scholarly journals Short-Wavelength Sensitive Cone (S-cone) Testing as an Outcome Measure for NR2E3 Clinical Treatment Trials

2019 ◽  
Vol 20 (10) ◽  
pp. 2497 ◽  
Author(s):  
Alejandro J. Roman ◽  
Christian A. Powers ◽  
Evelyn P. Semenov ◽  
Rebecca Sheplock ◽  
Valeryia Aksianiuk ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Retinal Degeneration ◽  
Disease Severity ◽  
Short Wavelength ◽  
Outcome Measure ◽  
Gene Mutations ◽  
Normal Subjects ◽  
Efficacy Outcome ◽  
Cone Function ◽  
Enhanced S Cone Syndrome

Recessively-inherited NR2E3 gene mutations cause an unusual retinopathy with abnormally-increased short-wavelength sensitive cone (S-cone) function, in addition to reduced rod and long/middle-wavelength sensitive cone (L/M-cone) function. Progress toward clinical trials to treat patients with this otherwise incurable retinal degeneration prompted the need to determine efficacy outcome measures. Comparisons were made between three computerized perimeters available in the clinic. These perimeters could deliver short-wavelength stimuli on longer-wavelength adapting backgrounds to measure whether S-cone vision can be quantified. Results from a cohort of normal subjects were compared across the three perimeters to determine S-cone isolation and test-retest variability. S-cone perimetry data from NR2E3-ESCS (enhanced S-cone syndrome) patients were examined and determined to have five stages of disease severity. Using these stages, strategies were proposed for monitoring efficacy of either a focal or retina-wide intervention. This work sets the stage for clinical trials.

Evaluating Mortality with Erythropoietic Stimulating Agents (ESAs) in the Nephrology Setting: The Distinction between Evaluating Trials That Measure Survival as a Primary or Secondary Efficacy Endpoint Versus a Safety Endpoint.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 962-962
Author(s):  
Sara E. Barnato ◽  
Charles L. Bennett ◽  
Kathleen Elverman ◽  
Dennis P. West ◽  
Mark Courtney
Keyword(s):  
Clinical Trials ◽  
Relative Risk ◽  
Randomized Trials ◽  
Randomized Clinical Trials ◽  
Outcome Measure ◽  
Meta Analysis ◽  
Safety Measure ◽  
Significant Safety ◽  
Randomized Controlled ◽  
Efficacy Outcome

Abstract Background: At ASCO 2007, we reported increased mortality risks when ESAs are administered to anemic cancer patients who are receiving chemotherapy when target hemoglobin levels are beyond the correction of anemia. In February 2007, a meta-analysis of nine randomized clinical trials with 5,143 patients published in the Lancet [vol 369; 381–88] identified a statistically significant risk of all cause mortality (relative risk (RR) of 1.17, 95% confidence interval (CI) 1.01, 1.35) when anemic patients with chronic kidney disease received ESAs targeted to higher hemoglobin concentrations (120–150 g/L). A recent report from the RADAR (Research against Adverse Drug Reactions) group raises concern that survival analyses might differ depending on whether survival was evaluated as a measure of efficacy versus a measure of safety. Herein, we re-analyze the data by evaluating randomized clinical trials according to whether or not survival was prospectively included as a primary or secondary efficacy outcome. Methods: Risks of death in randomized controlled clinical trials included in the Lancet meta-analysis were evaluated. We classified those studies based on their mortality outcomes, either as an efficacy outcome or as a safety outcome. Effect estimates for RR and 95% CI were derived from Stata (version 9.1, College Station, TX), calculated with random-effects models and pooled by use of the Dersimonian and Laird method. Results: In studies where survival was measured as an efficacy endpoint, the relative risk of mortality with ESAs targeted to higher hemoglobin levels was 1.27 (1.08, 1.49), a number greater than the relative risk reported in the Lancet meta-analysis. Conclusions: Randomized controlled trials should be included in meta-analyses that evaluate harms only if the relevant safety measure is prospectively included as a primary or secondary efficacy outcome measure in the study protocol. When survival was included as part of the efficacy analysis, a statistically significant safety signal was present. Randomized trials that included harms as a measure of safety did not present a statistically significant safety signal. Including randomized trials that include harms as a safety measure introduce noise and can mask safety signals. Studies: Events: RR (95% CI) Survival included as a primary or secondary efficacy outcome measure: High vs Low Hb Target: Besarab 1998 (n=1233) 183/618 vs 150/615 1.21 (1.01, 1.46) Gouva 2004 (n=88) 4/43 vs 3/45 1.40 (0.33, 5.87) Drueke 2006 (n=602) 31/300 vs 21/302 1.49 (0.87, 2.53) Singh 2006 (n=1432) 52/715 vs 36/717 1.45 (0.96, 2.19) Subtotal (n=3355) 270/1676 vs 210/1679 1.27 (1.08, 1.49) Survival included only as a safety measure: High vs Low Hb Target: Foley 2000 (n=146) 4/73 vs 3/73 1.33 (0.31, 5.75) Furuland 2003 (n=416) 29/216 vs 27/200 0.99 (0.61, 1.62) Roger 2005 (n=154) 0/75 vs 0/79 not estimable Levin 2005 (n=152) 1/74 vs 3/78 0.35 (0.04, 3.30) Parfrey 2005 (n=696) 12/396 vs 20/300 0.45 (0.23, 0.92) Rossert 2006 (n=390) 1/195 vs 6/195 0.17 (0.02, 1.37) Subtotal (n=1954) 47/1029 vs 59/925 0.67 (0.37, 1.19)

scholarly journals DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 441
Author(s):  
Fanny Pineau ◽  
Davide Caimmi ◽  
Sylvie Taviaux ◽  
Maurane Reveil ◽  
Laura Brosseau ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Methylation ◽  
Clinical Trials ◽  
Lung Disease ◽  
Disease Severity ◽  
Genome Wide ◽  
A Genome ◽  
Lung Disease Severity ◽  
Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

scholarly journals Duration of Treatment Effect Should Be Considered in the Design and Interpretation of Clinical Trials: Results of a Discrete Choice Experiment

2019 ◽  
Vol 39 (4) ◽  
pp. 461-473 ◽  
Author(s):  
Bethan Copsey ◽  
James Buchanan ◽  
Raymond Fitzpatrick ◽  
Sarah E. Lamb ◽  
Susan J. Dutton ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Disease Severity ◽  
Discrete Choice Experiment ◽  
Discrete Choice ◽  
Treatment Effect ◽  
Heart Attack ◽  
Choice Experiment ◽  
Ulcer Bleeding ◽  
Duration Of Treatment ◽  
Duration Of Effect

Objective. This study examined whether duration of treatment effect should be considered in a benefit-risk assessment using a case study of osteoarthritis medications. Study Design and Setting. A discrete choice experiment was completed by 300 residents of the United Kingdom with hip and/or knee osteoarthritis. In 16 choice tasks, participants selected their preferred option from 2 medications. Medications were described in terms of effect on pain, stiffness, and function; duration of treatment effect; and risk of heart attack and stomach ulcer bleeding. The analysis used mixed-effects logistic regression. Results. Pain, disease severity, and duration of treatment effect had the greatest influence on medication preferences, whereas stiffness did not significantly affect medication choice. Participants were willing to accept an increase in the risk of heart attack of 2.6% (95% confidence interval: 2.0% to 3.2%) to increase the duration of treatment effect from 1 month to 12 months. Reducing pain from moderate to mild was valued the same as increasing duration of effect from 1 month to 3 months; both were seen as equivalent to an absolute reduction of 1.2% in the risk of heart attack in the next year. Subgroup analysis suggested disease severity influenced patient preferences. Conclusions. Along with treatment benefits and risks, the results suggest that duration of treatment effect is an important factor in the medication choices of people with osteoarthritis. This could have implications for the design and interpretation of clinical trials, for example, incorporating longer-term surveillance of trial participants and accounting for duration of treatment effect in risk-benefit assessments. Future research is needed to assess whether these findings are generalizable to other samples, disease areas, and levels of duration of effect.

scholarly journals Full-field stimulus testing: Role in the clinic and as an outcome measure in clinical trials of severe childhood retinal disease

2021 ◽  
pp. 101000
Author(s):  
Alejandro J. Roman ◽  
Artur V. Cideciyan ◽  
Vivian Wu ◽  
Alexandra V. Garafalo ◽  
Samuel G. Jacobson
Keyword(s):  
Clinical Trials ◽  
Outcome Measure ◽  
Retinal Disease ◽  
Full Field

SMN mRNA and protein levels in peripheral blood

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1067-1073 ◽  
Author(s):  
C. J. Sumner ◽  
S. J. Kolb ◽  
G. G. Harmison ◽  
N. O. Jeffries ◽  
K. Schadt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Muscular Atrophy ◽  
Gene Copy ◽  
Blood Levels ◽  
Type I ◽  
Protein Levels ◽  
Smn Protein

Background: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.Objective: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.Methods: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.Results: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.Conclusion: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

scholarly journals Current Psoriasis Efficacy Outcome Measures in Clinical Trials

2018 ◽  
Vol 7 (4) ◽  
pp. 261-268 ◽  
Author(s):  
Todd Wechter ◽  
Michael Heath ◽  
David Aung-Din ◽  
Dev Sahni ◽  
Abigail Cline ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Outcome Measures ◽  
Efficacy Outcome

scholarly journals Efficacy and Safety of Oritavancin Relative to Vancomycin for Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the Outpatient Setting: Results From the SOLO Clinical Trials

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Thomas P. Lodise ◽  
Mark Redell ◽  
Shannon O. Armstrong ◽  
Katherine A. Sulham ◽  
G. Ralph Corey
Keyword(s):  
Clinical Trials ◽  
Composite Endpoint ◽  
Outpatient Setting ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Double Blind ◽  
Skin Structure ◽  
Efficacy Outcome ◽  
End Of Treatment ◽  
Secondary Endpoints

Abstract Background The objective of this analysis was to evaluate the efficacy and safety of oritavancin compared with vancomycin for patients with acute bacterial skin and skin structure infections (ABSSSIs) who received treatment in the outpatient setting in the Phase 3 SOLO clinical trials. Methods SOLO I and SOLO II were 2 identically designed comparative, multicenter, double-blind, randomized studies to evaluate the efficacy and safety of a single 1200-mg dose of intravenous (IV) oritavancin versus 7–10 days of twice-daily IV vancomycin for the treatment of ABSSSI. Protocols were amended to allow enrolled patients to complete their entire course of antimicrobial therapy in an outpatient setting. The primary efficacy outcome was a composite endpoint (cessation of spread or reduction in size of the baseline lesion, absence of fever, and no rescue antibiotic at early clinical evaluation [ECE]) (48 to 72 hours). Key secondary endpoints included investigator-assessed clinical cure 7 to 14 days after end of treatment (posttherapy evaluation [PTE]) and 20% or greater reduction in lesion area at ECE. Safety was assessed until day 60. Results Seven hundred ninety-two patients (oritavancin, 392; vancomycin, 400) received entire course of treatment in the outpatient setting. Efficacy response rates at ECE and PTE were similar (primary composite endpoint at ECE: 80.4% vs 77.5% for oritavancin and vancomycin, respectively) as was incidence of adverse events. Five patients (1.3%) who received oritavancin and 9 (2.3%) vancomycin patients were subsequently admitted to a hospital. Conclusions Oritavancin provides a single-dose alternative to multidose vancomycin for treatment of ABSSSI in the outpatient setting.

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