Alzheimer DiseasePhase 2NCT02702817
Randomized Trial of Low-dose Naproxen in Cognitively Intact Persons at Risk of Alzheimer's Dementia
A Phase 2 study testing Naproxen in people with Alzheimer Disease and Cognitive Decline Due to Alzheimer Disease, run by Douglas Mental Health University Institute at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 55 years and olderHealthy volunteers can take part
- Conditions the study is for
- Alzheimer Disease, Cognitive Decline Due to Alzheimer Disease, Mild Cognitive Impairment Due to Alzheimer Disease
- What is being tested?
- Naproxen
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 200 participants
- Where
- 1 siteCanada
- Study dates
- 1 Aug 2012to 15 Jul 2017
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Investigations of Naproxen Treatment Effects in Pre-clinical Alzheimer's Disease (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.
Read the 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.
- Conditions
- Alzheimer Disease, Cognitive Decline Due to Alzheimer Disease, Mild Cognitive Impairment Due to Alzheimer Disease
- Being tested
- Naproxen, Placebo
- Keywords
- Alzheimer's disease, biomarkers, cognitive decline, pre-clinical
- Medical subject headings
- Alzheimer Disease, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NaproxenDrug
Also called Naprosyn, Anaprox, Aleve
pale blue oval tablets
PlaceboDrug
Also called sugar pill
pale blue oval tablets with no active ingredients, identical in appearance to naproxen intervention
| Study group | Role | What they receive |
|---|---|---|
| naproxen | Active comparator | naproxen sodium tablets 220 mg twice daily for two years Receives: Drug: Naproxen |
| placebo | Placebo comparator | tablets identical in appearance to naproxen tablets twice daily for two years Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Trajectory of composite Alzheimer Progression Score (APS) from multiple cognitive and biomarker measures of pre-clinical Alzheimer's disease
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
Measured: Two years for primary outcome, with intent to follow participants off-treatment for two-year observational delayed washout
Secondary outcomes (5)
frequency and severity of treatment-emergent adverse events
classified by organ system involvement and need for treatment interruption or cessation.
Measured: collected in real-time over two years following RZ
trajectory of cognitive abilities measured by global score on Repeatable Battery for Assessment of Neuropsychological Status
global score of primary interest, although individual scale scores will be used in secondary analyses
Measured: observed at baseline, annually thereafter over two years following randomization (RZ), and two years further (delayed washout)
ratio of total and protein-bound naproxen concentrations as well as kinetics of drug accumulation and washout
estimate of blood brain barrier permeability and rapidity of drug accumulation and washout in both plasma and CSF partitions
Measured: estimated at three months and annually thereafter for two years following RZ, with further two years delayed washout
biomarkers of inflammatory processes
quantitative measures of 44 different inflammatory cytokines measured in plasma, and in CSF when available
Measured: measured at three months and annually thereafter for two years following RZ, with further two years delayed washout
CSF biomarkers of AD pathogenesis
concentrations of total tau protein, phosphorylated tau protein, Amyloid beta 1-40 and Amyloid beta 1-42, apolipoprotein E
Measured: observed at baseline, after three months, and annually thereafter over two years following randomization (RZ), and two years thereafter off-treatment (delayed washout)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Mar 2016 (estimated)
- Study start1 Aug 2012
- Primary completion31 Mar 2017
- Study completion15 Jul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 200 participants (actual)
Sponsor and investigators
- Lead sponsor
- Douglas Mental Health University Institute
- Sponsor type
- University, hospital or other
- Collaborators
- McGill University, Johns Hopkins University
- Responsible party
- Principal investigator, John C. S. Breitner, Douglas Mental Health University Institute
- Investigators
- John C S Breitner, MD, MPH, Principal investigator, Dept of Psychiatry, McGill University Faculty of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02702817
- Sponsor's protocol ID
- INTREPAD
- Status last verified
- Jul 2017
- First submitted
- 19 Dec 2015
- Last updated
- 1 Aug 2017
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Only de-identified data will be made available, after completion of trial including delayed washout phase.
Study at a glance
From the registry record, last updated by the sponsor on 1 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigations of Naproxen Treatment Effects in Pre-clinical Alzheimer's Disease (INTREPAD)
- ClinicalTrials.gov ID
- NCT02702817
- Acronym / sponsor ID
- INTREPAD
- Conditions
- Alzheimer Disease, Cognitive Decline Due to Alzheimer Disease, Mild Cognitive Impairment Due to Alzheimer Disease
- Keywords
- Alzheimer's disease, biomarkers, cognitive decline, pre-clinical
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 200 participants (actual)
- Lead sponsor
- Douglas Mental Health University InstituteUniversity, hospital or other
- Collaborators
- McGill University, Johns Hopkins University
- Study start
- 1 Aug 2012 (actual)
- Primary completion
- 31 Mar 2017 (actual)
- Study completion
- 15 Jul 2017 (actual)
- First posted
- 9 Mar 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| naproxen | Active comparator | Drug: Naproxennaproxen sodium tablets 220 mg twice daily for two years |
| placebo | Placebo comparator | Drug: Placebotablets identical in appearance to naproxen tablets twice daily for two years |
Who may qualify
- Ages
- 55 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NaproxenAlso: Naprosyn, Anaprox, Alevepale blue oval tablets | Drug | naproxen |
| PlaceboAlso: sugar pillpale blue oval tablets with no active ingredients, identical in appearance to naproxen intervention | Drug | placebo |
Primary outcome
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
5 secondary outcomes
frequency and severity of treatment-emergent adverse events
Time frame: collected in real-time over two years following RZ
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)
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Aug 2017.
- Individual participant dataSharing planned: Yes. Only de-identified data will be made available, after completion of trial including delayed washout phase.
Related trials for Alzheimer Disease
RecruitingPhase 2
Neuroplasticity Enhancement From Cognitive Training Reinforced by Psilocybin
Alzheimer's Disease
Not yet recruiting
Acupressure as Long-term Intervention to Slow the Progression of Early/Mild Alzheimer's Disease
Alzheimer's Disease
RecruitingObservational study
Effectiveness and Safety of Disease-Modifying Therapy for Alzheimer's Disease: A Multicenter Retrospective Study
Alzheimer's Disease (AD)
RecruitingPhase 3
A Phase 3 Study to Evaluate the Safety and Efficacy of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease (ADAGIO-1)
Alzheimer Disease
RecruitingPhase 3
A Study of Trontinemab in Cognitively Unimpaired Individuals at Risk for Progression to Symptomatic Alzheimer's Disease
Alzheimer's Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John C S Breitner, MD, MPH principal investigator
Dept of Psychiatry, McGill University Faculty of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Naproxen in people with Alzheimer Disease and Cognitive Decline Due to Alzheimer Disease, run by Douglas Mental Health University Institute at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2017.