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Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease
Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE et al.. Archives of neurology, 2008-08-01
Topic: Amyloid, tau and blood-test diagnosis
Objective To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. Design Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. Setting Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. Main outcome measures Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. Results Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P Conclusions LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.
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APA 7th
Fleisher, A. S., Raman, R., Siemers, E. R., Becerra, L., Clark, C. M., Dean, R. A., et al. (2008). Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Archives of neurology. https://doi.org/10.1001/archneur.65.8.1031
Vancouver
Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, et al. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Archives of neurology. 2008. doi:10.1001/archneur.65.8.1031. PMID: 18695053.
BibTeX
@article{fleisher2008-18695053,
author = {Fleisher, A. S. and Raman, R. and Siemers, E. R. and Becerra, L. and Clark, C. M. and Dean, R. A. and Farlow, M. R. and Galvin, J. E. and others},
title = {{Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease}},
journal = {Archives of neurology},
year = {2008},
doi = {10.1001/archneur.65.8.1031},
pmid = {18695053},
url = {https://doi.org/10.1001/archneur.65.8.1031}
}
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Key findings
- Main outcome measures Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results.
- Results Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups.
Why it matters
This phase 2 safety trial of 51 individuals with mild to moderate Alzheimer disease found that the gamma-secretase inhibitor LY450139 reduced plasma Abeta(40) concentration and was associated with skin and subcutaneous tissue concerns, including possible drug rashes and reports of hair color change. The study was designed primarily to assess safety and tolerability, not to determine whether the treatment improves symptoms.
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Study details
- Participants15
- Effect sizereduced by 58.2%; 64.6%
- Evidence strengthHigh
How this study scored 69/100
Published in a peer-reviewed journal, and it is a mid-stage phase 2 trial.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Archives of neurology) |
| Journal's citation record | 3 / 4 | Archives of Neurology: journal h-index 353 (OpenAlex, 2026-10-29) |
| Study design | 8 / 12 | A mid-stage phase 2 trial (from PubMed type “Clinical Trial, Phase II”) |
| 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 | 2008 — within 20 year(s) of the newest study here |
| Sample size | 1 / 4 | 15 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 332 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.6 citations a year over 20 year(s) since 2008 |
| Impact for its field and year | 5 / 6 | Cited 23.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 8 other studies in this library |
| Still being cited | 1 / 4 | Cited 7 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Leon J. Thal: h-index 90 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 18695053) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 69 / 100 | — |
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