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A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease
Rachelle Smith Doody, Rema Raman, Martin Rhys Farlow, Takeshi Iwatsubo, Bruno J. Vellas, Steven Joffe, Karl D. Kieburtz, Feng He, Xiaoying Sun, Ronald G. Thomas, Paul S. S. Aisen, Eric Siemers, Gopalan Sethuraman, Richard C. Mohs. New England Journal of Medicine, 2013-07-24
Topic: Amyloid, tau and blood-test diagnosis
BACKGROUND: Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. METHODS: We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. RESULTS: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.)
Why it matters
In a trial of 1537 patients with probable Alzheimer's disease, semagacestat, a gamma-secretase inhibitor, was compared with placebo, and the trial was stopped early. Semagacestat did not improve cognition, the higher dose significantly worsened daily functioning, and it was associated with more adverse events including skin cancers and infections.
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How this study scored 58/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on strength of evidence, so that was left out: it earned 55 of the 95 points we could judge it on, which is 58 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (New England Journal of Medicine) |
| Journal's citation record | 4 / 4 | New England Journal of Medicine: journal h-index 1,505 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | — / 5 | No evidence rating recorded — left out of this score |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2013 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 7 / 7 | Cited 1,223 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 81.5 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 6 / 6 | Cited 60.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 3 / 4 | Cited 191 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Richard C. Mohs: h-index 75 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California San Diego: institution h-index 1,852 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 23883379) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 55 / 95 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 55 of the 95 points we could judge it on is 58 out of 100. |
| Total | 58 / 100 | — |
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Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 14 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Doody, R. S., Raman, R., Farlow, M. R., Iwatsubo, T., Vellas, B. J., Joffe, S., et al. (2013). A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease. New England Journal of Medicine. https://doi.org/10.1056/nejmoa1210951
Vancouver
Doody RS, Raman R, Farlow MR, Iwatsubo T, Vellas BJ, Joffe S, et al. A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease. New England Journal of Medicine. 2013. doi:10.1056/nejmoa1210951. PMID: 23883379.
BibTeX
@article{doody2013-23883379,
author = {Doody, Rachelle Smith and Raman, Rema and Farlow, Martin Rhys and Iwatsubo, Takeshi and Vellas, Bruno J. and Joffe, Steven and Kieburtz, Karl D. and He, Feng and Sun, Xiaoying and Thomas, Ronald G. and Aisen, Paul S. S. and Siemers, Eric and Sethuraman, Gopalan and Mohs, Richard C.},
title = {{A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease}},
journal = {New England Journal of Medicine},
year = {2013},
doi = {10.1056/nejmoa1210951},
pmid = {23883379},
url = {https://doi.org/10.1056/nejmoa1210951}
}
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