Institute, 1018 Waterman Ave	East Providence	Rhode Island	United States	02914
83	Butler Hospital, 345 Blackstone Blvd.	Providence	Rhode Island	United States	02906
84	Roper Hospital, 316 Calhoun Street 5th Floor	Charleston	South Carolina	United States	29401
85	Novartis Investigative Site	Knoxville	Tennessee	United States	37920
86	Novartis Investigative Site	Memphis	Tennessee	United States	38119
87	Novartis Investigative Site	Nashville	Tennessee	United States	37212
88	Novartis Investigative Site	Austin	Texas	United States	78757
89	Novartis Investigative Site	Dallas	Texas	United States	75231
90	Novartis Investigative Site	Houston	Texas	United States	77030
91	Novartis Investigative Site	Houston	Texas	United States	77054
92	Novartis Investigative Site	San Antonio	Texas	United States	78229
93	Novartis Investigative Site	Bennington	Vermont	United States	05201
94	Novartis Investigative Site	Tacoma	Washington	United States	98405
95	Novartis Investigative Site	Milwaukee	Wisconsin	United States	53226
96	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1428AQK
97	Novartis Investigative Site	Buenos Aires		Argentina	C1012AAR
98	Novartis Investigative Site	Darlinghurst	New South Wales	Australia	2010
99	Novartis Investigative Site	Heidelberg West	Victoria	Australia	3081
100	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
101	Novartis Investigative Site	Gent		Belgium	9000
102	Novartis Investigative Site	Leuven		Belgium	3000
103	Novartis Investigative Site	Kelowna	British Columbia	Canada	V1Y1Z9
104	Novartis Investigative Site	Kentville	Nova Scota	Canada	B4N 4K9
105	Novartis Investigative Site	Halifax	Nova Scotia	Canada	B3S 1M7
106	Novartis Investigative Site	Ottawa	Ontario	Canada	K1G 1Z3
107	Toronto Memory Program, 1 Valleybrook Drive Suite 400	Toronto	Ontario	Canada	M3B 2S7
108	Novartis Investigative Site	Toronto	Ontario	Canada	M4G 3E8
109	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
110	Novartis Investigative Site	Gatineau	Quebec	Canada	J8T 8J1
111	Novartis Investigative Site	Greenfield Park	Quebec	Canada	J4V 2J2
112	Novartis Investigative Site	Quebec		Canada	G1J 1Z4
113	Novartis Investigative Site	Santiago		Chile	7500710
114	Novartis Investigative Site	Santiago		Chile	838 0456
115	Novartis Investigative Site	Shanghai	Shanghai	China	200080
116	Novartis Investigative Site	Beijing		China	100053
117	Novartis Investigative Site	Guangdong		China	510370
118	Novartis Investigative Site	Kuopio		Finland	70210
119	Novartis Investigative Site	Turku		Finland	20520
120	Novartis Investigative Site	Strasbourg	Cedex	France	67098
121	Novartis Investigative Site	Lille Cedex		France	59037
122	Novartis Investigative Site	PARIS Cedex 13		France	75651
123	Novartis Investigative Site	Rouen		France	76031
124	Novartis Investigative Site	Toulouse Cedex 9		France	31059
125	Novartis Investigative Site	Villeurbanne		France	69100
126	Novartis Investigative Site	Bayreuth		Germany	95445
127	Novartis Investigative Site	Berlin		Germany	13353
128	Novartis Investigative Site	Koeln		Germany	50937
129	Novartis Investigative Site	Leipzig		Germany	04107
130	Novartis Investigative Site	Mannheim		Germany	68159
131	Novartis Investigative Site	Siegen		Germany	57076
132	Novartis Investigative Site	Kopavogi		Iceland	IS-201
133	Novartis Investigative Site	Ashkelon		Israel	78278
134	Novartis Investigative Site	Haifa		Israel	31096
135	Novartis Investigative Site	Petach Tikva		Israel	49100
136	Novartis Investigative Site	Ramat Gan		Israel	52621
137	Novartis Investigative Site	Tel Aviv		Israel	6423906
138	Novartis Investigative Site	Brescia	BS	Italy	25100
139	Novartis Investigative Site	Roma	Lazio	Italy	00168
140	Novartis Investigative Site	Monza	MB	Italy	20900
141	Novartis Investigative Site	Milan		Italy	20112
142	Novartis Investigative Site	Tōon	Ehime	Japan	791-0295
143	Novartis Investigative Site	Fukuoka city	Fukuoka	Japan	814 0180
144	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	236-0004
145	Novartis Investigative Site	Suita city	Osaka	Japan	565 0871
146	Novartis Investigative Site	Bunkyo ku	Tokyo	Japan	113 8655
147	Novartis Investigative Site	Bunkyo ku	Tokyo	Japan	113-8431
148	Novartis Investigative Site	Kodaira	Tokyo	Japan	187-8551
149	Novartis Investigative Site	Shinjuku-ku	Tokyo	Japan	160 8582
150	Novartis Investigative Site	Chiba		Japan	260 8677
151	Novartis Investigative Site	Osaka		Japan	545-8586
152	Novartis Investigative Site	Suwon	Gyeonggi Do	Korea, Republic of	16499
153	Novartis Investigative Site	Busan		Korea, Republic of	49201
154	Novartis Investigative Site	Incheon		Korea, Republic of	22332
155	Novartis Investigative Site	Seoul		Korea, Republic of	05505
156	Novartis Investigative Site	Seoul		Korea, Republic of	06351
157	Novartis Investigative Site	Ciudad de Mexico	Mexico CP	Mexico	14080
158	Novartis Investigative Site	Monterrey	Nuevo Leon	Mexico	64710
159	Novartis Investigative Site	Culiacan	Sinaloa	Mexico	80020
160	Novartis Investigative Site	Den Bosch	Noord Brabant	Netherlands	5223 LA
161	Novartis Investigative Site	Amsterdam		Netherlands	1081 GN
162	Novartis Investigative Site	Torres Vedras	Lisbon	Portugal	2560-280
163	Novartis Investigative Site	Coimbra		Portugal	3000 075
164	Novartis Investigative Site	Lisboa		Portugal	1998-018
165	Novartis Investigative Site	Matosinhos		Portugal	4454 513
166	Inspira Clinical Research, Ave Hostos 405	San Juan		Puerto Rico	00918
167	Novartis Investigative Site	Singapore		Singapore	308433
168	Novartis Investigative Site	Rosebank	Johannesburg	South Africa	2132
169	Novartis Investigative Site	Cape Town	Western Cape	South Africa	7530
170	Novartis Investigative Site	George	ZAF	South Africa	6529
171	Novartis Investigative Site	Terrassa	Barcelona	Spain	08221
172	Novartis Investigative Site	Pozuelo de Alarcon	Madrid	Spain	28223
173	Novartis Investigative Site	Barcelona		Spain	08005
174	Novartis Investigative Site	Barcelona		Spain	08014
175	Novartis Investigative Site	Donostia-San Sebastian		Spain	20009
176	Novartis Investigative Site	Madrid		Spain	28034
177	Novartis Investigative Site	Madrid		Spain	28041
178	Novartis Investigative Site	Basel	CH	Switzerland	4002
179	Novartis Investigative Site	Geneve		Switzerland	1227
180	Novartis Investigative Site	Lausanne		Switzerland	CH-1011
181	Novartis Investigative Site	Kaoshiung		Taiwan	83301
182	Novartis Investigative Site	New Taipei City		Taiwan	23561
183	Novartis Investigative Site	Taipei		Taiwan	11217
184	Novartis Investigative Site	Exeter	Devon	United Kingdom	EX2 5DW
185	Novartis Investigative Site	Plymouth	Devon	United Kingdom	PL6 8BT
186	Novartis Investigative Site	London	GBR	United Kingdom	W12 7RH
187	Novartis Investigative Site	Guildford	Surrey	United Kingdom	GU27YD
188	Novartis Investigative Site	Avon		United Kingdom	BA1 3NG
189	Novartis Investigative Site	Birmingham		United Kingdom	B16 8QQ
190	Novartis Investigative Site	Bristol		United Kingdom	BS10 5NB
191	Novartis Investigative Site	Dundee		United Kingdom	DD1 9SY
192	Novartis Investigative Site	Glasgow		United Kingdom
193	Novartis Investigative Site	London		United Kingdom	W12 0HS
194	Novartis Investigative Site	London		United Kingdom	W1G 9JF

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Amgen
• Banner Alzheimer's Institute

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jan 7, 2020
• Statistical Analysis Plan - Jan 11, 2021

More Information

Additional Information:

• Generation Program Website

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03131453
• Other Study ID Numbers: CCNP520A2202J; 2016-002976-28
• First Posted: Apr 27, 2017
• Last Update Posted: Aug 5, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Placebo controlled; APOE4 carriers; Homozygotes; Heterozygotes; Brain Amyloid; Aβ lowering; BACE-1 inhibitor; CNP520; elderly; preclinical Alzheimers disease; Alzheimers Disease; Prevention; Unimpaired cognition
• Additional relevant MeSH terms: Alzheimer Disease; CNP520

Study Results

Participant Flow

Pre-assignment Detail	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

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 Participants	455	233	456	1144
Age, Customized (participants) [Number]
<=64	76 16.7%	45 19.3%	80 17.5%	201 17.6%
65-69	181 39.8%	82 35.2%	162 35.5%	425 37.2%
>70	198 43.5%	106 45.5%	214 46.9%	518 45.3%
Sex: Female, Male (Count of 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 (participants) [Number]
Caucasian	416 91.4%	213 91.4%	422 92.5%	1051 91.9%
Black	7 1.5%	1 0.4%	5 1.1%	13 1.1%
Asian	18 4%	12 5.2%	22 4.8%	52 4.5%
Native American	3 0.7%	2 0.9%	1 0.2%	6 0.5%
Pacific Islander	2 0.4%	1 0.4%	0 0%	3 0.3%
Other	4 0.9%	2 0.9%	0 0%	6 0.5%
Unknown	5 1.1%	2 0.9%	6 1.3%	13 1.1%
Baseline cognitive scale assessment (scores on a scale) [Mean (Standard Deviation) ]
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)

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
Measure Participants	455	233	456
Week 26 n=232,123,250	0.99	1.00	1.00
Week 52 n=52,24,57	0.97	0.99	0.99
Week 78 n=6,2,2	0.97	0.99	0.97

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
Measure Participants	269	144	275
Week 26 n=160,79,162	-3.1 (5.20)	-2.9 (5.00)	-1.7 (4.44)
Last on-treatment n=269,144,275	-2.2 (4.88)	-0.8 (4.67)	-1.3 (5.21)
Last off-treatment n=255,124,260	-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
Measure Participants	265	144	267
Week 26 n=160,78,160	0.17 (0.606)	0.20 (0.451)	0.08 (0.385)
Last on-treatment n=265,144,267	0.15 (0.557)	0.08 (0.449)	0.10 (0.468)
Last off-treatment n=254,117,256	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
Measure Participants	356	183	353
Total Week 26 n=162,81,162	-5.8 (8.54)	-6.3 (8.58)	-3.4 (8.35)
Total Last on-treatment n=356,183,353	-3.4 (8.66)	-3.5 (8.87)	-0.5 (8.88)
Total Last off-treatment n=259,125,265	-1.3 (8.12)	-2.4 (9.55)	-1.9 (8.56)
Immediate memory - Week 26 n=162,81,162	-9.8 (11.85)	-9.7 (12.10)	-5.2 (11.26)
Immediate memory - Last on-treatment n=347,183,353	-5.9 (13.01)	-4.0 (13.54)	-1.1 (13.04)
Immediate memory - Last off-treatment n=259,125,266	-3.1 (12.50)	-4.8 (13.52)	-3.0 (13.00)
Visuospatial Week 26 n=162,81,162	-5.6 (15.11)	-5.4 (15.51)	-2.6 (15.26)
Visuospatial Last on-treatment n=347,183,353	-3.7 (14.90)	-3.8 (15.14)	-1.2 (13.95)
Visuospatial Last off-treatment n=259,125,266	-1.5 (14.87)	-0.7 (14.37)	-1.2 (14.56)
Language Week 26 n=162,81,162	-0.8 (11.48)	-1.8 (11.05)	-3.1 (11.07)
Language Last on-treatment n=347,183,353	-0.3 (11.95)	-1.7 (11.69)	-1.3 (12.58)
Language Last off-treatment n=259,125,265	-1.0 (10.93)	-2.0 (12.68)	-3.4 (11.47)
Attention Week 26 n=162,81,162	0.1 (11.19)	-0.1 (10.37)	0.1 (10.56)
Attention Last on-treatment n=347,183,353	0.0 (11.30)	0.0 (10.68)	0.7 (10.99)
Attention Last off-treatment n=259,125,265	1.6 (11.59)	1.7 (10.65)	1.1 (9.81)
Delayed memory - Week 26 n=162,81,162	-5.5 (11.54)	-5.0 (11.68)	-2.1 (11.69)
Delayed memory - Last on-treatment n=346,183,353	-3.0 (11.58)	-2.8 (10.56)	0.8 (11.43)
Delayed memory - Last off-treatment n=259,125,265	-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
Measure Participants	266	143	268
Week 26 n=155,78,157	0.9 (7.90)	0.2 (5.52)	0.5 (6.76)
Last on-treatment n=266,143,268	1.6 (8.03)	0.4 (5.62)	0.7 (8.25)
Last off-treatment n=249,122,255	-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
Measure Participants	252	138	255
Week 26 n=153,76,153	-0.3 (7.55)	1.7 (7.77)	-1.2 (6.10)
Last on-treatment n=252,138,255	0.5 (7.58)	0.7 (8.49)	0.2 (7.00)
Last off-treatment n=223,113,239	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
Measure Participants	455	233	456
Presence of ARIA-H	0 0%	0 0%	0 0%
Questionable presence of ARIA-E	1 0.2%	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%
White matter disease worsening >8	0 0%	0 0%	0 0%
Any other MRI abnormalities	1 0.2%	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
Measure Participants	179	85	182
WB Week 26 n=169,83,169	-1.1016 (1.03196)	-0.9348 (0.85477)	-0.5552 (1.21385)
WB Last on-treatment n=179,85,182	-1.0427 (0.93751)	-0.9205 (0.75633)	-0.5378 (1.09542)
WB Last off-treatment n=72,44,81	-0.6984 (0.73644)	-0.9188 (0.94516)	-0.5811 (0.75412)
Hip Week 26 n=169,83,169	-2.0993 (2.77159)	-1.9100 (2.31406)	-1.2113 (2.71764)
Hip Last on-treatment n=179,85,182	-2.0052 (2.65898)	-1.7909 (2.06883)	-1.1628 (2.56183)
Hip Last off-treatment n=72,44,81	-1.3755 (1.90613)	-1.2522 (2.23213)	-1.1929 (1.81333)
LV Week 26 n=169,83,169	5.4388 (5.91870)	5.3457 (4.67788)	3.5415 (4.75268)
LV Last on-treatment n=179,85,182	5.0974 (5.31542)	5.0822 (3.88165)	3.4582 (4.35888)
LV Last off-treatment n=72,44,81	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
Measure Participants	16	5	14
AB40 Last on-treatment n=1,0,1	-7.320	-0.760
AB40 Last off-treatment n=16,5,13	-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
Measure Participants	16	5	13
AB42 Last on-treatment n=1,0,1	-366.200	-61.300
AB42 Last off-treatment n=16,5,13	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
Measure Participants	0	0	0

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
Measure Participants	0	0	0

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
Measure Participants	16	5	13
Total tau - Last on-treatment n=1,0,1	40.000	-12.600
Total tau - Last off-treatment n=16,5,13	-22.119 (28.6218)	-3.320 (21.1548)	-3.238 (23.4442)
Phosphorylated tau - Last on-treatment n=1,0,1	-2.360	-0.550
Phosphorylated tau - Last off-treatment n=16,5,13	-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
Measure Participants	33	17	40
Week 26 n=33,17,38	0.622 (4.5576)	0.901 (4.6732)	-5.731 (40.9042)
Last on-treatment n=33,15,40	0.932 (4.2494)	0.041 (3.4144)	-5.771 (39.8254)
Last off-treatment n=5,2,1	-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
Measure Participants	455	233	456
Any suicidal ideation n=13,3,9	25	6	12
Any suicidal behavior n=1,0,1	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.
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/455 (0%)		0/233 (0%)		0/456 (0%)
Serious Adverse Events
	CNP520 50 mg		CNP520 15 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/455 (3.3%)		9/233 (3.9%)		15/456 (3.3%)
Cardiac disorders
Aortic valve incompetence	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Coronary artery disease	2/455 (0.4%)		1/233 (0.4%)		0/456 (0%)
Mitral valve incompetence	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Supraventricular tachycardia	0/455 (0%)		1/233 (0.4%)		1/456 (0.2%)
Gastrointestinal disorders
Colitis ulcerative	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Nausea	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Pancreatitis	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
General disorders
Non-cardiac chest pain	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Hepatobiliary disorders
Drug-induced liver injury	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Hepatic cirrhosis	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Infections and infestations
Pneumonia	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Pneumonia influenzal	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Injury, poisoning and procedural complications
Femur fracture	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Fibula fracture	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Radius fracture	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Subdural haematoma	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Traumatic lung injury	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Investigations
Haemoglobin decreased	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Hepatic enzyme increased	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Serum ferritin decreased	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Osteoarthritis	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Bladder transitional cell carcinoma	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Breast cancer	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Chordoma	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Endometrial cancer	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Intraductal proliferative breast lesion	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Malignant melanoma	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Squamous cell carcinoma	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Squamous cell carcinoma of skin	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Nervous system disorders
Cerebellar infarction	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Cerebrovascular accident	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Dizziness	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Generalised tonic-clonic seizure	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Headache	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Ischaemic stroke	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Parkinson's disease	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Seizure	1/455 (0.2%)		1/233 (0.4%)		0/456 (0%)
Transient ischaemic attack	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Psychiatric disorders
Major depression	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Mania	1/455 (0.2%)		0/233 (0%)		0/456 (0%)
Suicidal ideation	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Renal and urinary disorders
Acute kidney injury	0/455 (0%)		0/233 (0%)		1/456 (0.2%)
Vascular disorders
Aortic aneurysm	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Hypertension	0/455 (0%)		1/233 (0.4%)		0/456 (0%)
Other (Not Including Serious) Adverse Events
	CNP520 50 mg		CNP520 15 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	137/455 (30.1%)		62/233 (26.6%)		89/456 (19.5%)
Infections and infestations
Bronchitis	6/455 (1.3%)		7/233 (3%)		4/456 (0.9%)
Nasopharyngitis	22/455 (4.8%)		9/233 (3.9%)		11/456 (2.4%)
Upper respiratory tract infection	18/455 (4%)		5/233 (2.1%)		16/456 (3.5%)
Urinary tract infection	8/455 (1.8%)		8/233 (3.4%)		7/456 (1.5%)
Injury, poisoning and procedural complications
Fall	11/455 (2.4%)		7/233 (3%)		5/456 (1.1%)
Investigations
Weight decreased	19/455 (4.2%)		3/233 (1.3%)		7/456 (1.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	11/455 (2.4%)		6/233 (2.6%)		11/456 (2.4%)
Back pain	14/455 (3.1%)		2/233 (0.9%)		4/456 (0.9%)
Nervous system disorders
Dizziness	14/455 (3.1%)		7/233 (3%)		8/456 (1.8%)
Headache	12/455 (2.6%)		8/233 (3.4%)		15/456 (3.3%)
Psychiatric disorders
Abnormal dreams	18/455 (4%)		7/233 (3%)		3/456 (0.7%)
Anxiety	21/455 (4.6%)		4/233 (1.7%)		8/456 (1.8%)
Skin and subcutaneous tissue disorders
Pruritus	32/455 (7%)		12/233 (5.2%)		16/456 (3.5%)

Limitations/Caveats

The study was terminated due to safety issues.

More Information

Certain Agreements

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

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.