GS1: A Study of CAD106 and 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: NCT02565511
• Collaborator: Banner Alzheimer's Institute (Other), National Institute on Aging (NIA) (NIH), Amgen (Industry)
• Enrollment: 480
• Locations: 129
• Arms: 4
• Actual Duration (Months): 53
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to test whether two investigational drugs called CAD106 and CNP520, administered separately, could slow down the onset and progression of clinical symptoms associated with Alzheimer's disease (AD) in participants at the risk to develop clinical symptoms based on their age and genotype.

Condition or Disease	Intervention/Treatment	Phase
Alzheimers Disease	Biological: CAD106 Immunotherapy; Other: Placebo to CAD106; Drug: CNP520; Other: Placebo to CNP520; Other: Alum	Phase 2/Phase 3

Detailed Description

The study (also known as the Generation Study 1, GS1) was conducted as part of the Alzheimer's Prevention Initiative (API) program.

This trial was a randomized, double-blind, placebo-controlled, parallel group, adaptive design with variable treatment duration planned in cognitively unimpaired APOE4 homozygotes (HMs) aged 60 to 75 years. Participants were enrolled into Cohort I (CAD106) or Cohort II (CNP520).

The planned treatment period of 5 to 8 years was not achieved due to early study termination.

The study was terminated due to unexpected changes in cognitive function, brain volume loss, and body weight loss. Cohort II (CNP520) treatment was stopped and evaluated through an off-treatment follow-up period. After the decision to terminate Cohort II of the study (CNP520), treatment with CAD106 (Cohort I) was also terminated.

Study Design

• Study Type: Interventional
• Actual Enrollment: 480 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, Two-cohort, Parallel Group Study to Evaluate the Efficacy of CAD106 and CNP520 in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease.
• Actual Study Start Date: Nov 30, 2015
• Actual Primary Completion Date: Apr 30, 2020
• Actual Study Completion Date: Apr 30, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort I (CAD106) CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Biological: CAD106 Immunotherapy; Participants will be given i.m. injections at Weeks 1, 7, 13 and quarterly i.m. injections (every 13 weeks) thereafter, until the last injection 3 month prior to completion of the Treatment Epoch.; Other: Alum; Alum was mixed with reconstituted CAD106 as adjuvant therapy to maximize the effectiveness of CAD106
Placebo Comparator: Cohort I (CAD106 Placebo) Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Other: Placebo to CAD106; Participants will be given i.m. injections at Weeks 1, 7, 13 and quarterly i.m. injections (every 13 weeks) thereafter, until the last injection 3 month prior to completion of the Treatment Epoch.; Other: Alum; Alum was mixed with reconstituted CAD106 as adjuvant therapy to maximize the effectiveness of CAD106
Experimental: Cohort II (CNP520) CNP520 (50 mg) capsules taken orally once daily	Drug: CNP520; CNP520 50 mg capsule p.o. for the duration of the Treatment Epoch.
Placebo Comparator: Cohort II (CNP520 Placebo) Matching Placebo to CNP520 capsules taken orally once daily	Other: Placebo to CNP520; Placebo to CNP520 p.o. for the duration of the Treatment Epoch

Outcome Measures

Primary Outcome Measures

1. Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD)) [Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII]

   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 [CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment]

   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 [CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment]

   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 Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). [CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment]

   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 Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). [CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment]

   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.

4. Change in the Everyday Cognition Scale (ECog-Subject) Total Scores [CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment]

   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. Change in the Everyday Cognition Scale (ECog-Informant) Total Scores [CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment]

   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. Cohort I=C I and Cohort II=C II.

6. Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities) [Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII]

   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 since baseline) and a general assessment of brain abnormalities. Assessment of cerebral amyloid angiopathy (CAA) is included in the overall safety MRI findings results.

7. Annualized Percent Change on Volume of Brain Regions [CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment]

   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.

8. Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 40 (Aβ40) [Baseline to last assessment]

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

9. Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 42 (Aβ42) [Baseline to last assessment]

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

10. Change in Cerebrospinal Fluid (CSF) Levels of Total Tau and Phosphorylated Tau [Baseline to last assessment]

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

11. Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available) [Baseline to last assessment]

    To demonstrate the effects of CNP520 vs placebo on tau pathology in the brain

12. Cohort I : Annualized Change in Amyloid Deposition as Measured by Centiloids of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer [Baseline up to approximately Week 104]

    To demonstrate the effects of CAD106 vs placebo on Alzheimer's Disease-related biomarkers

13. Change in Serum Neurofilaments [Baseline to Week 26 and week 52, CI baseline to last assessment. CII baseline to last on-treatment and to last off-treatment]

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

14. Number of Suicidal Ideation or Behavior Events [Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII]

    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.

15. Cohort I : Change in Cognition as Measured by APCC and CDR-SOB Scores and Antibody Response [Month 6 to Month 60]

16. Cohort I: Peak Concentration (Cmax) of CAD106 Induced Abeta-specific Antibody Titers [Week 9, 13, 15, 26 and quarterly thereafter (trough values)]

    Cmax is the maximum Titer Concentration of any post-baseline 'on treatment' visit. A visit is considered as 'on treatment' if visit date is within {last injection + 180 days}. - Geometric mean and CI's are back-transformed from the estimates for Log mean and CI's.

17. Cohort I: Area Under the Concentration Curve (AUC) of CAD106 Induced Abeta-specific Antibody Titers [Week 9, 13, 15, 26 and quarterly thereafter (trough values)]

    AUC is calculated based on 'on treatment' visit only.(missing values for peak visits were linearly interpolated for calculation; missing values for trough visits were imputed by average of non-missing trough values.).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Consented to receive disclosure of their risk estimates to develop clinical symptoms of AD based on their APOE genotype.

• Male or female, age 60 to 75 years inclusive. Females were to be post-menopausal.

• Mini-Mental State Examination (MMSE) total score ≥ 24 and cognitively unimpaired as evaluated by memory tests

• Homozygous APOE4 genotype.

• Participant willing to have a study partner.

Key Exclusion Criteria:

• Any disability that prevented the participant 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 may 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 60 months prior to screening.

• History of hypersensitivity to any of the investigational drugs or their excipients / adjuvant or to drugs of similar chemical classes.

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

• Contraindication or intolerance to MRI or PET investigations (with fluorinated radio ligands).

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

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

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

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

• Current clinically significant ECG findings. For Cohort - I only: Participants with previous organ transplantation or stem cell transplantation, or indication for treatment with anti-coagulants.

For Cohort - II only: Participants with depigmenting or hypopigmenting conditions (e.g. albinism vitiligo) or active / history of chronic urticarial in the past year.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Alzheimer's Institute	Phoenix	Arizona	United States	85006
2	Novartis Investigative Site	Phoenix	Arizona	United States	85006
3	Novartis Investigative Site	Scottsdale	Arizona	United States	85259
4	Banner Sun City Research Institute	Sun City	Arizona	United States	85351
5	ATP Clinical Research, Inc.	Costa Mesa	California	United States	92626
6	Irvine Center for Clinical Research	Irvine	California	United States	92614
7	University of Southern California Keck School of Medicine Alzheimer Disease Research Center	Los Angeles	California	United States	90033
8	Novartis Investigative Site	Palo Alto	California	United States	94304
9	Novartis Investigative Site	San Diego	California	United States	92103
10	Syrentis Clinical Research	Santa Ana	California	United States	92705
11	Novartis Investigative Site	Sebastopol	California	United States	95472
12	California Neuroscience Research Medical Group, Inc.	Sherman Oaks	California	United States	91316
13	Novartis Investigative Site	Temecula	California	United States	92591
14	Novartis Investigative Site	Basalt	Colorado	United States	81621
15	Yale University Alzheimer's Disease Research Unit	New Haven	Connecticut	United States	06510
16	New England Institute for Clinical Research	Stamford	Connecticut	United States	06905
17	Georgetown University	Washington	District of Columbia	United States	20057
18	Novartis Investigative Site	Washington	District of Columbia	United States	20059
19	JEM Research Institute	Atlantis	Florida	United States	33462-6608
20	Florida Atlantic University, Clinical Translational Research Unit	Boca Raton	Florida	United States	33431
21	Brain Matters Research	Delray Beach	Florida	United States	33445
22	Novartis Investigative Site	Jacksonville	Florida	United States	32224
23	Meridien Research	Maitland	Florida	United States	32751
24	Merritt Island Medical Research	Merritt Island	Florida	United States	32952
25	Mount Sinai Medical Center - The Wien Center	Miami Beach	Florida	United States	33140
26	University of Miami	Miami	Florida	United States	33136
27	Novartis Investigative Site	Orlando	Florida	United States	32806
28	Compass Research	Orlando	Florida	United States	32812
29	Progressive Medical Research	Port Orange	Florida	United States	32127
30	USF Health Byrd Alzheimer's Institute	Tampa	Florida	United States	33613
31	Novartis Investigative Site	Atlanta	Georgia	United States	30322
32	Medical Research & Health Education Foundation, Inc.	Columbus	Georgia	United States	31909
33	NeuroStudies	Decatur	Georgia	United States	30033
34	Advanced Clinical Research	Meridian	Idaho	United States	83642
35	Rush University Medical Center	Chicago	Illinois	United States	60612
36	Great Lakes Clinical Trials	Chicago	Illinois	United States	60640
37	Indiana University	Indianapolis	Indiana	United States	46202
38	University of Kansas Alzheimer's Disease Center	Fairway	Kansas	United States	66205
39	Via Christi Research	Wichita	Kansas	United States	67214
40	Sanders Brown Center on Aging, University of Kentucky	Lexington	Kentucky	United States	40504
41	Novartis Investigative Site	Bangor	Maine	United States	04401
42	Novartis Investigative Site	Boston	Massachusetts	United States	02115
43	Novartis Investigative Site	Boston	Massachusetts	United States	02118
44	Novartis Investigative Site	Kalamazoo	Michigan	United States	49008
45	Novartis Investigative Site	Saint Paul	Minnesota	United States	55130
46	Novartis Investigative Site	Saint Louis	Missouri	United States	63104
47	Memory Disorders Program, Department of Neurological Sciences, University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7680
48	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada	United States	89106
49	Memory Enhancement Center	Eatontown	New Jersey	United States	07724
50	The Memory Center of Northeastern New York	Latham	New York	United States	12110
51	NYU Langone Medical Center	New York	New York	United States	10016
52	The Nathan S. Kline Institute	Orangeburg	New York	United States	10962
53	University of Rochester Medical Center	Rochester	New York	United States	14620
54	Alzheimer's Memory Center	Charlotte	North Carolina	United States	28270
55	Duke University Medical center	Durham	North Carolina	United States	27705
56	Triad Clinical Trials, LLC	Greensboro	North Carolina	United States	27410
57	University Hospitals Cleveland Medical Center / Case Western Reserve University	Beachwood	Ohio	United States	44122
58	Novartis Investigative Site	Centerville	Ohio	United States	45459
59	Novartis Investigative Site	Columbus	Ohio	United States	43210
60	IPS Research Company	Oklahoma City	Oklahoma	United States	73103
61	Novartis Investigative Site	Oklahoma City	Oklahoma	United States	73112
62	Memory Health Center at Summit Research Network	Portland	Oregon	United States	97210
63	The Clinical Trial Center, LLC	Jenkintown	Pennsylvania	United States	19046
64	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19104
65	Abington Neurological Associates	Willow Grove	Pennsylvania	United States	19090
66	Butler Hospital Memory and Aging Program	Providence	Rhode Island	United States	02906
67	Roper St. Francis - CBRI	Charleston	South Carolina	United States	29401
68	Novartis Investigative Site	Knoxville	Tennessee	United States	37920
69	CNS Healthcare	Memphis	Tennessee	United States	38119
70	Novartis Investigative Site	Nashville	Tennessee	United States	37212
71	Senior Adults Specialty Research	Austin	Texas	United States	78757
72	Kerwin Research Center & Memory Care	Dallas	Texas	United States	75231
73	Houston Methodist Hospital	Houston	Texas	United States	77030
74	University of Texas Health Science Center, Houston	Houston	Texas	United States	77054
75	Clinical Trial Network	Houston	Texas	United States	77074
76	The Memory Clinic	Bennington	Vermont	United States	05201
77	Universal Research Group	Tacoma	Washington	United States	98405
78	The Medical College of WI	Milwaukee	Wisconsin	United States	53226
79	Novartis Investigative Site	Darlinghurst	New South Wales	Australia	2010
80	Novartis Investigative Site	Heidelberg Heights	Victoria	Australia	3081
81	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
82	Novartis Investigative Site	Gent		Belgium	9000
83	Novartis Investigative Site	Leuven		Belgium	3000
84	Okanagan Clinical Trials	Kelowna	British Columbia	Canada	V1Y1Z9
85	Novartis Investigative Site	Kentville	Nova Scota	Canada	B4N 4K9
86	Novartis Investigative Site	Halifax	Nova Scotia	Canada	B3S 1M7
87	Novartis Investigative Site	London	Ontario	Canada	N6C 0A7
88	Toronto Memory Program	Toronto	Ontario	Canada	M3B 2S7
89	The Centre for Memory and Aging	Toronto	Ontario	Canada	M4G 3E8
90	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
91	Novartis Investigative Site	Gatineau	Quebec	Canada	J8T 8J1
92	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1H 5N4
93	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1J 2G2
94	Novartis Investigative Site	Quebec		Canada	G1J 1Z4
95	Novartis Investigative Site	Turku		Finland	20520
96	Novartis Investigative Site	Bayreuth		Germany	95445
97	Novartis Investigative Site	Berlin		Germany	13353
98	Novartis Investigative Site	Boblingen		Germany	71032
99	Novartis Investigative Site	Gottingen		Germany	37075
100	Novartis Investigative Site	Halle		Germany	06120
101	Novartis Investigative Site	Kiel		Germany	24105
102	Novartis Investigative Site	Koeln		Germany	50937
103	Novartis Investigative Site	Leipzig		Germany	04107
104	Novartis Investigative Site	Mannheim		Germany	68159
105	Novartis Investigative Site	Münster		Germany	48149
106	Novartis Investigative Site	Siegen		Germany	57076
107	Novartis Investigative Site	Wenzenbach		Germany	93173
108	Novartis Investigative Site	Amsterdam		Netherlands	1081 GN
109	Novartis Investigative Site	Terrassa	Barcelona	Spain	08221
110	Novartis Investigative Site	Pozuelo de Alarcon	Madrid	Spain	28223
111	Novartis Investigative Site	Barcelona		Spain	08005
112	Novartis Investigative Site	Barcelona		Spain	08014
113	Novartis Investigative Site	Donostia-San Sebastian		Spain	20009
114	Novartis Investigative Site	Basel	CH	Switzerland	4002
115	Novartis Investigative Site	Westbruy On Trym	Bristol	United Kingdom	BS10 5NB
116	Novartis Investigative Site	Exeter	Devon	United Kingdom	EX2 5DW
117	Novartis Investigative Site	Plymouth	Devon	United Kingdom	PL6 8BT
118	Novartis Investigative Site	Guildford	Surrey	United Kingdom	GU27YD
119	Novartis Investigative Site	Avon		United Kingdom	BA1 3NG
120	Novartis Investigative Site	Birmingham		United Kingdom	B16 8QQ
121	Novartis Investigative Site	Dundee		United Kingdom	DD1 9SY
122	Novartis Investigative Site	Glasgow		United Kingdom	G20 0XA
123	Novartis Investigative Site	Glasgow		United Kingdom
124	Novartis Investigative Site	London		United Kingdom	SE5 8AD
125	Novartis Investigative Site	London		United Kingdom	W12 0HS
126	Novartis Investigative Site	London		United Kingdom	W1G 9JF
127	Novartis Investigative Site	London		United Kingdom	W2 1NY
128	Novartis Investigative Site	London		United Kingdom	W2 1PG
129	Novartis Investigative Site	Manchester		United Kingdom	M13 9WL

Sponsors and Collaborators

• Novartis Pharmaceuticals
• Banner Alzheimer's Institute
• National Institute on Aging (NIA)
• Amgen

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Jan 7, 2020
• Statistical Analysis Plan - Jan 29, 2021

More Information

Additional Information:

• Generation Program web site

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02565511
• Other Study ID Numbers: CAPI015A2201J; 2015-002715-15; 1UF1AG046150-01
• First Posted: Oct 1, 2015
• Last Update Posted: Jul 8, 2021
• Last Verified: Jul 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: Randomization; Placebo controlled; Parallel-group; APOE4 Homozygotes; Preclinical Alzheimers Disease (AD); Aβ lowering; CNP520; CAD106; elderly; Brain Amyloid; BACE-1 inhibitor; Prevention; Unimpaired cognition
• Additional relevant MeSH terms: Alzheimer Disease; CNP520

Study Results

Participant Flow

Pre-assignment Detail	713 participants were screened

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Period Title: Overall Study
STARTED	42	23	251	164
3 Patients Were Mis-randomized	0	0	2	1
COMPLETED	0	0	0	0
NOT COMPLETED	42	23	251	164

Baseline Characteristics

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo	Total
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally	Total of all reporting groups
Overall Participants	42	23	249	163	477
Age, Customized (participants) [Number]
<=64 years	20 47.6%	9 39.1%	77 30.9%	52 31.9%	158 33.1%
65-69 years	18 42.9%	7 30.4%	116 46.6%	65 39.9%	206 43.2%
>70 years	4 9.5%	7 30.4%	56 22.5%	46 28.2%	113 23.7%
Sex: Female, Male (Count of Participants)
Female	27 64.3%	17 73.9%	129 51.8%	102 62.6%	275 57.7%
Male	15 35.7%	6 26.1%	120 48.2%	61 37.4%	202 42.3%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	41 97.6%	22 95.7%	241 96.8%	162 99.4%	466 97.7%
Black	1 2.4%	1 4.3%	1 0.4%	0 0%	3 0.6%
Asian	0 0%	0 0%	4 1.6%	0 0%	4 0.8%
Pacific Islander	0 0%	0 0%	1 0.4%	0 0%	1 0.2%
Other	0 0%	0 0%	1 0.4%	0 0%	1 0.2%
Unknown	0 0%	0 0%	1 0.4%	1 0.6%	2 0.4%
Cohort I API Preclinical Composite Cognitive Battery (APCC) (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	78.0 (5.53)	79.0 (6.76)	78.3 (5.96)
Cohort I Repeatable Battery for Assessment of Neurological Status (RBANS) (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	104.4 (12.03)	108.7 (12.83)	106.0 (12.39)
Cohort I Clinical Dementia Rating Sum of Boxes (CDR-SOB) (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	0.10 (0.276)	0.04 (0.209)	0.08 (0.254)
Cohort II API Preclinical Composite Cognitive Battery (APCC) (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	29.0 (1.17)	28.9 (1.33)	29.0 (1.23)
Cohort II Repeatable Battery for Assessment of Neurological Status (RBANS) (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	102.6 (12.22)	103.2 (12.03)	102.9 (12.13)
Cohort II Clinical Dementia Rating Sum of Boxes (CDR-SOB) (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	0.16 (0.15)	0.15 (0.417)	0.16 (0.409)

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 end of exposure for a maximum of 1455 days for CI and 907 days for CII

Outcome Measure Data

Analysis Population Description

n=number of participants at risk to experience an event at the time-point

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	41	22	193	126
Week 26	1.00 2.4%	1.00 4.3%	0.98 0.4%	0.98 0.6%
Week 52	1.00 2.4%	1.00 4.3%	0.93 0.4%	0.95 0.6%
Week 78	0.97 2.3%	1.00 4.3%	0.88 0.4%	0.85 0.5%
Week 104	0.97 2.3%	1.00 4.3%	0.88 0.4%	0.85 0.5%

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	CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment

Outcome Measure Data

Analysis Population Description

Only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	41	23	179	125
Week 26	-1.1 (4.10)	-2.0 (3.90)	-3.3 (4.54)	-1.0 (4.65)
Week 52	0.9 (4.24)	1.4 (3.36)	0.3 (4.27)	2.2 (6.11)
Week 78	0.2 (4.15)	-0.7 (5.48)	-4.1 (4.14)	2.4 (4.23)
Week 104	-1.4 (4.67)	0.3 (4.00)	-6.7 (3.95)
CI-Last post BL assessment	0.0 (4.62)	0.1 (3.87)
CII - Last on treatment	-1.7 (4.81)	0.1 (4.58)
CII-Last off treatment	-0.1 (4.72)	0.2 (4.56)

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	CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment

Outcome Measure Data

Analysis Population Description

Only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	41	23	174	122
Week 26	-0.04 (0.234)	0.00 (0.000)	0.04 (0.361)	0.00 (0.336)
Week 52	-0.01 (0.237)	0.02 (0.104)	-0.02 (0.281)	-0.08 (0.541)
Week 78	-0.04 (0.237)	0.03 (0.118)	0.14 (0.802)	-0.14 (0.244)
Week 104	0.15 (0.460)	0.06 (0.167)	-0.17 (0.764)
CI Last post baseline assessment	0.04 (0.343)	0.00 (0.302)
CII Last on-treatment	0.06 (0.505)	0.03 (0.410)
CII Last off-treatment	0.05 (0.464)	-0.01 (0.519)

4. Secondary Outcome

Title	Change in the Total 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	CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment

Outcome Measure Data

Analysis Population Description

Only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	41	23	209	141
Total Week 26	-5.1 (7.25)	-3.0 (7.51)	-4.1 (8.58)	-2.6 (7.83)
Total Week 52	-1.2 (7.82)	4.5 (7.10)	-0.1 (7.91)	1.4 (8.06)
Total Week 78	-2.1 (7.69)	-4.0 (7.82)	-12.1 (7.40)	-4.8 (5.99)
Total Week 104	-1.4 (6.74)	-3.0 (8.34)	-7.7 (15.57)
Total CI Last post baseline assessment	-1.0 (9.27)	0.4 (7.20)
Total CII Last on-treatment	-2.7 (8.65)	-0.2 (9.22)
Total CII Last off-treatment	-1.5 (9.20)	-0.6 (8.83)

5. Secondary Outcome

Title	Change in the 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	CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment

Outcome Measure Data

Analysis Population Description

Only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	41	23	209	141
Immediate memory - Week 26	-8.6 (10.68)	-3.8 (11.16)	-7.4 (13.11)	-3.7 (12.15)
Immediate memory - Week 52	1.3 (10.81)	4.8 (8.68)	0.6 (13.55)	5.1 (11.73)
CI Immediate memory - Last post baseline assessment	-1.1 (13.11)	1.1 (14.52)
CII Immediate memory - Last on-treatment	-3.7 (14.43)	0.6 (13.54)
CII Immediate memory - Last off-treatment	-3.2 (13.76)	-2.0 (11.90)
Visuospatial Week 26	-6.5 (15.21)	0.7 (12.39)	-3.5 (14.98)	-2.4 (13.00)
Visuospatial Week 52	-6.5 (14.59)	3.0 (15.09)	-1.4 (14.29)	-4.8 (12.60)
CI Visuospatial Last post baseline assessment	-4.7 (13.91)	1.9 (12.72)
CII Visuospatial Last on-treatment n=	-3.5 (14.59)	-2.6 (14.92)
CII Visuospatial Last off-treatment	-1.2 (15.13)	-0.8 (15.18)
Language Week 26	-1.4 (12.91)	-2.8 (11.42)	-0.1 (12.05)	-1.5 (11.87)
Language Week 52	2.6 (10.29)	2.0 (11.51)	-0.3 (12.88)	0.8 (9.72)
CI Language Last post baseline assessment	1.9 (13.00)	-4.5 (12.86)
CII Language Last on-treatment	-0.1 (12.07)	-0.1 (11.93)
CII Language Last off-treatment	-1.0 (13.19)	-1.8 (11.25)
Attention Week 26	1.8 (9.40)	-0.6 (14.19)	-0.7 (10.42)	-0.6 (11.67)
Attention Week 52	0.9 (10.80)	-0.5 (13.09)	-0.2 (10.02)	2.7 (10.77)
CI Attention Last post baseline assessment	2.0 (12.91)	2.0 (10.25)
CII Attention Last on-treatment	0.1 (10.80)	0.8 (11.20)
CII-Attention Last off-treatment	1.0 (1.64)	1.2 (11.07)
Delayed memory - Week 26	-3.8 (7.83)	-2.7 (7.64)	-3.8 (11.20)	-2.6 (8.85)
Delayed memory - Week 52	-2.0 (8.01)	3.2 (6.23)	2.3 (9.09)	0.6 (11.73)
CI Delayed memory - Last post baseline assessment	-1.0 (10.20)	1.3 (8.44)
CII Delayed memory - Last on-treatment	-2.5 (10.61)	0.4 (10.28)
CII Delayed memory - Last off-treatment	-1.1 (10.75)	1.1 (11.28)

6. 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	CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment

Outcome Measure Data

Analysis Population Description

Only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	40	22	178	119
Week 26	-1.0 (2.94)	2.3 (4.80)	1.8 (6.03)	0.6 (6.45)
Week 52	0.6 (5.23)	0.4 (2.99)	2.7 (6.16)	0.2 (5.01)
CI Last post baseline assessment	0.6 (5.02)	1.6 (4.07)
CII Last on-treatment	2.6 (7.81)	0.9 (6.48)
CII Last off-treatment	1.6 (6.77)	0.8 (6.13)

7. 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. Cohort I=C I and Cohort II=C II.
Time Frame	CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment

Outcome Measure Data

Analysis Population Description

Only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	37	23	160	113
Week 26	-0.4 (4.21)	-1.0 (4.87)	0.1 (6.84)	-0.7 (8.69)
Week 52	-0.2 (3.15)	-0.3 (5.12)	1.4 (5.18)	-0.2 (9.59)
CI Last post baseline assessment	-1.1 (4.23)	-1.0 (4.88)
CII Last on-treatment	1.3 (8.76)	0.1 (9.12)
CII Last off-treatment	1.4 (8.49)	-0.5 (10.10)

8. 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 since baseline) and a general assessment of brain abnormalities. Assessment of cerebral amyloid angiopathy (CAA) is included in the overall safety MRI findings results.
Time Frame	Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII

Outcome Measure Data

Analysis Population Description

Safety analysis set - only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	42	23	249	163
Questionable presence of ARIA-E	0 0%	0 0%	0 0%	1 0.6%
Presence of ARIA-E	1 2.4%	0 0%	0 0%	2 1.2%
ARIA-E - If present, the worst Severity=moderate	1 2.4%	0 0%	0 0%	2 1.2%
Presence of ARIA-H - >4 microhemorrhages (new hemosiderin deposits < 10 mm)	2 4.8%	0 0%	6 2.4%	2 1.2%
White matter disease worsening: 1-3 increase	0 0%	2 8.7%	6 2.4%	1 0.6%
White matter disease worsening: 4 - 8 increase	0 0%	0 0%	0 0%	0 0%
White matter disease worsening > 8 increase	0 0%	0 0%	0 0%	0 0%
Any other MRI abnormalities	2 4.8%	1 4.3%	0 0%	0 0%

9. 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	CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment

Outcome Measure Data

Analysis Population Description

Safety analysis set - only participants with a value at both Baseline and that visit are included. For CI: last post-baseline assessment collected during the study. For CII: 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	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	42	23	201	135
WB Week 26	-0.7570 (1.33114)	-0.6044 (1.29608)	-0.9318 (1.06843)	-0.4616 (1.00537)
WB Week 52	-0.5144 (0.66578)	-0.3395 (0.75810)	-0.6590 (0.64838)	-0.4227 (0.58778)
WB CI Last post baseline assessment	-0.4645 (0.57503)	-0.5321 (0.46526)
WB CII Last on-treatment	-0.8268 (0.94889)	-0.5181 (0.92086)
WB CII Last off-treatment	-0.6748 (0.62542)	-0.3317 (0.62616)
Hip Week 26	-1.3262 (2.35453)	-0.9245 (2.81731)	-1.6603 (2.65529)	-0.8817 (2.06227)
Hip Week 52	-1.0376 (1.44310)	-0.7780 (1.81604)	-1.2438 (1.79988)	-0.9567 (1.42941)
Hip CI Last post baseline assessment	-1.0801 (1.38061)	-1.0477 (1.33603)
Hip CII Last on-treatment	-1.4790 (2.36526)	-0.9984 (1.85655)
Hip CII Last off-treatment	-1.9375 (2.03593)	-1.0498 (1.66596)
LV Week 26	4.1848 (5.77286)	2.5581 (7.54667)	4.5176 (5.59748)	3.9735 (4.23237)
LV Week 52	4.2060 (3.92877)	2.8232 (5.04358)	3.3854 (3.71214)	2.9059 (3.18734)
LV CI Last post baseline assessment	4.0543 (3.75310)	3.5427 (3.53772)
LV CII Last on-treatment	4.3588 (5.07839)	4.0308 (3.64102)
LV CII Last off-treatment	3.9617 (2.61831)	2.6052 (3.54903)

10. Secondary Outcome

Title	Change in Cerebrospinal Fluid (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 assessment

Outcome Measure Data

Analysis Population Description

No lumbar punctures for CSF collection were performed due to early termination of trial

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	0	0	0	0

11. Secondary Outcome

Title	Change in Cerebrospinal Fluid (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 assessment

Outcome Measure Data

Analysis Population Description

No lumbar punctures for CSF collection were performed due to early termination of trial

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	0	0	0	0

12. Secondary Outcome

Title	Change in Cerebrospinal Fluid (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 assessment

Outcome Measure Data

Analysis Population Description

No lumbar punctures for CSF collection were performed due to early termination of trial

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	0	0	0	0

13. 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 tau pathology in the brain
Time Frame	Baseline to last assessment

Outcome Measure Data

Analysis Population Description

No post baseline data collected

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	0	0	0	0

14. Secondary Outcome

Title	Cohort I : Annualized Change in Amyloid Deposition as Measured by Centiloids of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer
Description	To demonstrate the effects of CAD106 vs placebo on Alzheimer's Disease-related biomarkers
Time Frame	Baseline up to approximately Week 104

Outcome Measure Data

Analysis Population Description

Only available for Cohort I. For Cohort II, no post-baseline (year 2) amyloid PET scans could be obtained due to the early trial termination

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
Measure Participants	42	23
Mean (Standard Deviation) [Centiloids]	-0.911 (5.6596)	8.367 (6.6805)

15. 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 and week 52, CI baseline to last assessment. CII baseline to last on-treatment and to last off-treatment

Outcome Measure Data

Analysis Population Description

Only participants with a value at both Baseline and that visit are included. CI last post-baseline assessment. CII Last on-treatment is the last assessment before or at last day on study drug + 31 days.

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	20	10	72	53
Week 26	1.44 (3.165)	-3.89 (13.058)	0.644 (3.4879)	0.362 (6.7547)
Week 52	2.63 (5.716)	-6.09 (16.542)	1.921 (4.0515)	-4.852 (14.2270)
C I Last post baseline assessment	1.77 (4.643)	-3.31 (12.858)
C II Last on-treatment	0.647 (3.5357)	0.280 (6.8289)
C II Last off-treatment	-0.004 (3.7102)	-2.145 (2.6799)

16. 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 to end of exposure for a maximum of 1455 days for CI and 907 days for CII

Outcome Measure Data

Analysis Population Description

Safety analysis set which includes only participants with events

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	42	23	249	163
Any suicidal ideation	2	1	12	4
Any suicidal behavior	0	0	1	1

17. Secondary Outcome

Title	Cohort I : Change in Cognition as Measured by APCC and CDR-SOB Scores and Antibody Response
Time Frame	Month 6 to Month 60

Outcome Measure Data

Analysis Population Description

No analysis performed due to early termination, no month 60 data

Arm/Group Title	Cohort I (CI) CAD106	Cohort I (CI) CAD106 Placebo	Cohort II (CII) CNP520	Cohort II (CII) CNP520 Placebo
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter	CNP520 (50 mg) capsules taken once daily orally	Placebo to CNP520 capsules taken once daily orally
Measure Participants	0	0	0	0

18. Secondary Outcome

Title	Cohort I: Peak Concentration (Cmax) of CAD106 Induced Abeta-specific Antibody Titers
Description	Cmax is the maximum Titer Concentration of any post-baseline 'on treatment' visit. A visit is considered as 'on treatment' if visit date is within {last injection + 180 days}. - Geometric mean and CI's are back-transformed from the estimates for Log mean and CI's.
Time Frame	Week 9, 13, 15, 26 and quarterly thereafter (trough values)

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Cohort I (CI) CAD106
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
Measure Participants	41
Geometric Mean (95% Confidence Interval) [Days x titer levels rel. to ref. serum]	128.76

19. Secondary Outcome

Title	Cohort I: Area Under the Concentration Curve (AUC) of CAD106 Induced Abeta-specific Antibody Titers
Description	AUC is calculated based on 'on treatment' visit only.(missing values for peak visits were linearly interpolated for calculation; missing values for trough visits were imputed by average of non-missing trough values.).
Time Frame	Week 9, 13, 15, 26 and quarterly thereafter (trough values)

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Cohort I (CI) CAD106
Arm/Group Description	CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
Measure Participants	42
Geometric Mean (95% Confidence Interval) [Days x titer levels rel. to ref. serum]	34999.89

Adverse Events

Time Frame	Adverse events were reported from first dose of study treatment plus 31 days of washout period for a maximum duration of 1455 days for CI and 907 days for CII
Arm/Group Title	Cohort I @CAD106		Cohort I @Placebo		Cohort II (CNP520 50)		Cohort II Placebo
Arm/Group Description	Cohort I @CAD106		Cohort I @Placebo		CNP520 (50 mg) capsules taken once daily orally		Cohort II @Placebo
All Cause Mortality
	Cohort I @CAD106		Cohort I @Placebo		Cohort II (CNP520 50)		Cohort II Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Serious Adverse Events
	Cohort I @CAD106		Cohort I @Placebo		Cohort II (CNP520 50)		Cohort II Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/42 (9.5%)		3/23 (13%)		8/249 (3.2%)		7/163 (4.3%)
Cardiac disorders
Atrial flutter	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Cardiac failure congestive	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Coronary artery disease	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Stress cardiomyopathy	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Gastrointestinal disorders
Hiatus hernia	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Nausea	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
General disorders
Asthenia	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Feeling jittery	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Non-cardiac chest pain	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Infections and infestations
Abscess limb	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Cellulitis	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Injury, poisoning and procedural complications
Animal bite	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Fall	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Femoral neck fracture	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Fibula fracture	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Rib fracture	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Metabolism and nutrition disorders
Hyponatraemia	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Rotator cuff syndrome	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma in situ	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Nervous system disorders
Cerebellar haemorrhage	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Cerebrovascular accident	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Subarachnoid haemorrhage	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Syncope	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Transient ischaemic attack	0/42 (0%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Pulmonary mass	0/42 (0%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/42 (2.4%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Other (Not Including Serious) Adverse Events
	Cohort I @CAD106		Cohort I @Placebo		Cohort II (CNP520 50)		Cohort II Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/42 (85.7%)		21/23 (91.3%)		106/249 (42.6%)		76/163 (46.6%)
Cardiac disorders
Atrial fibrillation	0/42 (0%)		2/23 (8.7%)		1/249 (0.4%)		0/163 (0%)
Atrial flutter	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Palpitations	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Congenital, familial and genetic disorders
Type V hyperlipidaemia	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Ear and labyrinth disorders
Deafness bilateral	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Tinnitus	2/42 (4.8%)		0/23 (0%)		3/249 (1.2%)		0/163 (0%)
Endocrine disorders
Hypothyroidism	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Thyroid mass	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Eye disorders
Glaucoma	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Vitreous detachment	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Gastrointestinal disorders
Abdominal pain upper	0/42 (0%)		2/23 (8.7%)		0/249 (0%)		1/163 (0.6%)
Constipation	3/42 (7.1%)		0/23 (0%)		7/249 (2.8%)		2/163 (1.2%)
Diarrhoea	3/42 (7.1%)		1/23 (4.3%)		6/249 (2.4%)		3/163 (1.8%)
Eosinophilic oesophagitis	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Nausea	2/42 (4.8%)		0/23 (0%)		5/249 (2%)		4/163 (2.5%)
Pancreatic cyst	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Salivary gland disorder	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
General disorders
Chills	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Fatigue	11/42 (26.2%)		1/23 (4.3%)		3/249 (1.2%)		1/163 (0.6%)
Influenza like illness	5/42 (11.9%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Injection site erythema	1/42 (2.4%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Injection site pain	10/42 (23.8%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Injection site pruritus	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Injection site reaction	4/42 (9.5%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Malaise	3/42 (7.1%)		1/23 (4.3%)		1/249 (0.4%)		0/163 (0%)
Non-cardiac chest pain	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Oedema peripheral	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Pyrexia	7/42 (16.7%)		1/23 (4.3%)		4/249 (1.6%)		0/163 (0%)
Immune system disorders
Seasonal allergy	2/42 (4.8%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Infections and infestations
Acute sinusitis	0/42 (0%)		2/23 (8.7%)		1/249 (0.4%)		0/163 (0%)
Bronchitis	2/42 (4.8%)		1/23 (4.3%)		1/249 (0.4%)		8/163 (4.9%)
Cellulitis	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Conjunctivitis bacterial	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Dacryocanaliculitis	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Gastroenteritis	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Gastroenteritis viral	0/42 (0%)		1/23 (4.3%)		1/249 (0.4%)		1/163 (0.6%)
Influenza	1/42 (2.4%)		2/23 (8.7%)		3/249 (1.2%)		0/163 (0%)
Nasopharyngitis	4/42 (9.5%)		2/23 (8.7%)		10/249 (4%)		2/163 (1.2%)
Pharyngitis	1/42 (2.4%)		1/23 (4.3%)		1/249 (0.4%)		0/163 (0%)
Respiratory tract infection	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Sinusitis	3/42 (7.1%)		1/23 (4.3%)		5/249 (2%)		8/163 (4.9%)
Upper respiratory tract infection	7/42 (16.7%)		3/23 (13%)		11/249 (4.4%)		11/163 (6.7%)
Urinary tract infection	0/42 (0%)		2/23 (8.7%)		5/249 (2%)		4/163 (2.5%)
Injury, poisoning and procedural complications
Arthropod bite	0/42 (0%)		1/23 (4.3%)		2/249 (0.8%)		4/163 (2.5%)
Contusion	3/42 (7.1%)		0/23 (0%)		1/249 (0.4%)		3/163 (1.8%)
Fall	4/42 (9.5%)		1/23 (4.3%)		8/249 (3.2%)		4/163 (2.5%)
Injection related reaction	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Mallet finger	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Meniscus injury	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Pelvic fracture	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Skin abrasion	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Investigations
C-reactive protein increased	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Lumbar puncture	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Urine albumin/creatinine ratio increased	0/42 (0%)		0/23 (0%)		9/249 (3.6%)		2/163 (1.2%)
Weight decreased	0/42 (0%)		0/23 (0%)		7/249 (2.8%)		1/163 (0.6%)
Weight increased	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		1/163 (0.6%)
Metabolism and nutrition disorders
Hyperlipidaemia	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		0/163 (0%)
Vitamin B12 deficiency	1/42 (2.4%)		2/23 (8.7%)		4/249 (1.6%)		0/163 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/42 (9.5%)		1/23 (4.3%)		6/249 (2.4%)		7/163 (4.3%)
Back pain	4/42 (9.5%)		0/23 (0%)		7/249 (2.8%)		6/163 (3.7%)
Exostosis	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Flank pain	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Foot deformity	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Muscle spasms	2/42 (4.8%)		0/23 (0%)		5/249 (2%)		1/163 (0.6%)
Musculoskeletal pain	2/42 (4.8%)		0/23 (0%)		1/249 (0.4%)		3/163 (1.8%)
Musculoskeletal stiffness	2/42 (4.8%)		0/23 (0%)		1/249 (0.4%)		0/163 (0%)
Myalgia	3/42 (7.1%)		3/23 (13%)		3/249 (1.2%)		0/163 (0%)
Osteoarthritis	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Pain in extremity	4/42 (9.5%)		2/23 (8.7%)		6/249 (2.4%)		5/163 (3.1%)
Rotator cuff syndrome	2/42 (4.8%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Tendonitis	0/42 (0%)		1/23 (4.3%)		1/249 (0.4%)		1/163 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	2/42 (4.8%)		0/23 (0%)		0/249 (0%)		2/163 (1.2%)
Benign neoplasm of thyroid gland	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Haemangioma of liver	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Melanocytic naevus	1/42 (2.4%)		1/23 (4.3%)		0/249 (0%)		1/163 (0.6%)
Uterine leiomyoma	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Nervous system disorders
Ageusia	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Carpal tunnel syndrome	1/42 (2.4%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Cerebral cyst	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Cervical radiculopathy	0/42 (0%)		1/23 (4.3%)		1/249 (0.4%)		1/163 (0.6%)
Dizziness	0/42 (0%)		0/23 (0%)		7/249 (2.8%)		1/163 (0.6%)
Headache	7/42 (16.7%)		0/23 (0%)		6/249 (2.4%)		9/163 (5.5%)
Lethargy	2/42 (4.8%)		0/23 (0%)		2/249 (0.8%)		0/163 (0%)
Paraesthesia	1/42 (2.4%)		1/23 (4.3%)		2/249 (0.8%)		0/163 (0%)
Presyncope	0/42 (0%)		1/23 (4.3%)		1/249 (0.4%)		0/163 (0%)
Radiculopathy	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Psychiatric disorders
Abnormal dreams	2/42 (4.8%)		1/23 (4.3%)		19/249 (7.6%)		5/163 (3.1%)
Anxiety	0/42 (0%)		0/23 (0%)		11/249 (4.4%)		0/163 (0%)
Insomnia	2/42 (4.8%)		1/23 (4.3%)		4/249 (1.6%)		9/163 (5.5%)
Irritability	1/42 (2.4%)		1/23 (4.3%)		2/249 (0.8%)		0/163 (0%)
Renal and urinary disorders
Cystitis haemorrhagic	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Dysuria	1/42 (2.4%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Hypercalciuria	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	3/42 (7.1%)		0/23 (0%)		5/249 (2%)		2/163 (1.2%)
Oropharyngeal pain	0/42 (0%)		1/23 (4.3%)		4/249 (1.6%)		0/163 (0%)
Throat irritation	1/42 (2.4%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Skin and subcutaneous tissue disorders
Dermatitis contact	2/42 (4.8%)		0/23 (0%)		1/249 (0.4%)		2/163 (1.2%)
Nail disorder	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Pruritus	0/42 (0%)		0/23 (0%)		10/249 (4%)		5/163 (3.1%)
Urticaria	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)
Vascular disorders
Essential hypertension	0/42 (0%)		1/23 (4.3%)		0/249 (0%)		0/163 (0%)

Limitations/Caveats

The study was terminated due to unexpected changes in cognitive function, brain volume loss, and body weight loss. Cohort II (CNP520) treatment was stopped and evaluated through an off-treatment follow-up period. After the decision to terminate Cohort II of the study (CNP520), treatment with CAD106 (Cohort I) was also terminated

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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.