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Randomized Trial of Low-dose Naproxen in Cognitively Intact Persons at Risk of Alzheimer's Dementia

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ClinicalTrials.gov Identifier: NCT02702817
Recruitment Status : Completed
First Posted : March 9, 2016
Last Update Posted : August 1, 2017
Sponsor:
Collaborators:
McGill University
Johns Hopkins University
Information provided by (Responsible Party):
John C. S. Breitner, Douglas Mental Health University Institute

Tracking Information
First Submitted Date  ICMJE December 19, 2015
First Posted Date  ICMJE March 9, 2016
Last Update Posted Date August 1, 2017
Actual Study Start Date  ICMJE August 1, 2012
Actual Primary Completion Date March 31, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 29, 2017)
Trajectory of composite Alzheimer Progression Score (APS) from multiple cognitive and biomarker measures of pre-clinical Alzheimer's disease [ Time Frame: Two years for primary outcome, with intent to follow participants off-treatment for two-year observational delayed washout ]
Summary score derived using latent trait Item Response Theory analyses, trajectory estimated from mixed effects models based on multiple individual markers observed at baseline, three months, 12 months, and 24 months following randomization
Original Primary Outcome Measures  ICMJE
 (submitted: March 3, 2016)
  • trajectory of cognitive abilities measured by global score on Repeatable Battery for Assessment of Neuropsychological Status [ Time Frame: observed at baseline, annually thereafter over two years following randomization (RZ), and two years further (delayed washout) ]
  • Composite Alzheimer Progression Score (APS) derived from multiple cognitive and biomarker measures of pre-clinical Alzheimer's disease [ Time Frame: observed at baseline, after three months, and annually thereafter over two years following randomization (RZ), and two years thereafter off-treatment (delayed washout) ]
    variable derived using latent trait Item Response Theory analyses, and representing progression of pre-clinical disease process
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 29, 2017)
  • frequency and severity of treatment-emergent adverse events [ Time Frame: collected in real-time over two years following RZ ]
    classified by organ system involvement and need for treatment interruption or cessation.
  • trajectory of cognitive abilities measured by global score on Repeatable Battery for Assessment of Neuropsychological Status [ Time Frame: observed at baseline, annually thereafter over two years following randomization (RZ), and two years further (delayed washout) ]
    global score of primary interest, although individual scale scores will be used in secondary analyses
  • ratio of total and protein-bound naproxen concentrations as well as kinetics of drug accumulation and washout [ Time Frame: estimated at three months and annually thereafter for two years following RZ, with further two years delayed washout ]
    estimate of blood brain barrier permeability and rapidity of drug accumulation and washout in both plasma and CSF partitions
  • biomarkers of inflammatory processes [ Time Frame: measured at three months and annually thereafter for two years following RZ, with further two years delayed washout ]
    quantitative measures of 44 different inflammatory cytokines measured in plasma, and in CSF when available
  • CSF biomarkers of AD pathogenesis [ Time Frame: observed at baseline, after three months, and annually thereafter over two years following randomization (RZ), and two years thereafter off-treatment (delayed washout) ]
    concentrations of total tau protein, phosphorylated tau protein, Amyloid beta 1-40 and Amyloid beta 1-42, apolipoprotein E
Original Secondary Outcome Measures  ICMJE
 (submitted: March 3, 2016)
  • frequency and severity of treatment-emergent adverse events [ Time Frame: collected in real-time over two years following RZ ]
    classified by organ system involvement and need for treatment interruption or cessation.
  • ratio of total and protein-bound naproxen concentrations as well as kinetics of drug accumulation and washout [ Time Frame: estimated at three months and annually thereafter for two years following RZ, with further two years delayed washout ]
    estimate of blood brain barrier permeability and rapidity of drug accumulation and washout in both plasma and CSF partitions
  • biomarkers of inflammatory processes [ Time Frame: measured at three months and annually thereafter for two years following RZ, with further two years delayed washout ]
    quantitative measures of 44 different inflammatory cytokines measured in plasma, and in CSF when available
  • CSF biomarkers of AD pathogenesis [ Time Frame: observed at baseline, after three months, and annually thereafter over two years following randomization (RZ), and two years thereafter off-treatment (delayed washout) ]
    concentrations of total tau protein, phosphorylated tau protein, Amyloid beta 1-40 and Amyloid beta 1-42, apolipoprotein E
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized Trial of Low-dose Naproxen in Cognitively Intact Persons at Risk of Alzheimer's Dementia
Official Title  ICMJE Investigations of Naproxen Treatment Effects in Pre-clinical Alzheimer's Disease (INTREPAD)
Brief Summary Two-year double-masked trial of over-the-counter dosage of naproxen sodium vs placebo in 200 cognitively normal participants with a parental or multiplex first-degree family history Alzheimer's disease (AD) dementia. Primary outcomes are decline in cognitive function and slope of change in a summary Alzheimer Progression Score derived from serial assessment of neuroimaging, biochemical, and sensori-neural biomarker indicators of pre-clinical disease -- all believed likely to reflect progress of preclinical AD in this high risk cohort. Approximately 2/3 of participants have volunteered also for serial lumbar punctures for analysis of cerebrospinal fluid. A two-year off-treatment delayed-washout phase is planned to examine sustained treatment effects and evidence of disease modification.
Detailed Description The trial enrolled 195 cognitively normal persons aged 60+ with either a parental history of AD or a history of two or more affected first-degree relatives. Persons aged 55-59 were admitted if their current age was <= 15 years younger than AD onset in their index relative. Such persons are believed to be at approximately 3-fold increased risk of AD dementia. We expected a majority of them to show evidence of progressive pre-clinical AD. Participants were randomized 1:1 to receive the common non-steroidal anti-inflammatory drug (NSAID) naproxen in over-the-counter dosage (naproxen sodium 220 mg) or identical-appearing placebo tablets twice daily. At baseline and at three follow-up visits (3 months, 12 months and 24 months after randomization) they were tested for cognitive abilities and undergo brain imaging with both structural and functional MRI. They are also tested for sensori-neural capacities in olfactory identification and in the ability to discern spoken language in a distracting environment (to test central auditory processing). About 2/3 of participants also volunteered to undergo a series of lumbar punctures for donation of cerebrospinal fluid (CSF), which was assayed for several biochemical markers of AD that are now understood to be present for a decade or longer before the onset of symptoms. As well, their plasma and CSF are assayed for presence of naproxen and for numerous markers of inflammatory processes (cytokines and chemokines). The central hypothesis was that administration of naproxen would not only suppress these inflammatory markers but would also slow or reverse the progress of change in cognition and in biomarkers of the pre-clinical stage of AD. The analysis plan followed the principle of modified Intent-to-Treat, considering outcomes for all persons who had at least one follow-up examination while on-protocol. After completion of two years of treatment, these participants are being followed for a further two years to observe whether treatment-related changes are sustained -- indicating that the treatment effects represent modification of the disease process itself, as opposed to a temporary change in brain function.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Alzheimer Disease
  • Cognitive Decline Due to Alzheimer Disease
  • Mild Cognitive Impairment Due to Alzheimer Disease
Intervention  ICMJE
  • Drug: Naproxen
    pale blue oval tablets
    Other Name: Naprosyn, Anaprox, Aleve
  • Drug: Placebo
    pale blue oval tablets with no active ingredients, identical in appearance to naproxen intervention
    Other Name: sugar pill
Study Arms  ICMJE
  • Active Comparator: naproxen
    naproxen sodium tablets 220 mg twice daily for two years
    Intervention: Drug: Naproxen
  • Placebo Comparator: placebo
    tablets identical in appearance to naproxen tablets twice daily for two years
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 3, 2016)
200
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 15, 2017
Actual Primary Completion Date March 31, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • good physical health including normal hemoglobin and hematocrit
  • history or documentation of AD dementia in at least one parent, or in two siblings
  • cognitive performance without diagnosable deficit such as dementia, "mild cognitive impairment"
  • must have spouse or companion able to accompany participant for clinic visits
  • six or more years of formal education
  • fluent in either English or French
  • provision of informed consent

Exclusion Criteria:

  • no current peptic ulcer disease
  • no history of prior peptic ulcer with bleed, perforation, intestinal obstruction
  • no major psychiatric disturbance
  • no regular use (4 or more doses per week) of aspirin, other non-steroidal anti-inflammatory drug (NSAID), opiate or other pain medication
  • no use, present or past, of acetylcholinesterase inhibitors or memantine
  • no regular use of vitamin E at dosage of 600 i.u.
  • no drug or alcohol dependence
  • no allergy to NSAIDs or sulfa antibiotics
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02702817
Other Study ID Numbers  ICMJE INTREPAD
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Only de-identified data will be made available, after completion of trial including delayed washout phase.
Supporting Materials: Study Protocol
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Data will be available for completed trial in March, 2018. Data for delayed washout / continuation phase will be made available at biennial intervals thereafter
Access Criteria: Qualified personnel should contact principal investigator and Study Coordinator for Data Sharing Agreement form, which must be completed and reviewed prior to release of data.
Responsible Party John C. S. Breitner, Douglas Mental Health University Institute
Study Sponsor  ICMJE Douglas Mental Health University Institute
Collaborators  ICMJE
  • McGill University
  • Johns Hopkins University
Investigators  ICMJE
Principal Investigator: John C S Breitner, MD, MPH Dept of Psychiatry, McGill University Faculty of Medicine
PRS Account Douglas Mental Health University Institute
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP