Dataset Information

A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms.

ABSTRACT:

Introduction

S47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors that may emerge as a favorable candidate for the symptomatic treatment of cognitive and depressive disorders in patients suffering from Alzheimer's disease (AD) of mild to moderate severity and with depressive symptoms.

Methods

For this double-blind, placebo-controlled 24-week phase II trial, 520 outpatients aged between 55 and 85 years, with probable AD at mild to moderate stages (a Mini-Mental State Examination score of 24-15 inclusive) and exhibiting depressive symptoms (Cornell Scale for Depression in Dementia [CSDD] ≥ 8) were recruited in twelve countries and randomized to 3 doses of S47445 (5-15-50 mg) or placebo. The primary end point was the change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score at week 24. Secondary measures included the Disability Assessment for Dementia, Mini-Mental State Examination, ADAS-Cog 13-item, CSDD, Clinical Global Impression of Change (Alzheimer's Disease Cooperative Study-CGIC), Neuropsychiatric Inventory (NPI), and safety criteria.

Results

Baseline characteristics were comparable between the 4 groups. After 24 weeks, no statistically significant treatment difference was demonstrated between S47445 (5, 15 or 50 mg/d) and placebo on cognition (ADAS-Cog), function (Disability Assessment for Dementia), or depressive symptoms (CSDD). An improvement on neuropsychiatric symptoms assessed by NPI was evidenced at the lower dose 5 mg/d (Δ -2.55, P = .023, post hoc analysis) compared to placebo. CSDD and total NPI scores improved in all groups including placebo. There were no specific and/or unexpected safety signals observed with any of the S47445 doses.

Discussion

S47445 administered for 24 weeks was safe and well tolerated by patients with mild to moderate AD; the compound did not show significant benefits over placebo on cognition, function, or depressive symptoms.

SUBMITTER: Bernard K

PROVIDER: S-EPMC6597919 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms.

Bernard Katy K Gouttefangeas Sylvie S Bretin Sylvie S Galtier Stéphanie S Robert Philippe P Holthoff-Detto Vjera V Cummings Jeffrey J Pueyo Maria M

Alzheimer's & dementia (New York, N. Y.) 20190624

<h4>Introduction</h4>S47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors that may emerge as a favorable candidate for the symptomatic treatment of cognitive and depressive disorders in patients suffering from Alzheimer's disease (AD) of mild to moderate severity and with depressive symptoms.<h4>Methods</h4>For this double-blind, placebo-controlled 24-week phase II trial, 520 outpatients aged between 55 and 85 years, with probable ...[more]

PMID: 31297437

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Project description:Background/Objectives: The global prevalence of mental health disorders, particularly anxiety and depression, has increased significantly, with rates further elevated by the COVID-19 pandemic. Conventional pharmacological treatments, while effective, often lead to side effects that can impact patient adherence and quality of life. This has driven interest in safer, natural adjunctive therapies. Crocus sativus L. (Iridaceae) (saffron) and Scutellaria baicalensis Georgi (Lamiaceae) (scutellaria) have individually shown potential, in humans and animals, respectively, as mood regulators, with bioactive compounds that modulate neurotransmitter systems and possess anti-inflammatory and anxiolytic effects. This study aimed (1) to explore the efficacy and safety of scutellaria extracts in humans and (2) to test a possible synergistic effect when combining scutellaria and saffron on mood regulation in individuals experiencing mild-to-moderate depressive symptoms. Methods: In a randomized, double-blind, placebo-controlled trial, 180 participants with mild-to-moderate depressive symptoms were assigned to receive either scutellaria extract alone (SCUTELL'UP®), saffron extract alone (SAFFR'ACTIV®), a combination of scutellaria and saffron extracts (SAFFR'UP®), or a placebo for six weeks. The primary outcome was assessed using a standardized depression scale (Beck Depression Inventory). The secondary outcomes, including anxiety, emotional state, well-being level, and sleep quality, were all assessed using validated questionnaires. Safety and tolerability were evaluated throughout the study period. Results: The results confirmed the beneficial effects of saffron extract on depressive and anxious symptoms, as well as its role in improving sleep quality. For the first time in humans, scutellaria extract demonstrated a positive effect on mood regulation. Furthermore, a synergistic effect of the combination of these two extracts was identified, leading to enhanced improvements in depressive and anxious symptoms and emotional well-being among individuals with mild-to-moderate depression, compared to the placebo group. Minimal adverse effects were reported across all treatment groups. Conclusions: This natural adjunctive nutritional strategy offers a promising alternative for individuals seeking safer options for mental health support. Further research is warranted to exclude potential long-term side effects and to explore potential mechanisms of this combined supplementation.

Project description:BackgroundIn preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.MethodsThe REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau181), Aβ1-40, Aβ1-42, neurogranin, and neurofilament light chain].ResultsAt randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau181 [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.Conclusions and relevanceA 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.Trial registrationClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.

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Project description:ObjectivesTo determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening.MethodsWe conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10.ResultsThe trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58-86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45-2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points.ConclusionIn this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo.Trial registrationClinicalTrials.gov Identifier: NCT04325893 (https://clinicaltrials.gov/ct2/show/NCT04325893).

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Dataset Information

A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms.

Introduction

Methods

Results

Discussion

Publications

A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms.

Similar Datasets

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