Trial design

The need for properly and rationally designed clinical trials for cardioprotection cannot be overstated and has been discussed elsewhere4,48,129. One criticism that has 

ELISSAVET KARDAMI, KAREN DET1LLIEUX, SARAH JIMENEZ, PETER CATTIN1 

Seiler, M. Billingcr, E. Herren, K. Wustmann, H. Mehta, S. Windecker, F.R. Eberli, and B. Meier, Frequency distribution of collateral flow and factors influencing collateral channel development. Functional collateral channel measurement in 450 patients with coronary artery disease, J Am Coll Cardiol 38,1872-1878 (2001). 

Epstein, S. Fuchs, Y.F. Zhou, R. Baffour, and R. Kornowski, Therapeutic interventions for enhancing collateral development by administration of growth factors basic principles, early results and potential hazards, Cardiovasc Res 49, 532-542 (2001). 

Garcia-Dorado, Prime causes of rapid cardiomyocytc death during reperfusion, Ann Thorac Surg 68, 1913-1919 (1999). 

---

This is close to the assumed value of U. It does not, however, consider fouling in service. Additional trial designs may be used, or the temperature difference may be adjusted upward. 

Do several trial designs using different materials and geometries to perform the required function. 

Evaluate the trial designs on a cost effectiveness basis. Determine several levels of performance and the specific costs associated with each to the extent that it can be done with available data. 

Clinical trials should be designed so as to mirtimise potential sources of bias. It is known that patients can demonstrate a positive response to treatments that they believe will benefit them, even if no pharmaceutical agent has been admrrtistered (the placebo effect ). Similarly, investigators may be biased in their observations by an expectation of particular results. To avoid such bias, blinded trial designs are used. 

Table 5.1 A simple factorial trial design involving two drugs.

Factorial trial designs are used to evaluate, simultaneously, two or more treatments through the use of varying combinations of the treatments. An example of a simple trial to evaluate drugs A and B is illustrated in Table 5.1. These trials are particularly relevant where multiple drug therapies are anticipated. 

Appropriate study design should be selected to achieve the desired outcome. A description of the type/design of frial to be conducted (e.g., double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design. 

PREDICTIVE MODELS FOR BETTER DECISIONS FROM UNDERSTANDING PHYSIOLOGY TO OPTIMIZING TRIAL DESIGN... 

Modeling data and simulating trials can be used to increase the likelihood of trial success and safety and can ensure that trial design delivers adequate information for decisions in other areas such as marketing or resource allocation. 

The initial trial design tested two doses of drug, nominally low/medium and high, against a very high dose of comparator. Failure was defined as an... 

Figure 22.4 Monte Carlo techniques were used to simulate different hypothetical individuals for different instances of the trial design, using variability and uncertainty distributions from the model analysis. The result is a collection of predicted outcomes, shown as a binned histogram (top figure). Success was defined as a difference in end point measurement of X or smaller between drug and comparator. Likelihood of success (shown in the bottom figure as a cumulative probability) for this example (low/medium drug dose and high comparator dose) is seen to be low, about 33%.

Bibliography for Computer-Assisted Trial Design, at www.pharsight.com/solu-... 

Protocol rules, also known as business rules, are the rules that reflect the trial design. For examples, a protocol rule states that up to 99 interim visits can be scheduled between two protocol visits, visits may occur before or after their expected dates given a predefined leeway, and if the trial has multiple... 

Brew BJ, Halman M, Catalan J, Sacktor N, Price RW, Brown S, Atkinson H, Clifford DB, Simpson D, Torres G, Hall C, Power C, Marder K, Me Arthur JC, Symonds W, Romero C (2007) Factors in AIDS dementia complex trial design results and lessons from the abacavir trial. PLoS Clin Trials 2(3) el3... 

The MERCI trial was a prospective single-arm, multicenter trial designed to test the safety and efficacy of the MERCI clot retrieval device to restore the patency of intracranial arteries in the first 8 hours of an acute stroke. All patients were ineligible for IV rt-PA. The occlusion sites were the intracranial vertebral artery, basilar... 

There are two main types of clinical trial design, parallel and cross-over. In a parallel study, subjects are assigned to one of two or more treatments, e.g. active and placebo, and proceed through the trial concurrently. In a cross-over design, subjects act as their own controls, undergoing two or more treatments in sequence (see Fig. 12.1). 

Further information and advice related to the use of the clinical trial design can be found in a variety of sources including textbooks, manuscripts, organizations and Internet sites. In addition to the chapter reference list which cites helpful sources of information related to clinical trial protocol development, design and analysis, the following sources are also recommended. 

Inhibitors of AR have been demonstrated to prevent a wide variety of biochemical, functional and structural alterations in animal models of diabetes. Early studies demonstrated arrest of both early cataract development and nerve conduction velocity. At least 30 clinical trials of AR inhibitors have been published involving nearly 1000 patients in total. However, there is little impressive data of their efficacy up to now but, rather than undermine the hypothesis linking excess polyol pathway activity to diabetic complications, it may reflect methodological difficulties and trial design errors. 

---