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by
Gopalan Sethuraman |
Total Records (
2 ) for
Gopalan Sethuraman |
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Martin Farlow
,
Steven E. Arnold
,
Christopher H. van Dyck
,
Paul S. Aisen
,
B. Joy Snider
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Anton P. Porsteinsson
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Stuart Friedrich
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Robert A. Dean
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Celedon Gonzales
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Gopalan Sethuraman
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Ronald B. DeMattos
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Richard Mohs
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Steven M. Paul
and
Eric R. Siemers
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Objectives
To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer‘s disease. Cognitive measures were also obtained.
Methods
In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer‘s disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer‘s Disease Assessment Scale–cognitive portion was administered.
Results
Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ1–40 and Aβ1–42 in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ1–40 and Aβ1–42 in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ1–40 in CSF (P < .01), but increased unbound Aβ1–42 in CSF in a dose-dependent manner. The Alzheimer‘s Disease Assessment Scale–cognitive portion was unchanged after the 12-week antibody administration.
Conclusions
Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ1–42 suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ1–42 from amyloid plaques. |
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David B. Henley
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Karen L. Sundell
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Gopalan Sethuraman
and
Eric R. Siemers
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Background
Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer‘s disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials.
Methods
We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer‘s Disease Neuroimaging Initiative study.
Results
AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%–5.8% of patients), headache (4.0%–5.5%), constipation (4.3%–4.7%), nausea (2.0%–5.8%), joint swelling (3.6%–3.7%), vomiting (3.6%–3.7%), and anxiety (3.2%–3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%–33.0% vs 8.2%–21.0%) and greater discontinuations due to AEs (9.5%–11.6% vs 2.7%–3.2%). Rates of death (1.8%–2.4%) and SAEs (19.9%–21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%–4.0%) where SAEs were reported.
Conclusions
In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer‘s Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients. |
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