Tramiprosate in mild-to-moderate Alzheimer's disease — a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study)
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INTRODUCTION: The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMED(TM)) in mild-to-moderate Alzheimer's disease (AD). MATERIAL AND METHODS: Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. INTERVENTION: 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. MEASUREMENTS: Alzheimer Disease Assessment Scale - cognitive subscale (ADAS-cog) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. RESULTS: A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. CONCLUSIONS: The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.
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An agent claimed to inhibit Aβ oligomer formation did not meet its primary endpoint and further development was discontinued.
“An agent claimed to inhibit Aβ oligomer formation did not meet its primary endpoint and further development was discontinued [257, 258].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [257]
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“…being explained by methodological difficulties, including the inclusion 58 of participants that are already in the later stages of the disease progression, and the selection 59 of outcome measures - such as dementia conversion rate - which are not sensitive enough 60 (Aisen et al., 2011).”
Background
- Authors
- Aisen, P. S., Gauthier, S., Ferris, S. H., Saumier, D., Haine, D., Garceau, D., Duong, A., Suhy, J., Oh, J., Lau, W. C., & Sampalis, J.
- Affiliations
- University of California San Diego (US)
- McGill University Research Centre for Studies in Aging (CA)
- Nathan Kline Institute for Psychiatric Research (US)
- McGill University (CA)
- Bellus Health (Canada) (CA)
- McGill University Health Centre (CA)
- Corresponding author
- Duong, Anh
- Venue
- Archives of Medical Science
- Publisher
- Termedia Sp. z.o.o.
- Published
- 2011
- Volume
- 1
- Issue
- 1
- Pages
- 102-111
- ISSN
- 1734-1922 (ISSN-L)
- PMC
- PMC3258678
- OpenAlex
- W2048780418
- Cited by
- 295
- References
- 27
- Citations by year
- 2026: 22 · 2025: 14 · 2024: 23 · 2023: 15 · 2022: 20 · 2021: 21 · 2020: 19 · 2019: 19 · 2018: 18 · 2017: 20 · 2016: 19 · 2015: 20 · 2014: 26 · 2013: 19 · 2012: 13
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- Archives of Medical Science (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG008051)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- tramiprosate, homotaurine, Alzheimer's disease, disease-modifying therapy, hippocampal atrophy, cognitive decline, ADAS-Cog, Clinical Dementia Rating, cholinesterase inhibitors, memantine, drug safety
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