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The efficacy, safety and disease-modification of tramiprosate (homotaurine)were investigated in a recently completed large-scale Phase III clinical study in patients with mild to moderate Alzheimer's disease (AD), the Alphase study. Disease-modification was assessed using longitudinal volumetric MRI (vMRI) measurements of the hippocampus in a subgroup of patients. The present study describes the vMRI, cognitive and clinical results obtained in this subgroup. Multi-center, double-blind, randomized, placebocontrolled study in a subset of the 1052 patients of the Alphase study. 51 vMRI investigative sites in the United States and Canada. A total of 508 patients underwent vMRI scanning. Of these, 312 provided scan pairs for assessing hippocampus volume changes and were included in the analyses. Patients were randomized to receive Placebo BID (n = 109), tramiprosate 100 mg BID (n = 103), or tramiprosate 150 mg BID (n = 100) for 78 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum-of-boxes CDR-SB assessments were conducted at Baseline and at Weeks 13, 26, 39, 52, 65 and 78. Exploratory analyses were performed using similar First and Final mixed-effects repeated-measures models that were used for the analysis of the entire patient dataset. Psychometric score results showed numerical trends in favour of tramiprosate that did not reach statistical significance. While there were no statistically significant group differences in hippocampus volume using the First modeling approach, a significant dose-response reduction in hippocampus volume change was found in the Final models. Moreover, there was a marginally significant overall treatment main effect and a significant slope difference in favour of tramiprosate according to the Final model analysis of the ADAS-cog scores. ADAS-cog scores analyzed according to this model also revealed differences in favor of the tramiprosate 150 mg group at weeks 26 and 52, with marginally significant differences at Weeks 13 and 39. Slope analyses of ADAS-cog score changes showed significant differences in favor of the 150 mg BID group, and when both active groups were combined, in comparison to the placebo group. No between-group differences with respect to changes to each visit in the CDR-SB were observed with either modeling approach. Although there was a similar dose-response relationship observed in the hippocampus volume and ADAS-cog Final model analyses, the overall changes in psychometric scores and hippocampus volume were not significantly correlated. Exploratory analysis of the vMRI subgroup suggests that tramiprosate slows hippocampal atrophy, and reveals some evidence of a beneficial effect on cognition. The clinical validity of the vMRI biomarker is discussed.

Tramiprosate (homotaurine, ALZHEMED™) was recently investigated for its efficacy, safety and disease-modification effects in a Phase III clinical study in mild to moderate Alzheimer's disease (AD) patients (the Alphase study). The primary cognitive endpoint measure of that study was the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). To characterize potential cognitive benefits of tramiprosate, the present study describes exploratory analyses performed on scores obtained from the specific ADAS-cog subscales in order to determine whether specific domains of cognition may be differentially affected by tramiprosate, which would not have been evident from the measure's total score. Multi-center, double-blind, randomized, placebo-controlled study. 67 investigative sites in the United States and Canada. A total of 1,052 patients were randomized. Interventions: Patients were randomized to receive twice a day Placebo (n=353), tramiprosate 100 mg (n=352) and tramiprosate 150 mg (n=347). ADAS-cog assessments were conducted every three months over the 78-week study period. Exploratory analyses were performed by comparing ADAS-cog subscale scores between Placebo and each active treatment arm at each visit. The findings of this analysis revealed statistically significant differences or statistical trends in favour of tramiprosate on six ADAS-cog subscales, namely Following Commands, Language Comprehension, Ideational Praxis, Object Naming, Remembering Test Instructions, and Spoken Language Ability. Differences in favor of Placebo were only observed on the Constructional Praxis subscale. This exploratory analysis suggests that tramiprosate may have some benefit on memory, language and praxis skills in mild to moderate AD individuals. Future clinical studies of tramiprosate should include specialized neuropsychological tests to validate its effects within these cognitive domains.

Background Traumatic stress is a global mental health problem requiring novel, easily implemented treatment solutions. We compared the effectiveness and efficiency of Reconsolidation Therapy (RT) to the well-established antidepressant paroxetine, in reducing symptoms of traumatic stress among patients from Nepal, a low-income country. Methods Forty-six adults with posttraumatic stress disorder (PTSD) were randomized to one of two groups. The reconsolidation blocker propranolol was administered 90 min before briefly recalling a traumatic memory with a therapist, weekly for six consecutive weeks. This was compared to daily paroxetine for 26 weeks. Self-reported PTSD symptoms were assessed blindly at the 7th, 13th, and 26th weeks. Results An intent-to-treat analysis revealed a robust pre- to post-treatment main effect ( β 1  = − 4.83, 95% CI  = [− 5.66, − 4.01], p  < .001), whereby both groups improved, with Cohen’s effect sizes of d  = 2.34 (95% CI  = [1.57, 3.12]) for paroxetine, and of 2.82 (95% CI  = [1.98, 3.66]) for RT after 7 weeks, suggesting treatment effectiveness for both groups in a real-world setting. Three and six-month follow-up yielded further significant improvement in both groups, which did not differ from each other. Conclusion RT also displayed promising efficiency, considering that it had been discontinued weeks earlier while the paroxetine treatment was continued, as recommended. RT could be taught in low-income countries as part of the local therapeutic resources to treat the core symptoms of PTSD, provided that such results are replicated on a broader scale. Trial registration ISRCTN34308454 (11/10/2017).

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). 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. 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. 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. 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. 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.

ABSTRACT Background: Tramiprosate (3-amino-1-propanesulfonic acid, 3APS, ALZHEMED™) is an investigational product candidate that is believed to reduce amyloid deposition in the brain by binding to soluble Aβ, thereby slowing or halting the progression of Alzheimer Disease (AD). Design and Methods: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic profiles of tramiprosate in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or tramiprosate 50, 100, or 150 mg BID for 3 months. At the end of the double-blind study, 42 of these patients entered an open-label extension study in which they received tramiprosate 150 mg BID for an additional 17 months. Assessments included plasma and CSF tramiprosate concentrations, CSF Aβ42 concentrations, and psychometric tests (Alzheimer's Disease Assessment Scale – cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating Scale – Sum of Boxes). Results: Tramiprosate had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild-to-moderate in severity. Overall, six tramiprosate-treated patients discontinued because of side effects (all causalities) and there were no drug-related serious adverse events. Tramiprosate crossed the blood–brain barrier and dose-dependently reduced CSF Aβ42 levels after 3 months of treatment. There were no psychometric score differences between treatment groups after 3 months of double-blind treatment. However, psychometric score changes over the 17-month open-label extension study are consistent with a slowing of cognitive and clinical decline, particularly in mild subjects. Interpretation: Long-term administration of tramiprosate is safe and tolerated in patients with mild-to-moderate AD. The short-term reduction of CSF Aβ42 levels and the long-term open-label cognitive and clinical assessments are consistent with disease-modification.

A visual search experiment using synthetic three-dimensional objects is reported. The target shared its constituent parts, the spatial organization of its parts, or both with the distractors displayed with it. Sharing of parts and sharing of spatial organization both negatively affected visual search performance, and these effects were strictly additive. These findings support theories of complex visual object perception that assume a parsing of the stimulus into its higher-order constituents (volumetric parts or visible surfaces). The additivity of the effects demonstrates that information on parts and information on spatial organization are processed independently in visual search.

Objectives: To examine whether the presence of domain-specific cognitive impairments would predict a response to donepezil medication in patients with mild-to-moderate Alzheimer disease (AD). Methods: The protocol was an open-label study of 30 AD subjects (mean age 74 years; education 11 years; Mini-Mental State Exam (MMSE) 23 of 30) beginning a 6-month course of treatment with donepezil. Global response to treatment was determined using a combination algorithm based on changes over 6 months in the ADAS-cog, MMSE and CIBIC. In addition, a set of neuropsychological and experimental cognitive tests designed to test five domains of cognition were administered before beginning therapy in order to determine which domain of testing would be predictive to response to treatment. The tests examined attention, short-term and working memory, learning and memory, visuo-spatial motor skills, and lexical-semantic knowledge. Results: Eighteen of the thirty subjects were rated as having responded (stable or improved scores on the combination algorithm) to the therapy. Responders were significantly less impaired prior to treatment on the following tests: the Clock Drawing Test, a Visual-Spatial Motor Tracking Test, and the Boston Picture Naming Test. No significant initial group differences were noted on the other neuropsychological or experimental cognitive measures. Conclusion: The tests that most reliably predicted response to donepezil in AD subjects were in the domains of visual-spatial motor abilities and lexical-semantic functioning.

Although the principles defining HIT find support within a variety of fields, the framework is currently underspecified in several respects, which prevents it from fully achieving its purpose. We highlight a number of such shortcomings and propose avenues for a resolution of some of these issues.