Browsing by Author "Dowsett, Sherie A."

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    Alzheimer’s disease progression by geographical region in a clinical trial setting
    (BioMed Central, 2015-06-25) Henley, David B.; Dowsett, Sherie A.; Chen, Yun-Fei; Liu-Seifert, Hong; Grill, Joshua D.; Doody, Rachelle S.; Aisen, Paul; Raman, Rema; Miller, David S.; Hake, Ann M.; Cummings, Jeffrey; Department of Medicine, IU School of Medicine
    INTRODUCTION: To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer's disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology. METHODS: Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). RESULTS: Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. CONCLUSIONS: These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm.
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    Improvement in Function after Lasmiditan Treatment: Post Hoc Analysis of Data from Phase 3 Studies
    (Springer, 2020-12) Smith, Timothy; Krege, John H.; Rathmann, Suchitrita S.; Dowsett, Sherie A.; Hake, Ann; Nery, Emel S. M.; Matthews, Brandy R.; Doty, Erin G.; Neurology, School of Medicine
    Introduction: Migraine is associated with substantial functional impairment and affects many aspects of daily life. Methods: Using data from SAMURAI and SPARTAN (double-blind, placebo-controlled, phase 3 studies) and GLADIATOR (an open-label, phase 3 study enrolling patients who had completed SAMURAI or SPARTAN), we assessed the effects of lasmiditan on migraine-related functional disability at multiple time points from 0.5 to 48 h post dose by asking patients to rate how much the migraine was interfering with normal activities. Pooled data from SAMURAI and SPARTAN (SAMURAI + SPARTAN) and data from GLADIATOR were analyzed using the intention-to-treat populations. Results: For SPARTAN + SAMURAI, significantly more patients who received lasmiditan at any dose versus placebo reported freedom from migraine-related functional disability at every timepoint from 2 h post dose, and this difference persisted to 48 h (p < 0.05). Significant differences from placebo in freedom from migraine-related functional disability commenced at 1 h post dose for lasmiditan 200 mg, 1.5 h for lasmiditan 100 mg, and 2 h for lasmiditan 50 mg. Findings from GLADIATOR supported those from SAMURAI + SPARTAN. Conclusion: All doses of lasmiditan resulted in an improvement in migraine-related functional disability that persisted to 48 h. In SAMURAI + SPARTAN, a significant difference from placebo was observed as early as 1 h post dose. TRIAL REGISTRATION AT CLINICALTRIALS.GOV: SAMURAI (NCT02439320), SPARTAN (NCT02605174), and GLADIATOR (NCT02565186).
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    The systemic inflammatory response to dental plaque
    (2010) Wahaidi, Vivian Y.; Kowolik, Michael J.; Galli, Dominique M.; Dowsett, Sherie A.; Allen, Bradley L.; Gregory, Richard L.
    Introduction: Bacteremia involving oral bacteria and the systemic inflammatory responses are mechanisms that could causally link oral and systemic diseases. Objective: To use an experimental gingivitis model (EGM) in 2 clinical studies to 1) examine the systemic inflammatory responses to dental plaque, and assess racial differences in these responses; 2) determine whether dental plaque accumulation causes bacteremia and subsequent systemic responses following toothbrushing. Additionally, a laboratory study was conducted to examine the interaction between circulating human neutrophils and Fusobacterium nucleatum. Methods: For both clinical studies, healthy adults, aged 18-31 years, were recruited. In the first study, black and white, males and females participated in a 21-day EGM; in the second study, white adults participated in a 7-day EGM. In both studies, subjects visited the clinic weekly for: 1) measurement of the plaque index (PI) and gingival index (GI); 2) collection of peripheral blood samples to evaluate systemic markers of inflammation. In the second study, to analyze bacteremic episodes during the experimental phase, peripheral blood samples were collected at baseline and at 0.5, 5, and 30 minutes post-toothbrushing. In the laboratory study, interactions between F. nucleatum and circulating neutrophils were examined using a luminol-enhanced chemiluminescence assay. Results: During the experimental phases of both clinical studies, PI and GI increased (p<0.05) with a correlation between PI and GI ≥0.79. In the first study, dental plaque accumulation resulted in a systemic response that manifested as changes (p<0.05) in the level of inflammatory markers, hematologic factors, markers of lipid metabolism, and markers of metabolic change. This systemic response differed between individuals of different gender and race. In the second study, bacteremic episodes and changes in hematologic factors were observed post-toothbrushing during the experimental phase. Activation of neutrophils with F. nucleatum, in the laboratory study, increased the levels of neutrophil chemiluminescence (p<0.05). Conclusions: Overall, the findings of these investigations may shed light on the mechanistic pathways by which oral infection may impose risk for systemic diseases and provide some evidence to support a possible causal association between oral and systemic diseases. The clinical significance of this in systemic inflammatory diseases requires further investigation.