Lessons learned in the use of volumetric MRI in therapeutic trials in Alzheimer's disease: The Alzhemedtm (Tramiprosate) experience

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

doi:10.1007/s12603-009-0047-4

Cited by 33 publications

(14 citation statements)

References 20 publications

(25 reference statements)

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“…Psychometric tests and vMRI may not measure precisely the same disease processes, and changes in biological and cognitive measures may not occur over the same time period [17, 30]. Nevertheless, volumetric MRI and cognitive measures are complementary and may be implemented in AD trials in order to document potential treatment effects on the underlying disease and to provide regulatory support for disease modification claims.…”

Section: Discussionmentioning

confidence: 99%

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

Aisen¹,

Gauthier²,

Ferris³

et al. 2011

aoms

236

146

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IntroductionThe 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 methodsDouble-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. ResultsA 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. ConclusionsThe 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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Section: Discussionmentioning

confidence: 99%

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

Aisen¹,

Gauthier²,

Ferris³

et al. 2011

aoms

236

146

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show abstract

“…Despite some early hopes, brain Aβ burden, measured with amyloid PET or in CSF, does not correlate well with disease severity and has not yet been proven an effective surrogate outcome [42, 43]. Several counterintuitive results in which increased brain atrophy was reported in response to anti-Aβ therapy [44–49] have also ruled out volumetric magnetic resonance imaging (MRI) measures as satisfactory surrogate markers for therapeutic Aβ reduction. However, MR measures may still be a highly useful outcome measure for neuroprotective interventions.…”

Section: Introductionmentioning

confidence: 99%

The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

Weiner

Veitch

Aisen

et al. 2016

Alzheimer's & Dementia

309

277

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INTRODUCTION The overall goal of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer’s disease (AD) clinical trials. ADNI-3, beginning August 1, 2016, is a five year renewal of the current ADNI-2 study. METHODS ADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment (MCI) and AD using innovative technologies such as tau imaging, magnetic resonance imaging (MRI) sequences for connectivity analyses, and a highly-automated immunoassay platform and mass spectroscopy approach for CSF biomarker analysis. A Systems Biology/Pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography (PET) scanning will be standardized using by the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition. RESULTS Multi-modal analyses will provide insight into AD pathophysiology and disease progression. DISCUSSION ADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.

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“…First, one can take the view that this trial did not prove that tramiprosate does not work, and certainly, one should not be discouraged from looking for other small molecules to treat AD. The trial, however, illustrates the confounding factors involved in testing any medicine, such as the use of other medications, indeterminate defi nitions of what a "control" group really is, and vagaries in the use of any endpoint, including the ones used in this study, as shown by the fact that the control group showed cognitive improvement over the test period (Wong 2007;Saumier et al 2009 ) . Underlying all of these problems is a lack of fundamental understanding of the mechanism of how the agent is supposed to work.…”

Section: Small Molecules In Clinical Trialsmentioning

confidence: 97%

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Lanning

Meredith

2011

Non-Fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

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Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid b -protein (A b ), huntingtin, a -synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the fi rst group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or a 1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include A b , islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are "peptide-like" in having domains with no unique, stable

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Lessons learned in the use of volumetric MRI in therapeutic trials in Alzheimer's disease: The Alzhemedtm (Tramiprosate) experience

Cited by 33 publications

References 20 publications

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

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

The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

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