INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease

Abstract

Objective: To evaluate the safety and efficacy of low-dose naproxen for prevention of progression in presymptomatic Alzheimer disease (AD) among cognitively intact persons at risk.

Methods: Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease (INTREPAD), a 2-year double-masked pharmaco-prevention trial, enrolled 195 AD family history-positive elderly (mean age 63 years) participants screened carefully to exclude cognitive disorder (NCT-02702817). These were randomized 1:1 to naproxen sodium 220 mg twice daily or placebo. Multimodal imaging, neurosensory, cognitive, and (in ∼50%) CSF biomarker evaluations were performed at baseline, 3, 12, and 24 months. A modified intent-to-treat analysis considered 160 participants who remained on-treatment through their first follow-up examination. The primary outcome was rate of change in a multimodal composite presymptomatic Alzheimer Progression Score (APS).

Results: Naproxen-treated individuals showed a clear excess of adverse events. Among treatment groups combined, the APS increased by 0.102 points/year (SE 0.014; p < 10^-12), but rate of change showed little difference by treatment assignment (0.019 points/year). The treatment-related rate ratio of 1.16 (95% confidence interval 0.64-1.96) suggested that naproxen does not reduce the rate of APS progression by more than 36%. Secondary analyses revealed no notable treatment effects on individual CSF, cognitive, or neurosensory biomarker indicators of progressive presymptomatic AD.

Conclusions: In cognitively intact individuals at risk, sustained treatment with naproxen sodium 220 mg twice daily increases frequency of adverse health effects but does not reduce apparent progression of presymptomatic AD.

Classification of evidence: This study provides Class I evidence that, for people who are cognitively intact, low-dose naproxen does not significantly reduce progression of a composite indicator of presymptomatic AD.

Figure 1. Consort flow

Fragile cognitive status indicates individuals with cognitive deficits suggestive of early mild cognitive impairment. GI = gastrointestinal; mITT = modified intent-to-treat; SAE = serious adverse event.

Figure 2. Trial timeline

Full assessment (on site): baseline (BL), 3 months, 12 months, 24 months. Safety follow-up (on site): 1 month, 6 months, 18 months. Safety follow-up (telephone): 9 months, 15 months, 21 months. ** T1-weighted (EN, BL, 3 months, 12 months, 24 months), fluid-attenuated inversion recovery (EN, 24 months), diffusion-weighted imaging (EN, 24 months), arterial spin labeling (BL, 3 months, 12 months, 24 months), resting-state fMRI (BL, 3 months, 12 months, 24 months), gradient echo quantitative T2* task (BL, 3 months, 12 months, 24 months), task fMRI (BL, 3 months, 12 months, 24 months). EN = enrollment; LP = lumbar puncture; RBANS = repeatable battery for assessment of neuropsychological status; UPSIT = University of Pennsylvania Smell Identification Test.

Figure 3. Treatment effects on Alzheimer Progression Score (APS)

Results for primary and exploratory secondary outcomes are represented. (A) There was no meaningful difference in APS rate of change between treatment groups. (B) Mean change from baseline (± standard error of the mean) in APS did not differ between the 2 treatment groups at any time during the treatment interval. However, APS for both groups increased after 12 and 24 months (*p < 0.05). Data are represented as point estimates (group means) with error bars (standard error of the mean). BL = Baseline; M = months.

Figure 4. Treatment effects on neurosensory and CSF biomarker measures

Linear mixed effect models did not indicate any difference between naproxen- and placebo-assigned groups in rate of change of (A) cognitive or neurosensory or (B) biological markers of Alzheimer disease. University of Pennsylvania Smell Identification Test (UPSIT) scores decreased over the 2-year trial period for the whole group (*p < 0.05). Data are represented as point estimates (group means) with error bars (standard error of the mean). BL = baseline; p-tau = phosphorylated tau; RBANS = Repeatable Battery for the Assessment of Neuropsychological Status; t-tau = total tau.