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

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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease; Cognitive Decline Due to Alzheimer Disease; Mild Cognitive Impairment Due to Alzheimer Disease	Drug: Naproxen; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Investigations of Naproxen Treatment Effects in Pre-clinical Alzheimer's Disease (INTREPAD)
• Actual Study Start Date: August 1, 2012
• Actual Primary Completion Date: March 31, 2017
• Actual Study Completion Date: July 15, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: naproxen; naproxen sodium tablets 220 mg twice daily for two years	Drug: Naproxen; pale blue oval tablets; Other Name: Naprosyn, Anaprox, Aleve
Placebo Comparator: placebo; tablets identical in appearance to naproxen tablets twice daily for two years	Drug: Placebo; pale blue oval tablets with no active ingredients, identical in appearance to naproxen intervention; Other Name: sugar pill

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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.
2. 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
3. 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
4. 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
5. 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

Eligibility Criteria

• Ages Eligible for Study: 55 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

Canada, Quebec

Douglas Hospital Research Centre

Montreal, Quebec, Canada, H4H1R3

Sponsors and Collaborators

Douglas Mental Health University Institute

McGill University

Johns Hopkins University

Investigators

• Principal Investigator: John C S Breitner, MD, MPH; Dept of Psychiatry, McGill University Faculty of Medicine

More Information

• Responsible Party: John C. S. Breitner, Director, Centre for Studies on Prevention of Alzheimer's Disease, Douglas Mental Health University Institute
• ClinicalTrials.gov Identifier: NCT02702817
• Other Study ID Numbers: INTREPAD
• First Posted: March 9, 2016
• Last Update Posted: August 1, 2017
• Last Verified: July 2017

Individual Participant Data (IPD) Sharing Statement:

• 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; 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.

Keywords provided by John C. S. Breitner, Douglas Mental Health University Institute:

Alzheimer's disease, biomarkers, cognitive decline, pre-clinical

Additional relevant MeSH terms:

Alzheimer Disease; Cognitive Dysfunction; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Naproxen; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Gout Suppressants; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action