Clinical Trials Commons^™

Simulations For Designing And Interpreting Intervention Trials In Infectious Diseases., M Elizabeth Halloran, Kari Auranen, Sarah Baird, Nicole E Basta, Steven E Bellan, +Several Additional Authors

Global Health Faculty Publications

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods.

DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, …

Long-Term Follow-Up Of Cardiac Function And Quality Of Life For Patients In Nsabp Protocol B-31/Nrg Oncology: A Randomized Trial Comparing The Safety And Efficacy Of Doxorubicin And Cyclophosphamide (Ac) Followed By Paclitaxel With Ac Followed By Paclitaxel And Trastuzumab In Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2, Patricia A. Ganz, Edward H. Romond, Reena S. Cecchini, Priya Rastogi, Charles E. Geyer Jr., Sandra M. Swain, Jong-Hyeon Jeong, Louis Fehrenbacher, Howard M. Gross, Adam M. Brufsky, Patrick J. Flynn, Tanya A. Wahl, Thomas E. Seay, James L. Wade Iii, David D. Biggs, James N. Atkins, Jonathan Polikoff, John L. Zapas, Eleftherios P. Mamounas, Norman Wolmark

Markey Cancer Center Faculty Publications

Purpose

Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment.

Patients and Methods

Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2–positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported …

Reducing Symptom Distress In Patients With Advanced Cancer Using An E-Alert System For Caregivers: Pooled Analysis Of Two Randomized Clinical Trials, David H. Gustafson, Lori L. Dubenske, Amy K. Atwood, Ming-Yuan Chih, Roberta A. Johnson, Fiona Mctavish, Andrew Quanbeck, Roger L. Brown, James F. Cleary, Dhavan Shah

Health and Clinical Sciences Faculty Publications

Background: Symptom distress in patients toward the end of life can change rapidly. Family caregivers have the potential to help patients manage those symptoms, as well as their own stress, if they are equipped with the proper resources. Electronic health (eHealth) systems may be able to provide those resources. Very sick patients may not be able to use such systems themselves to report their symptoms but family caregivers could.

Objective: The aim of this paper was to assess the effects on cancer patient symptom distress of an eHealth system that alerts clinicians to significant changes in the patient’s symptoms, as …

First-In-Human Clinical Trial Of Oral Onc201 In Patients With Refractory Solid Tumors, Mark N. Stein, Joseph R. Bertino, Howard L. Kaufman, Tina M. Mayer, Rebecca A. Moss, Ann W. Silk, Nancy Chan, Jyoti Malhotra, Loma Rodriguez, Joseph Aisner, Robert Aiken, Bruce G. Haffty, Robert S. Dipaola, Tracie Saunders, Andrew Zloza, Sherri Damare, Yasmeen Beckett, Bangning Yu, Saltanat Najmi, Christian Gabel, Sioghan Dickerson, Ling Zheng, Wafik S. El-Deiry, Joshua E. Allen, Martin Stogniew, Wolfgang Oster, Janice M. Mehnert

Internal Medicine Faculty Publications

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D).

Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, …

Novel Bayesian Adaptive Clinical Trial Designs In Early Phases, Haitao Pan

Dissertations and Theses (Open Access)

Early phase, or phase I and phase II, trials are the first step in testing new medicines that have been developed in the lab. The main goal of phase I clinical trials is to establish the recommended dose of new drugs for phase II trials. For the cytotoxic drugs, the goal is to find maximum tolerated dose (MTD). The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Therefore, dose escalation methods, especially Bayesian designs, are recommended to be used in phase I …

Burden Of Atopic Dermatitis In The United States: Analysis Of Healthcare Claims Data In The Commercial, Medicare, And Medi-Cal Databases, Sulena Shrestha, Raymond Miao, Li Wang, Jingdong Chao, Huseyin Yuce, Wenhui Wei

Publications and Research

Comparative data on the burden of atopic dermatitis (AD) in adults relative to the general population are limited. We performed a large-scale evaluation of the burden of disease among US adults with AD relative to matched non-AD controls, encompassing comorbidities, healthcare resource utilization (HCRU), and costs, using healthcare claims data. The impact of AD disease severity on these outcomes was also evaluated.

A Phase Iii, Randomized, Multi-Center, Double Blind, Placebo Controlled Study Of Safety And Efficacy Of Lofexidine For Relief Of Symptoms In Individuals Undergoing Inpatient Opioid Withdrawal, Charles W. Gorodetzky, Sharon L. Walsh, Peter R. Martin, Andrew J. Saxon, Kristen L. Gullo, Kousick Biswas

Center on Drug and Alcohol Research Faculty Publications

Background: Lofexidine is an alpha-2-adrenergic receptor agonist approved in the United Kingdom (UK) for the treatment of opioid withdrawal symptoms. Lofexidine has demonstrated better efficacy than placebo for reducing opioid withdrawal symptoms in patients undergoing opioid withdrawal with less reported hypotension than clonidine.

Methods: Designed as an FDA registration trial, this 8-day, randomized, double-blind, placebo-controlled, parallel-group study in 264 patients dependent on short-acting opioids evaluated the efficacy of lofexidine hydrochloride in reducing withdrawal symptoms in patients undergoing opioid withdrawal. The primary efficacy measures were SOWS-Gossop on Day 3 and time-to-dropout. Secondary endpoints included the proportion of participants who were completers; …

Evaluation Of Multiple Interventions Using A Stepped Wedge Design, Vivian H. Lyons, Lingyu Li, James Hughes, Ali Rowhani-Rahbar

UW Biostatistics Working Paper Series

Background: Stepped wedge cluster randomized trials are a class of unidirectional crossover studies that have historically been limited to evaluating a single intervention. This design is especially suitable for pragmatic trials where the study feasibility can be improved with a phased introduction of the intervention. We examined variations of stepped wedge designs that would support evaluation of multiple interventions. Methods: We propose four different design variants for implementing a stepped wedge trial with two interventions: concurrent design, supplementation, replacement, and factorial designs. Analyses were conducted comparing the precision of the estimated intervention effects for the different designs. Results: Concurrent, …

Treatment Pathway Of Bone Sarcoma In Children, Adolescents, And Young Adults, Damon R. Reed, Masanori Hayashi, Lars M. Wagner, Odion Binitie, Diana A. Steppan, Andrew S. Brohl, Eric T. Shinohara, Julia A. Bridge, David M. Loeb, Scott C. Borinstein, Michael S. Isakoff

Pediatrics Faculty Publications

When pediatric, adolescent, and young adult patients present with a bone sarcoma, treatment decisions, especially after relapse, are complex and require a multidisciplinary approach. This review presents scenarios commonly encountered in the therapy of bone sarcomas with the goal of objectively presenting a consensus, multidisciplinary management approach. Little variation was found in the authors' group with respect to local control or systemic therapy. Clinical trials were universally prioritized in all settings. Decisions regarding relapse therapies in the absence of a clinical trial had very minor variations initially, but a consensus was reached after a literature review and discussion. This review …

Lisinopril Or Coreg Cr In Reducing Cardiotoxicity In Women With Breast Cancer Receiving Trastuzumab: A Rationale And Design Of A Randomized Clinical Trial, Maya Guglin, Pamela Munster, Angelina Fink, Jeffrey Krischer

Internal Medicine Faculty Publications

Background—Trastuzumab (TZB) is an established therapy for HER2 positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin converting enzyme (ACE) inhibitors and beta blockers (BB) in the prevention of chemotherapy-induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a beta-blocker during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo.

Methods and Results—We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to …

Phase Iii Prospective Randomized Comparison Trial Of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab In Patients With Advanced Carcinoid Tumors: Swog S0518, James C. Yao, Katherine A. Guthrie, Cesar Moran, Jonathan R. Strosberg, Matthew H. Kulke, Jennifer A. Chan, Noelle Loconte, Robert R. Mcwilliams, Edward M. Wolin, Bassam Mattar, Shannon Mcdonough, Helen Chen, Charles D. Blanke, Howard S. Hochster

Markey Cancer Center Faculty Publications

Purpose

Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs.

Patients and Methods

Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary …

Safety And Immunogenicity Of An Inactivated Whole Cell Tuberculosis Vaccine Booster In Adults Primed With Bcg: A Randomized, Controlled Trial Of Dar-901, C. Fordham Von Reyn, Timothy Lahey, Robert D. Arbeit, Bernard Landry, Leway Kailani, Lisa Adams, Brenda Haynes, Todd Mackenzie, Wendy Wieland-Alter, Ruth Connor, Sue Tvaroha, David Hokey, Ann Ginsberg, Richard Waddell

Dartmouth Scholarship

Development of a tuberculosis vaccine to boost BCG is a major international health priority. SRL172, an inactivated whole cell booster derived from a non-tuberculous mycobacterium, is the only new vaccine against tuberculosis to have demonstrated efficacy in a Phase 3 trial. In the present study we sought to determine if a three-dose series of DAR-901 manufactured from the SRL172 master cell bank by a new, scalable method was safe and immunogenic.

Responsible Translation Of Stem Cell Research: An Assessment Of Clinical Trial Registration And Publications, Moses Fung, Yan Yuan, Harold Atkins, Qian Shi, Tania M. Bubela

Office of the Provost

We assessed the extent to which the publication of clinical trial results of innovative cell-based interventions reflects International Society for Stem Cell Research best practice guidelines. We assessed: (1) characteristics and time to publication of completed trials; (2) quality of reported trials; and (3) results of published trials. We identified and analyzed publications from 1,052 novel stem cell clinical trials: 179 (45.4%) of 393 completed trials had published results; 48 trials were registered by known stem cell tourism clinics, none of which reported results. Completed non-industry-sponsored trials initially published more rapidly, but differences with industry-sponsored trials decreased over time. Most …

Denoising Tandem Mass Spectrometry Data, Felix Offei

Electronic Theses and Dissertations

Protein identification using tandem mass spectrometry (MS/MS) has proven to be an effective way to identify proteins in a biological sample. An observed spectrum is constructed from the data produced by the tandem mass spectrometer. A protein can be identified if the observed spectrum aligns with the theoretical spectrum. However, data generated by the tandem mass spectrometer are affected by errors thus making protein identification challenging in the field of proteomics. Some of these errors include wrong calibration of the instrument, instrument distortion and noise. In this thesis, we present a pre-processing method, which focuses on the removal of noisy …

Inference On The Stress-Strength Model From Weibull Gamma Distribution, Mahmoud Mansour, Rashad El-Sagheer, M. A. W. Mahmoud Prof.

Basic Science Engineering

No abstract provided.

Polymer Micelle Formulation For The Proteasome Inhibitor Drug Carfilzomib: Anticancer Efficacy And Pharmacokinetic Studies In Mice, Ji Eun Park, Se-Eun Chun, Derek Alexander Reichel, Jee Sun Min, Su-Chan Lee, Songhee Han, Gongmi Ryoo, Yunseok Oh, Shin-Hyung Park, Heon-Min Ryu, Kyung Bo Kim, Ho-Young Lee, Soo Kyung Bae, Younsoo Bae, Wooin Lee

Pharmaceutical Sciences Faculty Publications

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic …

Effect Of Immediate Initiation Of Antiretroviral Therapy On Risk Of Severe Bacterial Infections In Hiv-Positive People With Cd4 Cell Counts Of More Than 500 Cells Per Μl: Secondary Outcome Results From A Randomised Controlled Trial., Jemma O'Connor, Michael J Vjecha, Andrew N Phillips, Brian Angus, David Cooper, Fred Gordin, +Several Additional Authors

Medicine Faculty Publications

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial.

METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells …

The Role Of Functional, Social, And Mobility Dynamics In Facilitating Older African Americans Participation In Clinical Research, Eve T. Shapiro, Jay T. Schamel, Kimberly A. Parker, Laura A. Randall, Paula M. Frew

Environmental & Global Health Faculty Research

Purpose: Older African Americans experience disproportionately higher incidence of morbidity and mortality related to chronic and infectious diseases, yet are significantly underrepresented in clinical research compared to other racial and ethnic groups. This study aimed to understand the extent to which social support, transportation access, and physical impediments function as barriers or facilitators to clinical trial recruitment of older African Americans. Methods: Participants (N=221) were recruited from six African American churches in Atlanta and surveyed on various influences on clinical trial participation.

Adaptive Non-Inferiority Margins Under Observable Non-Constancy, Brett S. Hanscom, Deborah J. Donnell, Brian D. Williamson, Jim Hughes

UW Biostatistics Working Paper Series

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as it had in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the `constancy' assumption. If the constancy assumption fails, the chosen non-inferiority margin is not valid and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be …

Further Advances For The Sequential Multiple Assignment Randomized Trial (Smart), Tianjiao Dai

Dissertations and Theses (Open Access)

ABSTRACT

FURTHER ADVANCES FOR THE SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMIZED TRIAL (SMART)

Tianjiao Dai, M.S.

Advisory Professor: Sanjay Shete, Ph.D.

Sequential multiple assignment randomized trial (SMART) designs have been developed these years for studying adaptive interventions. In my Ph.D. study, I mainly investigate how to further improve SMART designs and optimize the interventions for each individual in the trial. My dissertation has focused on two topics of SMART designs.

1) Developing a novel SMART design that can reduce the cost and side effects associated with the interventions and proposing the corresponding analytic methods. I have developed a time-varying SMART design in …

A Comparison Of The Quality Of Informed Consent For Clinical Trials Of An Experimental Hookworm Vaccine Conducted In Developed And Developing Countries., David J. Diemert, Lucas Lobato, Ashley Styczynski, Maria Zumer, Amanda Soares, Maria Flávia Gazzinelli

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Informed consent is one of the principal ethical requirements of conducting clinical research, regardless of the study setting. Breaches in the quality of the informed consent process are frequently described in reference to clinical trials conducted in developing countries, due to low levels of formal education, a lack of familiarity with biomedical research, and limited access to health services in these countries. However, few studies have directly compared the quality of the informed consent process in developed and developing countries using the same tool and in similar clinical trials. This study was conducted to compare the quality of the informed …

Variance Prior Specification For A Basket Trial Design Using Bayesian Hierarchical Modeling, Kristen Cunanan, Alexia Iasonos, Ronglai Shen, Mithat Gonen

Memorial Sloan-Kettering Cancer Center, Dept. of Epidemiology & Biostatistics Working Paper Series

Background: In the era of targeted therapies, clinical trials in oncology are rapidly evolving, wherein patients from multiple diseases are now enrolled and treated according to their genomic mutation(s). In such trials, known as basket trials, the different disease cohorts form the different baskets for inference. Several approaches have been proposed in the literature to efficiently use information from all baskets while simultaneously screening to find individual baskets where the drug works. Most proposed methods are developed in a Bayesian paradigm that requires specifying a prior distribution for a variance parameter, which controls the degree to which information is shared …

Studying The Optimal Scheduling For Controlling Prostate Cancer Under Intermittent Androgen Suppression, Sunil K. Dhar, Hans R. Chaudhry, Bruce G. Bukiet, Zhiming Ji, Nan Gao, Thomas W. Findley

Harvard University Biostatistics Working Paper Series

This retrospective study shows that the majority of patients’ correlations between PSA and Testosterone during the on-treatment period is at least 0.90. Model-based duration calculations to control PSA levels during off-treatment are provided. There are two pairs of models. In one pair, the Generalized Linear Model and Mixed Model are both used to analyze the variability of PSA at the individual patient level by using the variable “Patient ID” as a repeated measure. In the second pair, Patient ID is not used as a repeated measure but additional baseline variables are included to analyze the variability of PSA.

When Is A Randomised Controlled Trial Health Equity Relevant? Development And Validation Of A Conceptual Framework, J. Jull, M. Whitehead, M. Petticrew, E. Kristjansson, D. Gough, Sarah Baird, +Several Additional Authors

Global Health Faculty Publications

Background Randomised controlled trials can provide evidence relevant to assessing the equity impact of an intervention, but such information is often poorly reported. We describe a conceptual framework to identify health equity-relevant randomised trials with the aim of improving the design and reporting of such trials.

Methods An interdisciplinary and international research team engaged in an iterative consensus building process to develop and refine the conceptual framework via face-to-face meetings, teleconferences and email correspondence, including findings from a validation exercise whereby two independent reviewers used the emerging framework to classify a sample of randomised trials.

Results A randomised trial can …

A Predictive Probability Interim Design For Phase Ii Clinical Trials With Continuous Endpoints, Meng Liu

Theses and Dissertations--Epidemiology and Biostatistics

Phase II clinical trials aim to potentially screen out ineffective and identify effective therapies to move forward to randomized phase III trials. Single-arm studies remain the most utilized design in phase II oncology trials, especially in scenarios where a randomized design is simply not practical. Due to concerns regarding excessive toxicity or ineffective new treatment strategies, interim analyses are typically incorporated in the trial, and the choice of statistical methods mainly depends on the type of primary endpoints. For oncology trials, the most common primary objectives in phase II trials include tumor response rate (binary endpoint) and progression disease-free survival …

Analysis Of Data From A Study To Identify Potential Biomarkers To Indicate Renal Injury, Mitchell D. Tahtinen

Dissertations, Master's Theses and Master's Reports

Ureteropelvic junction obstruction is a disease in which flow from the kidney to the bladder is obstructed for extended periods of time causing irreversible damage to the kidney. Current tests to detect kidney damage caused by obstruction are not effective until significant damage occurs. The purpose of this report is to identify a panel of biomarkers in urine to detect kidney damage earlier by analyzing data collected from a two-part study. Currently, two established urinary biomarkers to indicate kidney damage are NGAL and KIM-1. Biomarkers of interest in this study are CD13, CD10, and CD26. Results from the linear mixed …