A Study of CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (Generation S2)

Study Description

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Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: CNP520 50mg; Drug: CNP520 15mg; Other: Placebo to CNP520	Phase 2; Phase 3

Detailed Description:

The study uses a randomized, double-blind, placebo-controlled, parallel group, adaptive design with variable treatment duration in approximately 2000 cognitively unimpaired participants aged 60 to 75 years, with at least one APOE4 allele (Homozygotes or Heterozygotes) and, if Heterozygotes, with evidence of elevated brain amyloid.

The screening period is expected to last about 12 weeks. Participants will receive disclosure of their individual test results for APOE genotyping and brain amyloid status.

Treatment duration is variable (event driven trial) for at least 60 months, and up to an expected maximum of 84 months.

Participants will return to the study site every three months for drug dispensing and every six months for safety and efficacy assessments, including neuropsychological scales with input from the study partner. Brain MRI scans will be conducted at month 6 and month 12, and on a yearly basis thereafter.

The Follow-up visit will be scheduled 12 weeks after the end of the Treatment Epoch. An additional CSF and / or PET AD biomarker assessments will be conducted on a voluntary basis at year 2 and 5.

The study (also known as the Generation Study 2) is conducted as part of the Alzheimer's Prevention Initiative (API) program.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	2000 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of CNP520 in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease (AD).
Actual Study Start Date :	February 14, 2014
Estimated Primary Completion Date :	July 30, 2024
Estimated Study Completion Date :	August 30, 2024

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Arm#1: CNP520 50 mg; CNP520 50 mg capsule given p.o.	Drug: CNP520 50mg; Arm#1; Other Name: CNP520 50 mg capsule p.o. for the duration of the Treatment Epoch
Experimental: Arm#2: CNP520 15 mg; CNP520 15 mg capsule given p.o.	Drug: CNP520 15mg; Arm#2; Other Name: CNP520 15 mg capsule p.o. for the duration of Treatment Epoch
Placebo Comparator: Arm#3: Placebo; Placebo to CNP520 capsule given p.o.	Other: Placebo to CNP520; Arm#3; Other Name: Placebo to CNP520 p.o. for the duration of Treatment Epoch

Outcome Measures

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Primary Outcome Measures :

1. Time to event [ Time Frame: Through study completion, at least 5 years ]
   Event is defined as diagnosis of MCI due to AD or dementia due to AD, whichever occurs first during the course of the study, after confirmation by the adjudication committee
2. Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score [ Time Frame: Baseline to Month 60 ]
   Composite score derived from the specific tests from the Repeatable Battery for the Assessment of Neurological Status (RBANS), Mini-Mental State Examination (MMSE), Raven's Progressive Matrices

Secondary Outcome Measures :

1. Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score [ Time Frame: Baseline to Month 60 ]
   To demonstrate the effects of CNP520, vs. placebo on global clinical status
2. Change on the Total Scale score and individual neurocognitive domain index scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [ Time Frame: Baseline to Month 60 ]
   To demonstrate the effects of CNP520, vs. placebo on cognition
3. Change in the Everyday Cognition scale (ECog) total scores [ Time Frame: Baseline to Month 60 ]
   To demonstrate the effects of CNP520, vs. placebo on function reported by the participant and study partner, respectively
4. Change in cerebral amyloid angiopathy (CAA) [ Time Frame: Through study completion, at least 5 years ]
   To demonstrate the effects of CNP520 vs placebo on CAA, as measured by Magnetic Resonance Imaging (MRI)
5. Change on volume of brain regions [ Time Frame: Baseline to Month 60 ]
   To demonstrate the effects of CNP520 vs placebo on brain atrophy, as measured by volumetric Magnetic Resonance Imaging (MRI)
6. Change in amyloid deposition as measured by standardized uptake ratio (SUVR) of positron emission tomography (PET) scan with amyloid radiotracer [ Time Frame: Baseline to Months 24 and 60 ]
   To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
7. Change in CSF levels of Aβ40, Aβ42 [ Time Frame: Baseline to Months 24 and 60 ]
   To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
8. Change in CSF levels of total tau and phosphorylated tau [ Time Frame: Baseline to Months 24 and 60 ]
   To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers
9. Number of participants with adverse events as a measure of safety [ Time Frame: Through study completion, at least 5 years ]
   To demonstrate the safety and tolerability of CNP520 vs placebo
10. Change in neurofibrillary tangle burden as measured by standardized uptake ratio (SUVR) of PET scans with tau radiotracer (where available) [ Time Frame: Baseline to Months 24 and 60 ]
    To demonstrate the effects of CNP520 vs placebo on Alzheimer's Disease-related biomarkers

Eligibility Criteria

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Ages Eligible for Study:	60 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

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 may prevent the participants from completing all study requirements. -
• Current medical or neurological condition that might impact cognition or performance on cognitive assessments.
• Advanced, severe progressive or unstable disease that may interfere 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, might pose a risk to the participant, or might prevent 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, this is due to drug abuse.
• Significantly abnormal laboratory results at Screening, not as a result of a temporary condition.
• Current clinically significant ECG findings.
• Clinically relevant depigmenting or hypopigmenting conditions (e.g. albinism, vitiligo) or active / history of chronic urticaria in the past year.

Contacts and Locations

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Contacts

Contact: Novartis Pharmaceuticals	1-888-669-6682	novartis.email@novartis.com
Contact: Novartis Pharmaceuticals	+41613241111	info@generationprogram.com

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Sponsors and Collaborators

Novartis Pharmaceuticals

Amgen

Banner Alzheimer's Institute

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Additional Information:

Generation Program Website 

Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT03131453 History of Changes
Other Study ID Numbers:	CCNP520A2202J; 2016-002976-28 ( EudraCT Number )
First Posted:	April 27, 2017
Last Update Posted:	June 7, 2018
Last Verified:	June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
URL:	http://

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Placebo controlled,; APOE4 carriers,; Homozygotes,; Heterozygotes,	Brain Amyloid,; Preclinical Alzheimer's Disease (AD),; Aβ lowering,; BACE-1 inhibitor

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases	Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders