Browsing by Subject "Research Design"
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Item Open Access A cross-sectional analysis of HIV and hepatitis C clinical trials 2007 to 2010: the relationship between industry sponsorship and randomized study design.(Trials, 2014-01) Goswami, Neela D; Tsalik, Ephraim L; Naggie, Susanna; Miller, William C; Horton, John R; Pfeiffer, Christopher D; Hicks, Charles BBackground
The proportion of clinical research sponsored by industry will likely continue to expand as federal funds for academic research decreases, particularly in the fields of HIV/AIDS and hepatitis C (HCV). While HIV and HCV continue to burden the US population, insufficient data exists as to how industry sponsorship affects clinical trials involving these infectious diseases. Debate exists about whether pharmaceutical companies undertake more market-driven research practices to promote therapeutics, or instead conduct more rigorous trials than their non-industry counterparts because of increased resources and scrutiny. The ClinicalTrials.gov registry, which allows investigators to fulfill a federal mandate for public trial registration, provides an opportunity for critical evaluation of study designs for industry-sponsored trials, independent of publication status. As part of a large public policy effort, the Clinical Trials Transformation Initiative (CTTI) recently transformed the ClinicalTrials.gov registry into a searchable dataset to facilitate research on clinical trials themselves.Methods
We conducted a cross-sectional analysis of 477 HIV and HCV drug treatment trials, registered with ClinicalTrials.gov from 1 October 2007 to 27 September 2010, to study the relationship of study sponsorship with randomized study design. The likelihood of using randomization given industry (versus non-industry) sponsorship was reported with prevalence ratios (PR). PRs were estimated using crude and stratified tabular analysis and Poisson regression adjusting for presence of a data monitoring committee, enrollment size, study phase, number of study sites, inclusion of foreign study sites, exclusion of persons older than age 65, and disease condition.Results
The crude PR was 1.17 (95% CI 0.94, 1.45). Adjusted Poisson models produced a PR of 1.13 (95% CI 0.82, 1.56). There was a trend toward mild effect measure modification by study phase, but this was not statistically significant. In stratified tabular analysis the adjusted PR was 1.14 (95% CI 0.78, 1.68) among phase 2/3 trials and 1.06 (95% CI 0.50, 2.22) among phase 4 trials.Conclusions
No significant relationship was found between industry sponsorship and use of randomization in trial design in this cross-sectional study. Prospective studies evaluating other aspects of trial design may shed further light on the relationship between industry sponsorship and appropriate trial methodology.Item Open Access A new trial design to accelerate tuberculosis drug development: the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP).(BMC Med, 2016-03-23) Phillips, Patrick PJ; Dooley, Kelly E; Gillespie, Stephen H; Heinrich, Norbert; Stout, Jason E; Nahid, Payam; Diacon, Andreas H; Aarnoutse, Rob E; Kibiki, Gibson S; Boeree, Martin J; Hoelscher, MichaelBACKGROUND: The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world's greatest infectious disease killer. METHODS: We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. RESULTS: With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. CONCLUSIONS: Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.Item Open Access A protocol to evaluate the efficacy, perceptions, and cost of a cholesterol packaging approach to improve medication adherence.(Contemporary clinical trials, 2014-09) Zullig, Leah L; Pathman, Joshua; Melnyk, S Dee; Brown, Jamie N; Sanders, Linda L; Koropchak, Celine; Howard, Teresa; Danus, Susanne; McCant, Felicia; Bosworth, Hayden BPurpose
Elevated low-density lipoprotein cholesterol (LDL-C) is a major modifiable risk factor for cardiovascular disease (CVD), a leading cause of death in the United States. Despite clinical practice guidelines aimed at facilitating LDL-C control, many Veterans do not achieve guideline-recommended LDL-C levels.Methods
We describe a study focused on VA healthcare system users at risk for CVD (i.e., LDL-C level >130 mg/dl and/or <80% cholesterol pill refill adherence in the last 12 months). We are conducting a two and a half year randomized controlled trial (i.e., intervention administered over 12 months) among Veterans with uncontrolled cholesterol receiving care at select VA-affiliated primary care clinics in North Carolina. We anticipate enrolling 250 diverse patients (10% women; 40% African American). Patients are randomized to an educational control group or intervention group. Intervention group participants' medication is provided in special blister packaging labeled for daily use that includes reminders; MeadWestvaco Corporation's pre-filled DosePak® contains standard doses of statins in accordance with the existing prescriptions.Conclusions
Pre-filled blister packaging may provide an inexpensive solution to improve medication adherence. Our study enrolls a diverse sample and provides information about whether an adherence packaging intervention can: 1) improve medication adherence; 2) improve patients' LDL-C levels; 3) be well received by patients and providers; and 4) provide a cost effective solution to improve medication adherence.Item Open Access A tutorial on Bayesian multi-model linear regression with BAS and JASP.(Behavior research methods, 2021-12) Bergh, Don van den; Clyde, Merlise A; Gupta, Akash R Komarlu Narendra; de Jong, Tim; Gronau, Quentin F; Marsman, Maarten; Ly, Alexander; Wagenmakers, Eric-JanLinear regression analyses commonly involve two consecutive stages of statistical inquiry. In the first stage, a single 'best' model is defined by a specific selection of relevant predictors; in the second stage, the regression coefficients of the winning model are used for prediction and for inference concerning the importance of the predictors. However, such second-stage inference ignores the model uncertainty from the first stage, resulting in overconfident parameter estimates that generalize poorly. These drawbacks can be overcome by model averaging, a technique that retains all models for inference, weighting each model's contribution by its posterior probability. Although conceptually straightforward, model averaging is rarely used in applied research, possibly due to the lack of easily accessible software. To bridge the gap between theory and practice, we provide a tutorial on linear regression using Bayesian model averaging in JASP, based on the BAS package in R. Firstly, we provide theoretical background on linear regression, Bayesian inference, and Bayesian model averaging. Secondly, we demonstrate the method on an example data set from the World Happiness Report. Lastly, we discuss limitations of model averaging and directions for dealing with violations of model assumptions.Item Open Access Assessing applicability when comparing medical interventions: AHRQ and the Effective Health Care Program.(Journal of clinical epidemiology, 2011-11) Atkins, David; Chang, Stephanie M; Gartlehner, Gerald; Buckley, David I; Whitlock, Evelyn P; Berliner, Elise; Matchar, DavidObjective
To describe a systematic approach for identifying, reporting, and synthesizing information to allow consistent and transparent consideration of the applicability of the evidence in a systematic review according to the Population, Intervention, Comparator, Outcome, Setting domains.Study design and setting
Comparative effectiveness reviews need to consider whether available evidence is applicable to specific clinical or policy questions to be useful to decision makers. Authors reviewed the literature and developed guidance for the Effective Health Care program.Results
Because applicability depends on the specific questions and needs of the users, it is difficult to devise a valid uniform scale for rating the overall applicability of individual studies or body of evidence. We recommend consulting stakeholders to identify the factors most relevant to applicability for their decisions. Applicability should be considered separately for benefits and harms. Observational studies can help determine whether trial populations and interventions are representative of "real world" practice. Reviewers should describe differences between available evidence and the ideally applicable evidence for the question being asked and offer a qualitative judgment about the importance and potential effect of those differences.Conclusion
Careful consideration of applicability may improve the usefulness of systematic reviews in informing practice and policy.Item Open Access Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation With Other Measures of Disease Severity.(American journal of ophthalmology, 2020-11) Duncan, Jacque L; Liang, Wendi; Maguire, Maureen G; Audo, Isabelle; Ayala, Allison R; Birch, David G; Carroll, Joseph; Cheetham, Janet K; Esposti, Simona Degli; Durham, Todd A; Erker, Laura; Farsiu, Sina; Ferris, Frederick L; Heon, Elise; Hufnagel, Robert B; Iannaccone, Alessandro; Jaffe, Glenn J; Kay, Christine N; Michaelides, Michel; Pennesi, Mark E; Sahel, José-Alain; Foundation Fighting Blindness Consortium Investigator GroupPurpose
To report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study.Design
Cross-sectional study within a natural history study.Methods
Setting: multicenter, international.Study population
Usher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A.Observation procedures
Repeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (VTOT) was assessed with general linear models. Associations between VTOT and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests.Main outcome measures
VTOT (SP) and III4e isopter area (KP).Results
USH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean VTOT measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher VTOT (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94).Conclusions
USH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. VTOT was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration.Item Open Access CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: study protocol for a randomised controlled trial.(Trials, 2016-03-31) Tong, Steven YC; Nelson, Jane; Paterson, David L; Fowler, Vance G; Howden, Benjamin P; Cheng, Allen C; Chatfield, Mark; Lipman, Jeffrey; Van Hal, Sebastian; O'Sullivan, Matthew; Robinson, James O; Yahav, Dafna; Lye, David; Davis, Joshua S; CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research NetworkBACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. METHODS/DESIGN: We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint. DISCUSSION: Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02365493 . Registered 24 February 2015.Item Open Access Can caregivers report their care recipients' post-stroke hospitalizations and outpatient visits accurately? Findings of an Asian prospective stroke cohort.(BMC health services research, 2018-10-25) Tyagi, Shilpa; Koh, Gerald Choon-Huat; Luo, Nan; Tan, Kelvin Bryan; Hoenig, Helen; Matchar, David B; Yoong, Joanne; Finkelstein, Eric A; Lee, Kim En; Venketasubramanian, N; Menon, Edward; Chan, Kin Ming; De Silva, Deidre Anne; Yap, Philip; Tan, Boon Yeow; Chew, Effie; Young, Sherry H; Ng, Yee Sien; Tu, Tian Ming; Ang, Yan Hoon; Kong, Keng He; Singh, Rajinder; Merchant, Reshma A; Chang, Hui Meng; Yeo, Tseng Tsai; Ning, Chou; Cheong, Angela; Ng, Yu Li; Tan, Chuen SengBackground
Health services research aimed at understanding service use and improving resource allocation often relies on collecting subjectively reported or proxy-reported healthcare service utilization (HSU) data. It is important to know the discrepancies in such self or proxy reports, as they have significant financial and policy implications. In high-dependency populations, such as stroke survivors, with varying levels of cognitive impairment and dysphasia, caregivers are often potential sources of stroke survivors' HSU information. Most of the work conducted on agreement analysis to date has focused on validating different sources of self-reported data, with few studies exploring the validity of caregiver-reported data. Addressing this gap, our study aimed to quantify the agreement across the caregiver-reported and national claims-based HSU of stroke patients.Methods
A prospective study comprising multi-ethnic stroke patient and caregiver dyads (N = 485) in Singapore was the basis of the current analysis, which used linked national claims records. Caregiver-reported health services data were collected via face-to-face and telephone interviews, and similar health services data were extracted from the national claims records. The main outcome variable was the modified intraclass correlation coefficient (ICC), which provided the level of agreement across both data sources. We further identified the amount of over- or under-reporting by caregivers across different service types.Results
We observed variations in agreement for different health services, with agreement across caregiver reports and national claims records being the highest for outpatient visits (specialist and primary care), followed by hospitalizations and emergency department visits. Interestingly, caregivers over-reported hospitalizations by approximately 49% and under-reported specialist and primary care visits by approximately 20 to 30%.Conclusions
The accuracy of the caregiver-reported HSU of stroke patients varies across different service types. Relatively more objective data sources, such as national claims records, should be considered as a first choice for quantifying health care usage before considering caregiver-reported usage. Caregiver-reported outpatient service use was relatively more accurate than inpatient service use over shorter recall periods. Therefore, in situations where objective data sources are limited, caregiver-reported outpatient information can be considered for low volumes of healthcare consumption, using an appropriate correction to account for potential under-reporting.Item Open Access Caveat emptor: the combined effects of multiplicity and selective reporting.(Trials, 2018-09-17) Li, Tianjing; Mayo-Wilson, Evan; Fusco, Nicole; Hong, Hwanhee; Dickersin, KayClinical trials and systematic reviews of clinical trials inform healthcare decisions. There is growing concern, however, about results from clinical trials that cannot be reproduced. Reasons for nonreproducibility include that outcomes are defined in multiple ways, results can be obtained using multiple methods of analysis, and trial findings are reported in multiple sources ("multiplicity"). Multiplicity combined with selective reporting can influence dissemination of trial findings and decision-making. In particular, users of evidence might be misled by exposure to selected sources and overly optimistic representations of intervention effects. In this commentary, drawing from our experience in the Multiple Data Sources in Systematic Reviews (MUDS) study and evidence from previous research, we offer practical recommendations to enhance the reproducibility of clinical trials and systematic reviews.Item Open Access Chapter 5: assessing risk of bias as a domain of quality in medical test studies.(Journal of general internal medicine, 2012-06) Santaguida, P Lina; Riley, Crystal M; Matchar, David BAssessing methodological quality is a necessary activity for any systematic review, including those evaluating the evidence for studies of medical test performance. Judging the overall quality of an individual study involves examining the size of the study, the direction and degree of findings, the relevance of the study, and the risk of bias in the form of systematic error, internal validity, and other study limitations. In this chapter of the Methods Guide for Medical Test Reviews, we focus on the evaluation of risk of bias in the form of systematic error in an individual study as a distinctly important component of quality in studies of medical test performance, specifically in the context of estimating test performance (sensitivity and specificity). We make the following recommendations to systematic reviewers: 1) When assessing study limitations that are relevant to the test under evaluation, reviewers should select validated criteria that examine the risk of systematic error, 2) categorizing the risk of bias for individual studies as "low," "medium," or "high" is a useful way to proceed, and 3) methods for determining an overall categorization for the study limitations should be established a priori and documented clearly.Item Open Access Citizen Science as a New Tool in Dog Cognition Research.(PLoS One, 2015) Stewart, L; MacLean, EL; Ivy, D; Woods, V; Cohen, E; Rodriguez, K; McIntyre, M; Mukherjee, S; Call, J; Kaminski, J; Miklósi, Á; Wrangham, RW; Hare, BFamily dogs and dog owners offer a potentially powerful way to conduct citizen science to answer questions about animal behavior that are difficult to answer with more conventional approaches. Here we evaluate the quality of the first data on dog cognition collected by citizen scientists using the Dognition.com website. We conducted analyses to understand if data generated by over 500 citizen scientists replicates internally and in comparison to previously published findings. Half of participants participated for free while the other half paid for access. The website provided each participant a temperament questionnaire and instructions on how to conduct a series of ten cognitive tests. Participation required internet access, a dog and some common household items. Participants could record their responses on any PC, tablet or smartphone from anywhere in the world and data were retained on servers. Results from citizen scientists and their dogs replicated a number of previously described phenomena from conventional lab-based research. There was little evidence that citizen scientists manipulated their results. To illustrate the potential uses of relatively large samples of citizen science data, we then used factor analysis to examine individual differences across the cognitive tasks. The data were best explained by multiple factors in support of the hypothesis that nonhumans, including dogs, can evolve multiple cognitive domains that vary independently. This analysis suggests that in the future, citizen scientists will generate useful datasets that test hypotheses and answer questions as a complement to conventional laboratory techniques used to study dog psychology.Item Open Access Colchicine effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): study protocol for a randomized controlled trial.(Trials, 2015-04-30) Leung, Ying-Ying; Thumboo, Julian; Wong, Bak Siew; Haaland, Ben; Chowbay, Balram; Chakraborty, Bibhas; Tan, Mann Hong; Kraus, Virginia BBACKGROUND: Despite the high prevalence and global impact of knee osteoarthritis (KOA), current treatments are palliative. No disease modifying anti-osteoarthritic drug (DMOAD) has been approved. We recently demonstrated significant involvement of uric acid and activation of the innate immune response in osteoarthritis (OA) pathology and progression, suggesting that traditional gout therapy may be beneficial for OA. We therefore assess colchicine, an existing commercially available agent for gout, for a new therapeutic application in KOA. METHODS/DESIGN: COLKOA is a double-blind, placebo-controlled, randomized trial comparing a 16-week treatment with standard daily dose oral colchicine to placebo for KOA. A total of 120 participants with symptomatic KOA will be recruited from a single center in Singapore. The primary end point is 30% improvement in total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at week 16. Secondary end points include improvement in pain, physical function, and quality of life and change in serum, urine and synovial fluid biomarkers of cartilage metabolism and inflammation. A magnetic resonance imaging (MRI) substudy will be conducted in 20 participants to evaluate change in synovitis. Logistic regression will be used to compare changes between groups in an intention-to-treat analysis. DISCUSSION: The COLKOA trial is designed to evaluate whether commercially available colchicine is effective for improving signs and symptoms of KOA, and reducing synovial fluid, serum and urine inflammatory and biochemical joint degradation biomarkers. These biomarkers should provide insights into the underlying mechanism of therapeutic response. This trial will potentially provide data to support a new treatment option for KOA. TRIAL REGISTRATION: The trial has been registered at clinicaltrials.gov as NCT02176460 . Date of registration: 26 June 2014.Item Open Access Conducting research with racial/ethnic minorities: methodological lessons from the NIDA Clinical Trials Network.(The American journal of drug and alcohol abuse, 2011-09) Burlew, A Kathleen; Weekes, Jerren C; Montgomery, La'Trice; Feaster, Daniel J; Robbins, Michael S; Rosa, Carmen L; Ruglass, Lesia M; Venner, Kamilla L; Wu, Li-TzyMultiple studies in the National Institute on Drug Abuse Clinical Trials Network (CTN) demonstrate strategies for conducting effective substance abuse treatment research with racial/ethnic minorities (REMs).The objectives of this article are to describe lessons learned within the CTN to (1) enhance recruitment, retention, and other outcomes; (2) assess measurement equivalence; and (3) use data analytic plans that yield more information.This article includes background information and examples from multiple CTN studies on inclusion, measurement, and data analysis.Seven recommendations are included for conducting more effective research on REMs.Item Open Access Data monitoring and interim analyses in the pharmaceutical industry: ethical and logistical considerations.(Stat Med, 1993-03) Rockhold, FW; Enas, GGThe characteristics of data monitoring and the need for the use of data monitoring committees in clinical trials sponsored by the pharmaceutical industry differ from those of trials sponsored by government. Data monitoring is a continuous process in industry trials due to the regulatory requirements and the need to more thoroughly evaluate safety of new compounds. As part of this process, interim analyses are employed to make decisions about treatment effects. In some cases, such analyses may require the use of an external data monitoring committee to assist in the data review, analysis and decision making. A number of examples of interim analyses, with and without data monitoring committees, are discussed. Issues surrounding the need for external data monitoring committees and recommendations are presented. In particular the issues of sponsor participation in the data monitoring committee and controls of the decision making process are considered.Item Open Access Deriving Real-World Insights From Real-World Data: Biostatistics to the Rescue.(Annals of internal medicine, 2018-09) Pencina, Michael J; Rockhold, Frank W; D'Agostino, Ralph BItem Open Access Design and rationale of the LAPLACE-TIMI 57 trial: a phase II, double-blind, placebo-controlled study of the efficacy and tolerability of a monoclonal antibody inhibitor of PCSK9 in subjects with hypercholesterolemia on background statin therapy.(Clinical cardiology, 2012-01) Kohli, Payal; Desai, Nihar R; Giugliano, Robert P; Kim, Jae B; Somaratne, Ransi; Huang, Fannie; Knusel, Beat; McDonald, Shannon; Abrahamsen, Timothy; Wasserman, Scott M; Scott, Robert; Sabatine, Marc SLowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60-80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C-lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia.Item Open Access Design of the NIDA clinical trials network validation study of tobacco, alcohol, prescription medications, and substance use/misuse (TAPS) tool.(Contemporary clinical trials, 2016-09) Wu, Li-Tzy; McNeely, Jennifer; Subramaniam, Geetha A; Sharma, Gaurav; VanVeldhuisen, Paul; Schwartz, Robert PSubstance use and its associated use disorders are under-detected and under-treated in primary care. There is a need for a clinically useful brief screening and assessment instrument to identify primary care patients with substance use, sub-threshold substance use disorder (SUD), and SUD to facilitate brief intervention and treatment.We describe the design of the recently completed National Drug Abuse Treatment Clinical Trials Network's tobacco, alcohol, prescription medications, and substance use/misuse screen and brief assessment tool validation study. Study aims included to: develop a 2-stage screening and brief assessment tool (TAPS Tool) to detect substance use, problem use, and SUD among adult primary care patients; examine the validity of both the screen component and the TAPS Tool by comparing them to reference standard screening and assessment measures of no use, problem use, and SUD; and determine the feasibility and acceptability of the self-administration and interviewer-administration of the tool. The design included a pilot testing phase (n=30) and the main study of 2000 adult primary care participants who were randomly assigned in counter-balanced order to have the interviewer-administration or the self-administration of the TAPS Tool followed by the other administration format. Participants' views of feasibility, acceptability and preference for format of self-administration versus interviewer-administration of the TAPS Tool were assessed. Criterion measures of use and DSM-5 SUDs were administered.The TAPS Tool study builds on prior work to develop a 2-stage clinical tool for facilitating the adoption of screening, brief assessment and treatment for SUDs in primary care.Item Open Access Design of the North Carolina Prostate Cancer Comparative Effectiveness and Survivorship Study (NC ProCESS).(Journal of comparative effectiveness research, 2015-01) Chen, Ronald C; Carpenter, William R; Kim, Mimi; Hendrix, Laura H; Agans, Robert P; Meyer, Anne-Marie; Hoffmeyer, Anna; Reeve, Bryce B; Nielsen, Matthew E; Usinger, Deborah S; Strigo, Tara S; Jackman, Anne M; Anderson, Mary; Godley, Paul AThe North Carolina Prostate Cancer Comparative Effectiveness & Survivorship Study (NC ProCESS) was designed in collaboration with stakeholders to compare the effectiveness of different treatment options for localized prostate cancer. Using the Rapid Case Ascertainment system of the North Carolina Central Cancer Registry, 1,419 patients (57% of eligible) with newly-diagnosed localized prostate cancer were enrolled from January 2011 to June 2013, on average 5 weeks after diagnosis. All participants were enrolled prior to treatment and this population-based cohort is sociodemographically diverse. Prospective follow-up continues to collect data on treatments received, disease control, survival and patient-reported outcomes. This study highlights several important considerations regarding stakeholder involvement, study design and generalizability regarding comparative effectiveness research in prostate cancer.Item Open Access Design, recruitment, logistics, and data management of the GEHA (Genetics of Healthy Ageing) project.(Exp Gerontol, 2011-11) Skytthe, A; Valensin, S; Jeune, B; Cevenini, E; Balard, F; Beekman, M; Bezrukov, V; Blanche, H; Bolund, L; Broczek, K; Carru, C; Christensen, K; Christiansen, L; Collerton, JC; Cotichini, R; de Craen, AJM; Dato, S; Davies, K; De Benedictis, G; Deiana, L; Flachsbart, F; Gampe, J; Gilbault, C; Gonos, ES; Haimes, E; Hervonen, A; Hurme, MA; Janiszewska, D; Jylhä, M; Kirkwood, TBL; Kristensen, P; Laiho, P; Leon, A; Marchisio, A; Masciulli, R; Nebel, A; Passarino, G; Pelicci, G; Peltonen, L; Perola, M; Poulain, M; Rea, IM; Remacle, J; Robine, JM; Schreiber, S; Scurti, M; Sevini, F; Sikora, E; Skouteri, A; Slagboom, PE; Spazzafumo, L; Stazi, MA; Toccaceli, V; Toussaint, O; Törnwall, O; Vaupel, JW; Voutetakis, K; Franceschi, C; GEHA consortiumIn 2004, the integrated European project GEHA (Genetics of Healthy Ageing) was initiated with the aim of identifying genes involved in healthy ageing and longevity. The first step in the project was the recruitment of more than 2500 pairs of siblings aged 90 years or more together with one younger control person from 15 areas in 11 European countries through a coordinated and standardised effort. A biological sample, preferably a blood sample, was collected from each participant, and basic physical and cognitive measures were obtained together with information about health, life style, and family composition. From 2004 to 2008 a total of 2535 families comprising 5319 nonagenarian siblings were identified and included in the project. In addition, 2548 younger control persons aged 50-75 years were recruited. A total of 2249 complete trios with blood samples from at least two old siblings and the younger control were formed and are available for genetic analyses (e.g. linkage studies and genome-wide association studies). Mortality follow-up improves the possibility of identifying families with the most extreme longevity phenotypes. With a mean follow-up time of 3.7 years the number of families with all participating siblings aged 95 years or more has increased by a factor of 5 to 750 families compared to when interviews were conducted. Thus, the GEHA project represents a unique source in the search for genes related to healthy ageing and longevity.Item Open Access Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design.(BMC Health Serv Res, 2012-01-18) Cho, Alex H; Killeya-Jones, Ley A; O'Daniel, Julianne M; Kawamoto, Kensaku; Gallagher, Patrick; Haga, Susanne; Lucas, Joseph E; Trujillo, Gloria M; Joy, Scott V; Ginsburg, Geoffrey SBACKGROUND: Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT) assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting. METHODS/DESIGN: Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive either a standard risk assessment (SRA) for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm), or the SRA alone ("SRA" arm). Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm). Risk counseling is provided by clinic staff (not study staff external to the clinic). Fasting plasma glucose, insulin levels, body mass index (BMI), and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes. DISCUSSION: The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk information in a primary care setting can help improve patients' clinical outcomes, risk perceptions, and/or their engagement in healthy behavior change. In addition, study design features such as the use of existing clinic personnel for risk counseling could inform the future development and implementation of care models for the use of individual genetic risk information in primary care. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00849563.