Secondary endpoints design

Several elements are mandatory for a trial, particularly a trial on humans, to adhere to modem scientific demands. The basic elements are an a priori defined primary hypothesis and definition of primary and secondary endpoint and in some cases also tertiary endpoints. Once this is defined the design of the trial, the statistical analysis and the control group can be defined. 

Phase II clinical trial studies are designed primarily to explore the relationship between the dose level and frequency of administration and the efficacy and safety observed in patients with a particular therapeutic indication or disorder. Normally, a primary endpoint is selected to evaluate the efficacy however, secondary endpoints are often included to establish criteria for monitoring patients in the more definitive phase III clinical trials. Phase II clinical trials are commonly... 

For each phase of drug development, the study design specifies the objectives, the enrollment procedure, the treatment plan over the study, data collection including the definition of primary and secondary endpoints, and data analysis. 

The CARE-HF (Cardiac Resynchronization-Heart Failure) study was designed specifically to evaluate the effects of CRT on morbidity and mortality (1). This trial was started in January 2001 and was published in April 2005. Eight hundred nineteen patients with EF <35% and evidence dyssyn-chrony were randomized to optimal medical therapy or CRT. Dyssynchrony was defined as either a QRS duration > 150 ms or a QRS duration of 120-149 ms with echocardiographic evidence of dyssynchrony. In the CRT group, there was a 37% risk reduction (p < 0.001) in the primary endpoint, which was a composite of death from any canse or unplanned hospitalization for a major cardiac event (Fig. 11.3). In terms of all-cause mortality (secondary endpoint), there was a 36% risk reduction (p < 0.002) in the CRT group compared to optimal medical therapy. This study went beyond COMPANION by showing that CRT alone, even without the defibrillator, could improve survival. 

In the absence of such specific requirements, the manufacturer must decide which data are sufficient for CE marking (i.e., number of subjects, type of study design, primary and secondary endpoints, type and schedule of assessments, minimum patient follow-up period, among others). The notified body may be consulted prior to initiating the clinical trial to verify whether or not the protocol is designed to yield adequate data for CE marking. This dynamic led to a lack of uniform evidence requirements... 

PTCA). The primary objective was to evaluate the occurrence of major adverse cardiac events (MACE) [death, recurrent myocardial infarction (Ml), or clinically driven target lesion revascularization] 30 days postprocedure. The secondary objectives were to evaluate the binary restenosis, incidence of (sub)acute stent thrombosis at 30 days follow-up, MACE at 6 and 12 months and the QCA endpoints at 6 months. This study was designed to allow a comparison with the patient population and the results of a larger randomized DISTINCT (BiodivYsio stent in controlled clinical trial) study previously conducted in the U.S. 

FIGURE 3.16 Spectral-structural models, designed through the principle of minimal SPECTRAL-SAR paths of Table 3.15, emphasizing the primary, secondary and tertiary hierarchies forward the endpoints of the Tetrahymena pyriformis eco-toxico logical activity according with data of Table 3.11, SPECTRAL-SAR equations of Table 3.13, and of the associated spectral norms computed upon Eq. (3.62) (Putz Lacrama, 2007). 

---