Barbara Koumaras

Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials

In contrast to previous studies, targeting the mGluR pathway in fragile X syndrome patients did not improve behavior independent of FMR1 methylation. The mGluR theory of fragile X, put to the test People with the genetic disorder fragile X syndrome exhibit a variable constellation of debilitating physical and cognitive problems. Promising evidence from mouse models had raised hopes that an overactive glutamate signaling pathway (mGluR) was a smoking gun at the heart of the disease and that it could be successfully repaired. A pilot study in patients supported the mouse work: Down-regulation of mGluR improved behavioral problems, at least in patients carrying a certain genetic methylation marker. Here, in a larger, well-powered clinical trial, these results are put to the test and come up short. In adolescent or adult fragile X patients, whether they have the methylation marker or not, the glutamate antagonist mavoglurant had no effect on patient behavior. The authors discuss what further trials will be required, however, before permanently putting the mGluR theory of fragile X syndrome out to pasture. Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)–mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist—Community Edition using the FXS-specific algorithm (ABC-CFX) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.

Effects of rivastigmine treatment on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable Alzheimer's disease: A 26-week, multicenter, open-label study

BACKGROUND Alzheimers disease (AD) is the most common form of dementia and is characterized clinically by a gradual decline in cognitive performance, an increasingly impaired ability to perform activities of daily living, and neuropsychiatric and behavioral disturbances. OBJECTIVE The goal of this study was to assess the effect of rivastigmine on the neuropsychiatric and behavioral disturbances of nursing home residents with moderate to severe probable AD and to evaluate the safety and tolerability of rivastigmine in this population. METHODS This prospective, 26-week, open-label study was conducted in 13 centers in the United States and involved a total of 29 nursing homes. The effects of rivastigmine 3 to 12 mg/d for 26 weeks were assessed in nursing home residents with moderate to severe probable AD. Efficacy was evaluated using the Neuropsychiatric Inventory-Nursing Home (NPI-NH) scale for neuropsychiatric and behavioral disturbances; the Mini-Mental State Examination and the naming subset of the Alzheimers Disease Assessment Scale-Cognitive subscale for cognitive performance; and the simplified Clinicians Interview-Based Impression of Change Plus Caregiver Input for global functioning. RESULTS A total of 173 patients (141 women, 32 men; mean [SD]age, 82.6 [5.9] years) were enrolled. After 26 weeks of rivastigmine treatment, the mean (SD) change from baseline for all treated patients in the observed cases population was -2.5 (16.4) (n = 100; P = 0.138); it was -0.8 (16.5) (n = 149; P = 0.576) for the last-observation-carried-forward population. Patients with at least 1 neuropsychiatric symptom present at baseline showed a 3.2-point mean improvement in NPI-NH total score (n = 92; P = 0.062), with 49% of these patients demonstrating a clinically meaningful (ie, > or = 30%) reduction from baseline. At 26 weeks, scores for 8 of the 12 neuropsychiatric and behavioral disturbances in patients with the specific symptom present at baseline showed statistically significant improvements from baseline (delusions [n = 32; P = 0.007], hallucinations [n = 15; P < 0.001], agitation [n = 58; P = 0.044], apathy/indifference [n = 37; P < 0.001], irritability/lability [n = 50; P < 0.001], aberrant motor behavior [n = 32; P < 0.001], nighttime disturbances [n = 22; P < 0.001], and appetite/eating changes [n = 28; P = 0.002]) in the observed cases population. Limitations of this study include that it was open label and not restricted to patients with behavioral disturbances at baseline. CONCLUSION In the current study, rivastigmine treatment for 26 weeks in nursing home residents with moderate to severe probable AD was associated with decreased NPI-NH item scores for a wide range of behavioral disturbances in the subgroup of patients with behavioral symptoms at baseline.

Effects of rivastigmine on cognitive function in patients with traumatic brain injury

Objective: To compare the efficacy and safety of rivastigmine (3 to 6 mg/day) vs placebo over 12 weeks in patients with traumatic brain injury and persistent cognitive impairment. Methods: This prospective, randomized, double-blind, placebo-controlled study was conducted in 157 patients at least 12 months after injury. The primary efficacy measures were the Cambridge Neuropsychological Test Automated Battery (CANTAB) Rapid Visual Information Processing (RVIP) A′ subtest and the Hopkins Verbal Learning Test (HVLT). The primary efficacy outcome was the proportion of patients who demonstrated 1.0 SD or greater improvement from baseline at week 12 on CANTAB RVIP A′ or HVLT. Results: The percentage of responders at week 12 on either the CANTAB RVIP A′ or HVLT was 48.7% for rivastigmine and 49.3% for placebo (p = 0.940). Furthermore, for the overall study population, there were no significant differences for any of the secondary efficacy variables. In a subgroup of patients with moderate to severe memory impairment (n = 81), defined as 25% impairment or greater on HVLT at baseline, rivastigmine was significantly better than placebo for a number of measures, including the proportion of HVLT responders and CANTAB RVIP mean latency. Conclusions: Rivastigmine was safe and well tolerated in patients with traumatic brain injury with cognitive deficits. Rivastigmine shows promising results in the subgroup of patients with traumatic brain injury with moderate to severe memory deficits.

Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer's disease: results of a 52-week open-label study.

SUMMARY Objectives: To evaluate the safety and efficacy of long-term treatment with rivastigmine (3–12 mg/day) and its effects on neuropsychiatric and behavioral disturbances in nursing home patients with moderate to severe probable Alzheimers disease (AD). Methods: A prospective, multicenter 26-week open-label extension to a 26-week open-label study (52 week results) of rivastigmine treatment in patients with Mini-Mental State Examination (MMSE) scores of 6–15 inclusive, residing in nursing homes at 13 centers in the US. Effects of treatment with rivastigmine for up to 52 weeks on neuropsychiatric and behavioral symptoms were examined using the Neuropsychiatric Inventory-Nursing Home (NPI-NH) scale. Cognitive function was assessed by the MMSE, and the Naming Objects and Fingers Test (NOFT) subset of the Alzheimers Disease Assessment Scale – Cognitive subscale (ADAS-Cog). Global functioning was assessed using the simplified Clinicians Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). Results: Rivastigmine (3–12 mg/day) significantly improved neuropsychiatric and behavioral symptoms compared to baseline (in patients with specific behavioral disturbances at baseline) in observed cases (OC) and last observation carried forward (LOCF) analyses. Over 52 weeks, treatment with rivastigmine significantly improved 10 of 12 individual NPI-NH domains from baseline in LOCF patients with symptoms present at baseline. Cognitive function was stable, indicated by the lack of decline in MMSE and the NOFT. Global function was stabilized or improved in greater than half of the patients as indicated by the simplified CIBIC-Plus scores. Conclusion: Rivastigmine showed potential benefit in the long-term treatment of behavioral symptoms as well as cognitive and global functioning in nursing home residents with moderate to severe AD with concurrent behavioral symptoms present at baseline. Although these results suggest that treatment with rivastigmine may have beneficial behavioral effects and cognitive benefits on patients with moderate to severe AD, they are subject to the limitations of an open-label study.

Long-term effects of rivastigmine capsules in patients with traumatic brain injury

Objective: To investigate the safety, tolerability and efficacy of rivastigmine capsules (3–12 mg/day) in a 26-week, multi-centre, open-label extension of a double-blind study. Methods: Patients with traumatic brain injury (TBI) and persistent cognitive impairment who had received rivastigmine (3–6 mg/day) or placebo for 12 weeks could enter the extension study and receive rivastigmine (≤12 mg/day). Patients were assessed using a range of cognitive tests including the Hopkins Verbal Learning Test (HVLT) and the Cambridge Neuropsychological Test Automated Battery Rapid Visual Information Processing (CANTAB RVIP) A’ sub-test. Safety measures included monitoring of adverse events. Results: In the extension study (n= 127), the mean duration of rivastigmine treatment was 23.8 weeks and the mean final dosage was 7.9 mg/day. Approximately 40% of patients were responders (≥1.0 SD improvement from baseline) on CANTAB RVIP A’ or HVLT total score at week 38 or endpoint. Statistically significant changes from week 12 at week 38 were observed for CANTAB-RVIP A’ and HVLT-total word recall for the sub-group of ex-placebo patients with greater severity of initial impairment. The safety profile of rivastigmine capsules was consistent with the label. Conclusions: Treatment with rivastigmine for up to 38 weeks was safe in patients with TBI and cognitive impairment.

Safety and tolerability of rivastigmine capsule with memantine in patients with probable Alzheimer's disease: a 26-week, open-label, prospective trial (Study ENA713B US32)†

Rivastigmine, a dual cholinesterase inhibitor (ChEI), is widely approved for the symptomatic treatment of both mild‐to‐moderate Alzheimers disease (AD) and Parkinsons disease dementia. Orally administered ChEIs may be associated with gastrointestinal (GI) side effects and add‐on therapy with memantine, an N‐methyl‐d‐aspartate receptor antagonist, approved for moderate‐to‐severe AD, may ameliorate such side effects. This was a 26‐week, prospective, multicenter, single‐arm, open‐label pilot study to assess the safety and tolerability of rivastigmine capsules plus memantine in patients with moderate AD.

Switching from donepezil tablets to rivastigmine transdermal patch in Alzheimer's disease.

Objective: Evaluate safety and tolerability of switching from donepezil to rivastigmine transdermal patch in patients with mild to moderate Alzheimers disease. Methods: Prospective, parallel-group, open-label study to evaluate immediate or delayed switch from 5-10 mg/day donepezil to 4.6 mg/24 h rivastigmine following a 4-week treatment period. Results: Rates of discontinuation due to any reason or adverse events were similar between groups. Incidences of gastrointestinal adverse events were 3.8% in the immediate and 0.8% in the delayed switch group. No patients discontinued secondary to nausea and vomiting. Discontinuations due to application site reactions were low (2.3%). Asymptomatic bradycardia was more common following the immediate switch (2.3% vs 0%); however, these patients had coexisting cardiac comorbidities. Conclusion: Both switch strategies were safe and well tolerated. The majority of patients may be able to switch directly to rivastigmine patches without a withdrawal period. Appropriate clinical judgment should be used for patients with existing bradycardia or receiving β blockers.

A Pilot Study Evaluating the Efficacy and Safety of Rivastigmine in Patients with Mixed Dementia

Background and objectiveThe two most common causes of dementia in the elderly are Alzheimer’s disease (AD) and vascular dementia (VaD), which can coexist as mixed dementia. The object of this study was to assess the efficacy and safety of rivastigmine in patients with mixed dementia (AD with VaD).Study designThis 26-week open-label pilot study was conducted at 19 centres in the US. To reduce bias, the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) raters were blinded to all efficacy measures and to patient dosage information. Patients were treated with rivastigmine and titrated to their highest tolerated dose, up to 12 mg/day (6mg twice daily). The primary efficacy measure was cognitive function assessed by the ADAS-Cog subscale (without the concentration/distractibility item, to be consistent with cognitive outcome measures used in previous rivastigmine trials).ResultsForty-seven percent of patients treated with rivastigmine 6–12 mg/day demonstrated improvement on the ADAS-Cog at 26 weeks, with >25% of patients having a clinically significant improvement of ≥4 points. Treatment with rivastigmine (6–12 mg/day) was well tolerated by the majority of patients. The most common adverse effects occurring in >10% of patients were nausea, vomiting, dizziness and diarrhoea.ConclusionThis pilot study suggests that rivastigmine treatment may have beneficial effects in the treatment of patients with mixed dementia.

Long-Term Effects of Rivastigmine Treatment on the Need for Psychotropic Medications in Nursing Home Patients with Alzheimer’s Disease

AbstractBackground and objective: Neuropsychiatric symptoms and behavioural disturbances occur in most patients with Alzheimer’s disease (AD), are a source of stress for caregivers, and are the primary cause of patient institutionalisation. These symptoms often are treated with psychotropic medications. However, adverse drug interactions, adverse effects and nursing home regulations make reducing the use of psychotropic medications in elderly AD patients an important goal of therapy. Fifty-two-week data including data from a 26-week prospective open-label, multicentre study and its 26-week open-label extension were analysed. Patients and methods: 173 patients with moderate to severe AD residing in nursing homes were treated with rivastigmine 1.5–6mg twice daily. In the study, psychotropic drug use and behavioural symptoms were measured at baseline and at 52 weeks. Results: Results showed that 40% of patients who were receiving psychotropic medications at baseline had discontinued use or reduced their dose of psychotropic medications at week 52. Furthermore, significant improvements were observed from baseline in 10 of the 12 behavioural domains of the Nursing Home version of the Neuropsychiatric Inventory, including delusions (mean change from baseline −2.0; p = 0.002), hallucinations (mean change −3.1; p < 0.001), anxiety (mean change −1.1; p = 0.014), and euphoria (mean change −3.2; p = 0.006). Conclusion: These data suggest favourable tolerability, behavioural and pharmacoeconomic outcomes in nursing home residents with AD who are treated with rivastigmine.

P4-357: Switching from oral cholinesterase inhibitors to the rivastigmine transdermal patch: Clinical data from two randomized trials

examined brain activation in a group of mild AD patients after a 3 month open-label treatment with Galantamine. The objective was to examine the changes in brain activation through treatment using visual processing tasks. There were two tasks to test brain function along both visual pathways. Methods: The first task was a face matching task to test the activation along the ventral visual pathway and the second task was a location matching task, to test neuronal function along the dorsal pathway. Brain activation was measured using functional magnetic resonance imaging (fMRI). Results: Six AD patients completed the study and the analysis was performed with data from 5 patients, as the data from a 6 patient contained fMRI-related artifacts. There were no differences in task performance and in the cognitive scores of the CERAD battery before and after treatment. In the location matching task, we found a statistically significant decrease in activation along the dorsal visual pathway after galantamine treatment. Conclusions: A previous study found that AD patients had higher activation in the location matching task compared to healthy controls. There were no differences in activation for the face matching task after treatment. Our data indicate that treatment with galantamine leads to more efficient visual processing of stimuli or changes the compensatory mechanism in the AD patients.