eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
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1/2011
vol. 7
 
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abstract:

Clinical research
Tramiprosate in mild-to-moderate Alzheimer’s disease – a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study)

Paul S. Aisen
,
Serge Gauthier
,
Steven H. Ferris
,
Daniel Saumier
,
Denis Haine
,
Denis Garceau
,
Anh Duong
,
Joyce Suhy
,
Joonmi Oh
,
Wan C. Lau
,
John Sampalis

Arch Med Sci 2011; 7, 1: 102-111
Online publish date: 2011/03/08
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Introduction: The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMEDTM) 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.
keywords:

tramiprosate, Alzheimer’s disease, amyloid, disease-modification, volumetric MRI

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