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A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment
Thal LJ, Ferris SH, Kirby L, Block GA, Lines CR, Yuen E, Assaid C, Nessly ML et al.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2005-06-01
Topic: Risk, prevention and care in population studies
Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients > or =65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.
Key findings
- Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD.
- The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD.
- In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.
Why it matters
In this double-blind trial, 1,457 people aged 65 or over with mild cognitive impairment took rofecoxib 25 mg (725) or a placebo (732) daily for up to 4 years to test whether the drug "could delay a diagnosis of AD." It did not: the estimated yearly rate of an Alzheimer's diagnosis was 6.4% on rofecoxib versus 4.5% on placebo (hazard ratio 1.46, 95% CI 1.09–1.94), and memory-and-thinking and global-function scores "did not demonstrate differences between treatment groups." Together with earlier negative trials in people who already had Alzheimer's, the authors say the findings "suggest that inhibition of COX-2 is not a useful therapeutic approach in AD."
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Study details
- Participants725
- Effect size6.4%; 4.5%
- Evidence strengthHigh
How this study scored 72/100
Published in a peer-reviewed journal, and it is a randomised controlled trial.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology) |
| Journal's citation record | 3 / 4 | Neuropsychopharmacology: journal h-index 306 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A randomised controlled trial (from PubMed type “Randomized Controlled Trial”) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2005 — older than 20 years, still counted |
| Sample size | 2 / 4 | 725 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 2 / 2 | Randomised and blinded or placebo-controlled (as stated in the record) |
| Times cited | 6 / 7 | Cited 403 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 17.5 citations a year over 23 year(s) since 2005 |
| Impact for its field and year | 4 / 6 | Cited 19.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 42 other studies in this library |
| Still being cited | 2 / 4 | Cited 20 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Scott A. Reines: h-index 25 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California San Diego: institution h-index 1,852 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 15742005) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 72 / 100 | — |
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APA 7th
Thal, L. J., Ferris, S. H., Kirby, L., Block, G. A., Lines, C. R., Yuen, E., et al. (2005). A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. https://doi.org/10.1038/sj.npp.1300690
Vancouver
Thal LJ, Ferris SH, Kirby L, Block GA, Lines CR, Yuen E, et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2005. doi:10.1038/sj.npp.1300690. PMID: 15742005.
BibTeX
@article{thal2005-15742005,
author = {Thal, L. J. and Ferris, S. H. and Kirby, L. and Block, G. A. and Lines, C. R. and Yuen, E. and Assaid, C. and Nessly, M. L. and others},
title = {{A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment}},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
year = {2005},
doi = {10.1038/sj.npp.1300690},
pmid = {15742005},
url = {https://doi.org/10.1038/sj.npp.1300690}
}
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