scholarly journals The Alzheimer’s Disease THErapy with NEuroaid II (ATHENE) Study: A Double-Blind Randomized Delayed-Start Trial to Assess the Safety and Efficacy of MLC901 (NeuroAiD™II) as an add-on Treatment to Cholinesterase Inhibitors or Memantine in Patients With Mild to Moderate Alzheimer's Disease

2021 ◽  
Author(s):  
Christopher Chen ◽  
Qingshu Liu ◽  
Rejesh Babu Moorakonda ◽  
Nagaendran Kandiah ◽  
Boon Yeow Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Cognitive Assessment ◽  
Standard Treatment ◽  
Serious Adverse Events ◽  
Significant Difference ◽  
Early Starters ◽  
Modifying Effect ◽  
Disease Modifying

Abstract BackgroundPreclinical and clinical studies indicate a role for MLC901 (NeuroAiDTMII) in Alzheimer’s Disease (AD). We investigated its safety and efficacy as add-on therapy to standard treatment and evaluated a disease modifying effect in mild to moderate AD.MethodsMild-moderate probable AD patients by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n=125) were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months during which all patients received MLC901, in a delayed-start design. The primary outcome measure was serious adverse events at 6 months, secondary outcomes included the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) and other cognitive assessment scales.ResultsThere was no significant difference in the risk of serious adverse events between early and delayed starters at month (M) 6 (22.6% vs. 27.0%, risk difference = -4.4%, 90% CI -16.9 to 8.3%). Furthermore, there was no significant difference in the risk of adverse events, including the occurrence of stroke or vascular events, between early and delayed starters throughout the 12-month study period. The early-starters differed significantly on ADAS-Cog from the delayed-starters at M9 (mean difference -3.36, 95% CI -5.64 to -1.09) and M12 (mean difference -2.35, 95% CI -5.45 to 0.74). Other cognitive assessment scales showed trends in favor of MLC901.ConclusionsMLC901 is a safe adjunct to standard treatment for mild-moderate AD. There is no indication that the risk of any adverse events, including vascular, is increased with MLC901 in the study population. The cognitive outcomes provide support for a disease-modifying effect of MLC901 which requires confirmation in further studies. Clinical trial registration: ClinicalTrials.gov, NCT03038035. https://clinicaltrials.gov/ct2/show/NCT03038035

DELAYED-START ANALYSES IN THE PHASE 3 SOLANEZUMAB EXPEDITION3 STUDY IN MILD ALZHEIMER’S DISEASE

2018 ◽  
pp. 1-7
Author(s):  
H. Liu-Seifert ◽  
M.G. Case ◽  
S.W. Andersen ◽  
K.C. Holdridge ◽  
P.S. Aisen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phase 3 ◽  
Significant Treatment ◽  
Treatment Difference ◽  
Significant Difference ◽  
Efficacy Measures ◽  
Modifying Effect ◽  
Disease Modifying ◽  
Significant Treatment Difference

OBJECTIVE: A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer’s disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. METHODS: EXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period. RESULTS: No significant difference was observed between the placebo and solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer’s Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer’s Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. CONCLUSIONS: Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.

scholarly journals Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer’s Disease Dementia

2021 ◽  
pp. 1-16
Author(s):  
Albert C. Lo ◽  
Cynthia Duggan Evans ◽  
Michele Mancini ◽  
Hong Wang ◽  
Sergey Shcherbinin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Functional Decline ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
System Organ Class ◽  
Serious Adverse Events ◽  
Study Results ◽  
Significant Difference

Background: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)1–40 and Aβ1–42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD). Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild. Methods: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. Conclusion: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

scholarly journals 416 - Risk of Mortality Associated with Antipsychotics in Alzheimer's Disease

2020 ◽  
Vol 32 (S1) ◽  
pp. 132-132
Author(s):  
Liliana P. Ferreira ◽  
Núria Santos ◽  
Nuno Fernandes ◽  
Carla Ferreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Mortality Risk ◽  
Antipsychotic Treatment ◽  
Serious Adverse Events ◽  
Risk Of Death ◽  
Mesh Terms ◽  
Risk Of Mortality ◽  
Increased Risk

Objectives: Alzheimer's disease (AD) is the most common cause of dementia and it is associated with increased mortality. The use of antipsychotics is common among the elderly, especially in those with dementia. Evidence suggests an increased risk of mortality associated with antipsychotic use. Despite the short-term benefit of antipsychotic treatment to reduce the behavioral and psychological symptoms of dementia, it increases the risk of mortality in patients with AD. Our aim is to discuss the findings from the literature about risk of mortality associated with the use of antipsychotics in AD.Methods: We searched Internet databases indexed at MEDLINE using following MeSH terms: "Antipsychotic Agents" AND "Alzheimer Disease" OR "Dementia" AND "Mortality" and selected articles published in the last 5 years.Results: Antipsychotics are widely used in the pharmacological treatment of agitation and aggression in elderly patients with AD, but their benefit is limited. Serious adverse events associated with antipsychotics include increased risk of death. The risk of mortality is associated with both typical and atypical antipsychotics. Antipsychotic polypharmacy is associated with a higher mortality risk than monotherapy and should be avoided. The mortality risk increases after the first few days of treatment, gradually reducing but continues to increase after two years of treatment. Haloperidol is associated with a higher mortality risk and quetiapine with a lower risk than risperidone.Conclusions: If the use of antipsychotics is considered necessary, the lowest effective dose should be chosen and the duration should be limited because the mortality risk remains high with long-term use. The risk / benefit should be considered when choosing the antipsychotic. Further studies on the efficacy and risk of adverse events with antipsychotics are needed for a better choice of treatment and adequate monitoring with risk reduction.

scholarly journals Potentially inappropriate medication use in older adults with mild-moderate Alzheimer’s disease: prevalence and associations with adverse events

2020 ◽  
Vol 49 (4) ◽  
pp. 580-587
Author(s):  
Claire Murphy ◽  
Adam H Dyer ◽  
Brian Lawlor ◽  
Sean P Kennelly ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Inappropriate Medication ◽  
Potentially Inappropriate Medication ◽  
Randomised Control Trial ◽  
Vulnerable Group ◽  
Serious Adverse Events

Abstract Aim Potentially inappropriate medication (PIM) use is prevalent in older adults and is associated with adverse events, hospitalisation and mortality. We assessed the patterns and associations of PIM use in older adults with mild-to-moderate Alzheimer’s Disease (AD), who may represent a particularly vulnerable group. Design Analysis of data from NILVad, an 18-month Randomised Control Trial of Nilvadapine in mild-to-moderate AD. The v2 STOPP criteria were applied in duplicate to identify PIM use. Associations between PIM use and adverse events/unscheduled healthcare visits in addition to the associations between PIM use and AD progression were evaluated. Setting and Participants 448 older adults with mild-to-moderate AD from 23 centres in nine European countries. Results Of 448 participants (mean age: 72.56 ± 8.19 years), over half (55.8%) were prescribed a PIM with 30.1% being prescribed 2+ PIMs. The most frequent PIMs were (i) long-term benzodiazepines (11.6% N = 52/448), (ii) selective serotonin reuptake inhibitors without appropriate indication (11.1% N = 50/448), and (iii) Proton-Pump Inhibitors (PPIs) without appropriate indication (10.7% N = 48/448). Increasing number of PIMs was associated with a greater risk of adverse events (IRR 1.17, 1.13–1.19, P < 0.001), serious adverse events (IRR 1.27; 1.17–1.37, P < 0.001), unscheduled hospitalisations (IRR 1.16, 1.03–1.30, P = 0.016) and GP visits (IRR 1.22, 1.15–1.28, P < 0.001). PIM use was not associated with dementia progression. Conclusions and Implications PIM use is highly prevalent in mild-to-moderate AD and is associated with adverse events and unscheduled healthcare utilisation. Further attention to de-prescribing in this vulnerable group is warranted.

scholarly journals Efficacy, Safety and tolerability of the once-daily 10 cm² rivastigmine patch formulation in the patients with dementia (with probable Alzheimer’s disease)

2013 ◽  
Vol 29 (1) ◽  
pp. 5-14
Author(s):  
Anisul Haque ◽  
Quazi Deen Mohammad ◽  
Nirmalendu Bikash Bhowmik ◽  
Biplob Kumar Roy ◽  
Md Rafiqul Islam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Event ◽  
Adverse Events ◽  
Patch Size ◽  
Tolerability Profile ◽  
Rivastigmine Patch ◽  
Significant Difference ◽  
Lost To Follow Up

Back ground: Treatment compliance in patients with Alzheimer’s disease is particularly important as patients receiving regular treatment have a greater chance of slowing or delaying disease progression. Transdermal delivery has the potential for providing continuous drug delivery and steady plasma levels. Current study aimed to evaluate safety and tolerability of rivastigmine patch, to assess patient compliance and to assess the efficacy of treatment in patients with dementia (with probable Alzheimer’s disease). Methods: A total of 112 dementia patients (with a diagnosis of probable Alzheimer’s disease) from 12 centers were enrolled who were residing with someone in the communities throughout the study. After eligibility, and baseline assessments, patients were entered a 24-week open label treatment phase. All patients were started with application of one 5 cm² patch, followed by an up-titration to the target dose of 10 cm² patch size. Efficacy assessments were performed at weeks 12 and 24 in terms of MMSE and GDS score. Safety was monitored at all assessment points based mainly on the frequency of adverse events. Results: Analysis of baseline and available data until the drop out revealed no significant differentials. Around 95% of the study participants could receive 10 cm² patch size, showing a very high tolerability of the patch. Concurrent medication use also showed significant reduction to 16.3% patient in the end from 25% at baseline. The average MMSE score increased to 19.3 (±3.1) at 12th week and to 20.6(±3.4) at 24th week from 16.8 (±3.2) at baseline. GDS score reduced to 3.7 (±1.4) at 12th week and to 3.2 (±1.3) at 24th week from 4.3 (±1.5) at baseline. Only eight occasions of adverse event was reported (8.2%); no serious adverse event (SAE) were reported. Lost to follow up in the study was 14 (12.5%). Analysis of baseline data shows no significant difference. Their withdrawal seems to be unrelated to the adverse events and treatment outcome. Among the lost to follow up only one 1 (7.1%) had some side effect. Conclusion: Our study supports the pharmacokinetic rationale for the rivastigmine patch, indicating that smooth and continuous delivery of rivastigmine translates into an improved tolerability profile versus conventional oral administration, while maintaining clinical effectiveness. Bangladesh Journal of Neuroscience 2013; Vol. 29 (1) : 5-14

Alzheimer's Disease: Progress in the Development of Anti-amyloid Disease-Modifying Therapies

CNS Spectrums ◽  
2007 ◽  
Vol 12 (2) ◽  
pp. 113-123 ◽  
Author(s):  
Daniel D. Christensen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Amyloid Β ◽  
Phase Iii ◽  
Peroxisome Proliferator ◽  
Serious Adverse Events ◽  
Amyloid Disease ◽  
Aβ Aggregation ◽  
Disease Modifying

ABSTRACTThe amyloid hypothesis—the leading mechanistic theory of Alzheimer's disease—states that an imbalance in production or clearance of amyloid β (Aβ) results in accumulation of Aβ and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Aβ or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Aβ42-lowering agents; statins; anti-Aβ aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and γ-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Aβ42 production (eg, tarenflurbil), enhance the activity of α-secretase (eg, statins), and block Aβ aggregation (eg, transiposate).

scholarly journals Safety and efficacy of Melissa officinalis extract containing rosmarinic acid in the prevention of Alzheimer’s disease progression

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Moeko Noguchi-Shinohara ◽  
Kenjiro Ono ◽  
Tsuyoshi Hamaguchi ◽  
Toshitada Nagai ◽  
Shoko Kobayashi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rosmarinic Acid ◽  
Neuropsychiatric Symptoms ◽  
Clinical Effects ◽  
Melissa Officinalis ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Mild Dementia ◽  
Significant Difference

Abstract We conducted a randomized placebo-controlled double-blind 24-week trial using Melissa officinalis (M. officinalis) extract richly containing rosmarinic acid (RA) on patients with mild dementia due to Alzheimer’s disease (AD) with the aim to examine the safety and tolerability (primary endpoint) of RA (500 mg daily) and its clinical effects and disease-related biomarker changes (secondary endpoints). Patients (n = 23) diagnosed with mild dementia due to probable AD were randomized to either the placebo or M. officinalis extract group. No differences in vital signs or physical and neurologic examination results were detected between the M. officinalis and placebo groups. No serious adverse events occurred. There were no significant differences in cognitive measures; however, the mean Neuropsychiatric Inventory Questionnaire (NPI-Q) score improved by 0.5 points in the M. officinalis group and worsened by 0.7 points in the placebo group between the baseline and 24-week visit, indicating a significant difference (P = 0.012). No significant differences were apparent in disease-related biomarkers between the groups. M. officinalis extract containing 500 mg of RA taken daily was safe and well-tolerated by patients with mild dementia due to AD. Our results suggest that RA may help prevent the worsening of AD-related neuropsychiatric symptoms. Trial registration: The registration number for this clinical trial is UMIN000007734 (16/04/2012).

Sign in / Sign up

Export Citation Format

Share Document