Clinical Trial Design for Alcoholic Hepatitis

2017 ◽  
Vol 37 (04) ◽  
pp. 332-342 ◽  
Author(s):  
Gyongyi Szabo
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Trial Design ◽  
Alcoholic Hepatitis ◽  
Treatment Options ◽  
Clinical Trial Design ◽  
Therapeutic Interventions ◽  
Common Data Elements ◽  
Definition Of ◽  
Data Elements

AbstractAlcoholic hepatitis (AH) is an acute and clinically distinct manifestation of alcoholic liver disease. While severe AH causes 30% or higher mortality in 3 months, treatment options are limited and ineffective. Recent advances on the understanding of the pathomechanisms of AH have identified numerous potential targets for new therapeutic interventions. Many of those targets are currently under preclinical testing and/or in human clinical trials for nonalcoholic steatohepatitis. Thus, the field of AH should be ready to launch new efforts and targeted clinical trials for this underserved patient population. There are remaining challenges in designing clinical trials in AH that include definition of the severity of disease, common data elements in clinical trial design, and selection of clinically meaningful endpoints. Future efforts and consensus meetings between regulatory agencies, academic and clinical experts, and industry will be instrumental to advance this emerging and greatly needed field of clinical investigations.

Novel definition of BCG failure to enhance recruitment into clinical trials.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 246-246
Author(s):  
Daniel Levi Willis ◽  
Eugene K. Lee ◽  
Rian J. Dickstein ◽  
Roosevelt Anderson ◽  
Shanna M. Pretzsch ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Prospective Clinical Trial ◽  
Fish Analysis ◽  
Free Survival ◽  
Bcg Therapy ◽  
Bcg Failure ◽  
Definition Of

246 Background: Designing clinical trials after BCG failure can be problematic without a reasonable control arm. Thus, there is a need for early identification of BCG failure relevant to clinical trial design which allows one arm to continue on BCG. Here we present a definition of BCG failure based on FISH profile at 6th week of induction BCG that would facilitate such trials. Methods: The definition presented is based on findings from our IRB-approved, prospective clinical trial where Urovysion FISH assays were performed serially during the normal course of BCG therapy (SWOG protocol) at various time points (pre-BCG, 6 weeks, 3 and 6 mo.). Herein we incorporated the FISH analysis at 6 weeks in patients with a negative 3 month cystoscopy and correlated the result with recurrence and progression rates at 24 months. A novel definition of BCG failure was proposed by focusing the analysis on 84 patients with high grade disease (cTa: 33, cT1: 44, cTis 7). The 6 week FISH was selected as this would allow the control arm to proceed with BCG maintenance in a timely fashion, taking into account the time required for obtaining FISH results, registration of patients, and randomization. Results: Of the 36 patients with a positive FISH at 6 weeks (and no tumor at 3 months), 17 recurred (PPV = 47%) and 11 progressed (PPV = 31%), while among those with a negative FISH, 5 recurred (NPV = 90%) and 4 progressed (NPV = 92%) (p<0.001). Kaplan Meier estimates of recurrence free survival with a positive 6 week FISH were 67% and 52%, and for progression free survival were 75% and 52%, at 1 and 2 years respectively. Therefore, if patients with a positive 6 week FISH (and negative 3 month cystoscopy) were considered as "molecular" BCG failures, a prospective clinical trial with 101 patients in the control (i.e. BCG maintenance) and experimental arms to detect a 20% difference in recurrence rates (α=0.05) with 80% power. Conclusions: Using the FISH status of patients at the 6 week interval on BCG therapy would allow a clinical trial design that incorporates one arm with continued BCG therapy, while enriching for events of interest, namely recurrence and progression. This would allow meaningful comparisons while negating any ethical concerns regarding a lack of “standard treatment” in BCG failure studies.

scholarly journals Conceptual Framework to Support Clinical Trial Optimization and End-to-End Enrollment Workflow

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Neha M. Jain ◽  
Alison Culley ◽  
Teresa Knoop ◽  
Christine Micheel ◽  
Travis Osterman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Knowledge Representation ◽  
Conceptual Framework ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Prospective Clinical Trial ◽  
Future Trends ◽  
Current State ◽  
Evaluation Strategies

In this work, we present a conceptual framework to support clinical trial optimization and enrollment workflows and review the current state, limitations, and future trends in this space. This framework includes knowledge representation of clinical trials, clinical trial optimization, clinical trial design, enrollment workflows for prospective clinical trial matching, waitlist management, and, finally, evaluation strategies for assessing improvement.

scholarly journals Edaravone in Amyotrophic Lateral Sclerosis’Lessons from the Clinical Development Program and the Importance of a Strategic Clinical Trial Design

US Neurology ◽  
2018 ◽  
Vol 14 (1) ◽  
pp. 47 ◽  
Author(s):  
Said R Beydoun ◽  
Jeffrey Rosenfeld
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Trial Design ◽  
Development Program ◽  
Clinical Trial Design ◽  
Clinical Development ◽  
Disease Heterogeneity ◽  
Clinical Development Program ◽  
Lateral Sclerosis

Edaravone significantly slows progression of amyotrophic lateral sclerosis (ALS), and is the first therapy to receive approval by the Food and Drug Administration (FDA) for the disease in 22 years. Approval of edaravone has marked a new chapter in pharmaceutical development since the key trial included a novel strategic clinical design involving cohort enrichment. In addition, approval was based on clinical trials that had a relatively small patient number and were performed outside of the US. Edaravone was developed through a series of clinical trials in Japan where it was determined that a well-defined subgroup of patients was required to reveal a treatment effect within the study period. Amyotrophic lateral sclerosis is associated with wide-ranging disease heterogeneity (both within the spectrum of ALS phenotypes as well as in the rate of progression). The patient cohort enrichment strategy aimed to address this heterogeneity and should now be considered as a viable, and perhaps preferred, trial design for future studies. Future research incorporating relevant biomarkers may help to better elucidate edaravone’s mechanism of action, pharmacodynamics, and subsequently ALS phenotypes that may preferentially benefit from treatment. In this review, we discuss the edaravone clinical development program, outline the strategic clinical trial design, and highlight important lessons for future trials.

Clinical Trial Design and Statistics

2018 ◽  
Author(s):  
Julie Ann Sosa
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Data Analysis ◽  
Trial Design ◽  
New Technologies ◽  
Drug Application ◽  
Clinical Trial Design ◽  
Double Blind Study ◽  
Type I ◽  
End Points

A clinical trial is a planned experiment designed to prospectively measure the efficacy or effectiveness of an intervention by comparing outcomes in a group of subjects treated with the test intervention with those observed in one or more comparable group(s) of subjects receiving another intervention.  Historically, the gold standard for a clinical trial has been a prospective, randomized, double-blind study, but it is sometimes impractical or unethical to conduct such in clinical medicine and surgery. Conventional outcomes have traditionally been clinical end points; with the rise of new technologies, however, they are increasingly being supplemented and/or replaced by surrogate end points, such as serum biomarkers. Because patients are involved, safety considerations and ethical principles must be incorporated into all phases of clinical trial design, conduct, data analysis, and presentation. This review covers the history of clinical trials, clinical trial phases, ethical issues, implementing the study, basic biostatistics for data analysis, and other resources. Figures show drug development and clinical trial process, and type I and II error. Tables list Food and Drug Administration new drug application types, and types of missing data in clinical trials. This review contains 2 highly rendered figures, 2 tables, and 38 references

A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder

2019 ◽  
Vol 16 (5) ◽  
pp. 555-560 ◽  
Author(s):  
Heather R Adams ◽  
Sara Defendorf ◽  
Amy Vierhile ◽  
Jonathan W Mink ◽  
Frederick J Marshall ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Rare Diseases ◽  
Trial Design ◽  
Neurodegenerative Disorder ◽  
Clinical Trial Design ◽  
Trial Participation ◽  
Local Participation ◽  
Cln3 Disease ◽  
Study Participants

Background Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. Methods We created a “hub and spoke” model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the “hub,” conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating “spoke” site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. Results A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6–9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. Conclusions This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

Recommendations for improving clinical trial design to facilitate the study of youth-onset type 2 diabetes

2019 ◽  
Vol 17 (1) ◽  
pp. 87-98
Author(s):  
Muhammad Yazid Jalaludin ◽  
Margarita Barrientos-Pérez ◽  
Mona Hafez ◽  
Jane Lynch ◽  
Naim Shehadeh ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Control Group ◽  
Onset Type ◽  
Therapeutic Choice ◽  
Glycemic Targets ◽  
Definition Of

Background The prevalence of type 2 diabetes is increasing in youths and differs from adult-onset type 2 diabetes in its characteristics and progression. Currently, only two drugs are approved for youth-onset type 2 diabetes and many patients are not meeting glycemic targets. Clearly, there is an urgent need to complete clinical trials in youths with type 2 diabetes to increase the therapeutic choice for these patients. However, factors such as limited patient numbers, unwillingness of patients to participate in trials, failure to meet strict inclusion and exclusion criteria, and poor clinic attendance have limited the size and number of trials in this complicated patient demographic. Recommendations This is a narrative opinion piece on the design of clinical trials in youth-onset type 2 diabetes prepared by researchers who undertake this type of study in different countries. The review addresses possible ways to enhance trial designs in youth-onset type 2 diabetes to meet regulatory requirements, while minimizing the barriers to patients’ participation. The definition of adolescence, recruitment of sufficient patient numbers, increasing flexibility in selection criteria, improving convenience of trial visits, requirements of a control group, possible endpoints, and trial compliance are all considered. The authors recommend allowing extrapolation from adult data, using multiple interventional arms within future trials, broadening inclusion criteria, and focusing on endpoints beyond glucose control, among others, in order to improve the successful completion of more trials in this population. Conclusions Improvements in trial design will enable better recruitment and retention and thereby more evidence for treatment outcomes for youth-onset type 2 diabetes.

Metastatic colorectal cancer (mCRC) patterns of care: Implications for clinical trial design

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4079-4079 ◽  
Author(s):  
C. S. Denlinger ◽  
M. A. Collins ◽  
Y. Wong ◽  
S. Litwin ◽  
N. J. Meropol
Keyword(s):  
Clinical Trial ◽  
Decision Making ◽  
Clinical Trials ◽  
Trial Design ◽  
Clinical Trial Design ◽  
New Drugs ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Treatment Change ◽  
Therapy Regimen

4079 Background: New approaches have expanded options for patients (pts) with mCRC. To characterize current practice paradigms that might bear on clinical trial design, we analyzed decision-making and treatment patterns in pts treated at a Comprehensive Cancer Center since the introduction of cetuximab (CET), and bevacizumab (BV). Methods: A retrospective review of all pts diagnosed with mCRC between 3/1/04 and 8/28/06 treated at Fox Chase Cancer Center. Results: 160 pts were treated, with 157 pts receiving at least one therapy regimen by 10 attending oncologists. There were 350 changes in therapy with 246 (70%) including continuation of at least one prior drug (92 BV, 111 fluoropyrimidines, 43 other). The most common reasons for treatment change were toxicity (33%), progressive disease (PD) (29%), treatment breaks (15%), and metastasectomy (11%) ( Table ). PD was a more common cause for treatment discontinuation in later phases of treatment (18% initial regimen vs. 36% subsequent regimens, p=0.0002). 24% of pts treated with oxaliplatin (OX) discontinued due to neuropathy. Hypersensitivity caused discontinuation in 5% of pts with OX and 7% of pts with CET. Resection of metastases was undertaken in 38% of pts. 43% of these pts received neoadjuvant therapy, and 56% received adjuvant therapy. 30% of pts have died, 29% remain on active treatment, 28% are on a treatment break, 3% are on hospice, and 11% are lost to follow-up. Conclusions: PD is no longer the primary reason for change of therapy in pts with mCRC. Metastasectomy is common and OX neuropathy is often treatment-limiting. These findings have important implications for endpoint selection and design of clinical trials in mCRC. Future clinical trials in mCRC must recognize treatment complexities and capture key components of decision-making that may result in prolonged survival. Furthermore, treatment breaks represent a potential window for the evaluation of new drugs. [Table: see text] No significant financial relationships to disclose.

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