This trial is active, not recruiting.

Conditions alzheimer disease, cognitive decline due to alzheimer disease, mild cognitive impairment due to alzheimer disease
Treatments naproxen, placebo
Phase phase 2
Sponsor Douglas Mental Health University Institute
Collaborator McGill University
Start date August 2012
End date March 2017
Trial size 200 participants
Trial identifier NCT02702817, INTREPAD


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.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose prevention
(Active Comparator)
naproxen sodium tablets 220 mg twice daily for two years
naproxen Naprosyn, Anaprox, Aleve
pale blue oval tablets
(Placebo Comparator)
tablets identical in appearance to naproxen tablets twice daily for two years
placebo sugar pill
pale blue oval tablets with no active ingredients, identical in appearance to naproxen intervention

Primary Outcomes

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)

Secondary Outcomes

frequency and severity of treatment-emergent adverse events
time frame: collected in real-time over two years following RZ
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
biomarkers of inflammatory processes
time frame: measured at three months and annually thereafter for two years following RZ, with further two years delayed washout
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)

Eligibility Criteria

Male or female participants at least 55 years old.

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

Additional Information

Official title Investigations of Naproxen Treatment Effects in Pre-clinical Alzheimer's Disease (INTREPAD)
Principal investigator John C S Breitner, MD, MPH
Description The trial has enrolled 200 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 may be admitted if their current age is <= 15 years younger than AD onset in their index relative. Such persons are at approximately 3-fold increased risk of AD dementia. We expect a majority of them to show evidence of progressive pre-clinical AD. Participants are 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 are 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 have also volunteered to undergo a series of lumbar punctures for donation of cerebrospinal fluid (CSF), which is 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 is that administration of naproxen will not only suppress these inflammatory markers but will also slow or reverse the progress of change in cognition and in biomarkers of the pre-clinical stage of AD. Upon completion of two years of treatment, participants are to be 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.
Trial information was received from ClinicalTrials.gov and was last updated in March 2016.
Information provided to ClinicalTrials.gov by Douglas Mental Health University Institute.