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

Alzheimers Disease Clinical Trial

— GS2  

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).

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03131453
• Other study ID #: CCNP520A2202J
• Secondary ID: 2016-002976-28
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: August 3, 2017
• Est. completion date: March 26, 2020

Study information

• Verified date: August 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1145
• Est. completion date: March 26, 2020
• Est. primary completion date: March 26, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimers Disease

Intervention

Drug:
• CNP520 50mg
50 mg capsule
• CNP520 15mg
15 mg capsule

Other:
• Matching placebo
Matching placebo for 15 and 50 mg capsules

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Australia	Novartis Investigative Site	Darlinghurst	New South Wales
Australia	Novartis Investigative Site	Heidelberg West	Victoria
Australia	Novartis Investigative Site	Nedlands	Western Australia
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	Gatineau	Quebec
Canada	Novartis Investigative Site	Greenfield Park	Quebec
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	Kelowna	British Columbia
Canada	Novartis Investigative Site	Kentville	Nova Scota
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Toronto Memory Program, 1 Valleybrook Drive Suite 400	Toronto	Ontario
Chile	Novartis Investigative Site	Santiago
Chile	Novartis Investigative Site	Santiago
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Guangdong
China	Novartis Investigative Site	Shanghai	Shanghai
Finland	Novartis Investigative Site	Kuopio
Finland	Novartis Investigative Site	Turku
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	PARIS Cedex 13
France	Novartis Investigative Site	Rouen
France	Novartis Investigative Site	Strasbourg	Cedex
France	Novartis Investigative Site	Toulouse Cedex 9
France	Novartis Investigative Site	Villeurbanne
Germany	Novartis Investigative Site	Bayreuth
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mannheim
Germany	Novartis Investigative Site	Siegen
Iceland	Novartis Investigative Site	Kopavogi
Israel	Novartis Investigative Site	Ashkelon
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Tel Aviv
Italy	Novartis Investigative Site	Brescia	BS
Italy	Novartis Investigative Site	Milan
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Roma	Lazio
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Chiba
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Kodaira	Tokyo
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Japan	Novartis Investigative Site	Suita city	Osaka
Japan	Novartis Investigative Site	Toon	Ehime
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Busan
Korea, Republic of	Novartis Investigative Site	Incheon
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Suwon	Gyeonggi Do
Mexico	Novartis Investigative Site	Ciudad de Mexico	Mexico CP
Mexico	Novartis Investigative Site	Culiacan	Sinaloa
Mexico	Novartis Investigative Site	Monterrey	Nuevo Leon
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Den Bosch	Noord Brabant
Portugal	Novartis Investigative Site	Coimbra
Portugal	Novartis Investigative Site	Lisboa
Portugal	Novartis Investigative Site	Matosinhos
Portugal	Novartis Investigative Site	Torres Vedras	Lisbon
Puerto Rico	Inspira Clinical Research, Ave Hostos 405	San Juan
Singapore	Novartis Investigative Site	Singapore
South Africa	Novartis Investigative Site	Cape Town	Western Cape
South Africa	Novartis Investigative Site	George	ZAF
South Africa	Novartis Investigative Site	Rosebank	Johannesburg
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Donostia-San Sebastian
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Pozuelo de Alarcon	Madrid
Spain	Novartis Investigative Site	Terrassa	Barcelona
Switzerland	Novartis Investigative Site	Basel	CH
Switzerland	Novartis Investigative Site	Geneve
Switzerland	Novartis Investigative Site	Lausanne
Taiwan	Novartis Investigative Site	Kaoshiung
Taiwan	Novartis Investigative Site	New Taipei City
Taiwan	Novartis Investigative Site	Taipei
United Kingdom	Novartis Investigative Site	Avon
United Kingdom	Novartis Investigative Site	Birmingham
United Kingdom	Novartis Investigative Site	Bristol
United Kingdom	Novartis Investigative Site	Dundee
United Kingdom	Novartis Investigative Site	Exeter	Devon
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Guildford	Surrey
United Kingdom	Novartis Investigative Site	London	GBR
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Plymouth	Devon
United States	Albuquerque Neuroscience, 101 Hospital Loop ne, 209 209	Albuquerque	New Mexico
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Atlantis	Florida
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Bangor	Maine
United States	Mountain Neurological Research, 350 Market Street, Suite 316	Basalt	Colorado
United States	Novartis Investigative Site	Bennington	Vermont
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Brooklyn	New York
United States	Roper Hospital, 316 Calhoun Street 5th Floor	Charleston	South Carolina
United States	ANI Neurology, PLLC dba Alzhe, 7809 Sardis Road	Charlotte	North Carolina
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Colorado Springs Neurological, 2312 North Nevada Avenue, Suite 100	Colorado Springs	Colorado
United States	Novartis Investigative Site	Columbus	Georgia
United States	ATP Clinical Research Inc, 3151 Airway Avenue T 3	Costa Mesa	California
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Decatur	Georgia
United States	Quantum Laboratories	Deerfield Beach	Florida
United States	Brain Matters Research, Inc., 800 NW 17th Avenue	Delray Beach	Florida
United States	Denver Neurological Clinic, 950 E Harvard Ave	Denver	Colorado
United States	Novartis Investigative Site	Durham	North Carolina
United States	Rhode Island Hospital and Memory Research Institute, 1018 Waterman Ave	East Providence	Rhode Island
United States	Novartis Investigative Site	East Syracuse	New York
United States	Alexian Brothers Neuroscience, 800 Biesterfield Rd, Neuroscience Institute Brock	Elk Grove Village	Illinois
United States	Novartis Investigative Site	Fairway	Kansas
United States	QUEST Research Institute, 28595 Orchard Lake Road, Suite 301	Farmington Hills	Michigan
United States	Novartis Investigative Site	Greensboro	North Carolina
United States	Hattiesburg Clinic, 415 South 28th Avenue	Hattiesburg	Mississippi
United States	Infinity Clinical Research LLC, 4925 Sheridan Street, Suite 200	Hollywood	Florida
United States	Hawaii Pacific Neuroscience, 2230 Liliha st 104	Honolulu	Hawaii
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Irvine Center for Clinical Res, 2515 McCabe Way	Irvine	California
United States	Novartis Investigative Site	Jenkintown	Pennsylvania
United States	Novartis Investigative Site	Kalamazoo	Michigan
United States	Novartis Investigative Site	Knoxville	Tennessee
United States	Alzheimer's Research and Treatment Center, 5065 State Road 7, Suite 102	Lake Worth	Florida
United States	Novartis Investigative Site	Latham	New York
United States	Novartis Investigative Site	Lexington	Kentucky
United States	Torrance Clinical Research Institute, 25043 Narbonne Avenue	Lomita	California
United States	Meridien Research, 2300 Maitland center, Pkwy Ste 230	Maitland	Florida
United States	Novartis Investigative Site	Melbourne	Florida
United States	Novartis Investigative Site	Memphis	Tennessee
United States	Advanced Clinical Research, 2950 E Magic View Dr, Suite 182	Meridian	Idaho
United States	Novartis Investigative Site	Merritt Island	Florida
United States	Miami-Dade Medical Research, 8955 SW 87 CT, Suite 112	Miami	Florida
United States	New Horizon Research Center, 11880 SW 40 St., Suite 405	Miami	Florida
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Miami Beach	Florida
United States	Novartis Investigative Site	Milwaukee	Wisconsin
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Yale University, One Church Street, Suite 600	New Haven	Connecticut
United States	NYU Langone Medical Center, 145 East 32nd Street, 2nd Floor, Room 226	New York	New York
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Orangeburg	New York
United States	Compass Research, LLC,100 West Gore Street, Suite 202	Orlando	Florida
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	Ormond Beach	Florida
United States	Novartis Investigative Site	Oxnard	California
United States	Novartis Investigative Site	Palm Beach Gardens	Florida
United States	Novartis Investigative Site	Palo Alto	California
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Banner Alzheimer's Institute, 901 East Willetta Street	Phoenix	Arizona
United States	Novartis Investigative Site	Port Orange	Florida
United States	Novartis Investigative Site	Portland	Oregon
United States	Summit Research Network, 2701 NW Vaughn St, Suite 350	Portland	Oregon
United States	Butler Hospital, 345 Blackstone Blvd.	Providence	Rhode Island
United States	Novartis Investigative Site	Rochester	New York
United States	Novartis Investigative Site	Rochester	Minnesota
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Diego	California
United States	Syrentis Clinical Research, 1401 N Tustin Ave, Suite 130	Santa Ana	California
United States	Roskamp Institute, Inc., 2040 Whitfield Avenue	Sarasota	Florida
United States	Novartis Investigative Site	Sebastopol	California
United States	Novartis Investigative Site	Sherman Oaks	California
United States	Novartis Investigative Site	Stamford	Connecticut
United States	Banner Sun Health Research Institute, 10515 West Santa Fe Drive, Building B	Sun City	Arizona
United States	Novartis Investigative Site	Tacoma	Washington
United States	Novartis Investigative Site	Tallahassee	Florida
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Tucson	Arizona
United States	Tulsa Clinical Research LLC, 1705 E 19th ST., STE 406/408	Tulsa	Oklahoma
United States	Novartis Investigative Site	Washington	District of Columbia
United States	Novartis Investigative Site	West Long Branch	New Jersey
United States	Novartis Investigative Site	West Palm Beach	Florida
United States	Novartis Investigative Site	Wichita	Kansas
United States	Novartis Investigative Site	Wichita	Kansas
United States	Abington Neurological Associate Ltd., 2325 Maryland Road, Suite 100	Willow Grove	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	Amgen, Banner Alzheimer's Institute

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  Chile,  China,  Finland,  France,  Germany,  Iceland,  Israel,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Portugal,  Puerto Rico,  Singapore,  South Africa,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD))	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.	Baseline to last cognitive assessment performed (up to day 648)
Primary	Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score	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.	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score	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	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Change in the Total and Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)	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.	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Change in the Everyday Cognition Scale (ECog-Subject) Total Scores	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.	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Change in the Everyday Cognition Scale (ECog-Informant) Total Scores	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.	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities)	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.	Baseline up to study termination approximately 617 days
Secondary	Annualized Percent Change on Volume of Brain Regions	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.	Baseline to Week 26, Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Change in CSF Levels of Amyloid Beta 40 (Aß40)	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 40 (Aß40)	Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Change in CSF Levels of Amyloid Beta 42 (Aß42)	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): Amyloid Beta 42 (Aß42).	Baseline to Last on-treatment (Day 547) and Baseline to Last off-treatment (Day 648)
Secondary	Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available)	To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers	Baseline to Months 24 and 60
Secondary	Change in Amyloid Deposition as Measured by Standardized Uptake Ratio (SUVR) of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer	To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers	Baseline to Months 24 and 60
Secondary	Change in CSF Levels of Total Tau and Phosphorylated Tau	Alzheimer's Disease-related biomarkers analyzed in cerebrospinal fluid (CSF): total tau protein and phosphorylated tau protein levels	Baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)
Secondary	Change in Serum Neurofilaments	Alzheimer's Disease-related biomarkers analyzed in blood serum: light chain neurofilaments (NfL)	Baseline to Week 26, baseline to Last on-treatment (Day 547) Baseline to Last off-treatment (Day 648)
Secondary	Number of Suicidal Ideation or Behavior Events	Prospective suicidality assessment was performed with the use of Columbia-Suicide Severity Rating Scale (C-SSRS), a questionnaire using a detailed branched logic algorithm evaluating participant's suicidality ideation and behavior. Answer "yes" on item 4 or 5 of the Suicidal Ideation section or "yes" on any item of the Suicidal Behavior section was considered positive.	Baseline up to study termination approximately 617 days

External Links

•   Generation Program Website