Primary endpoints design

ECASS-II was designed to test a lower dose of rt-PA (0.9 mg/kg) during the same 0-6-hours time period after stroke onset, using similar inclusion criteria as in ECASS-I. ° The primary endpoint was the proportion with a favorable outcome on the mRS scale (defined as a score of 0 or 1). There was no difference in this outcome between rt-PA-treated and placebo controls (40% vs. 37%, p = 0.28). A separate analysis of the 158 subjects enrolled within 3 hours of stroke onset also showed no difference in the proportion with a favorable outcome (42% vs. 38%, p = 0.63) this result, however, must be treated with caution because in ECASS-II there was a substantially lower number of patients treated within 3 hours of stroke onset, compared to the 1995 NINDS rt-PA study. Parenchymal hematoma on post-treatment CT was seen in 12% of rt-PA-treated and 3% of placebo patients (p < 0.001). The 90-day mortality rate was 11 % for the rt-PA group and 11 % for the placebo group (p = 0.54). Protocol violations were much less frequent in ECASS-II compared to ECASS-I (9% vs. 18%), probably because of standardized training in CT interpretation at the study sites. 

Erlotinib (Tarceva) took a differenf approach to a pivotal trial. In the study of Tarceva for patients with advanced, previously treated non-small cell lung cancer, where survival was the primary endpoint, patients were randomized to receive either Tarceva or placebo. Tarceva clearly prolonged overall survival (6.7 vs. 4-7 months, p = 0.001). In addition, Tarceva improved progression-free survival, and improved fime-fo-deferiora-tion of patients reported symptoms (cough, dyspnea, and pain). Obviously, this was a definitive trial (drug vs. placebo) however, it could be a controversial trial as it was a survival trial with no provisions to crossover to the active Tarceva. It is doubtful fhaf many trials with this noncrossover design (with a survival endpoint) will be done in the future. 

The remaining quantities would depend on the primary endpoint and the design assume we are dealing with the parallel group case. 

Finally most therapeutic specific guidelines contain recommendations that directly impact on statistical considerations, for example in terms of the definition of endpoints, the requirement for more than one primary endpoint, the definition of analysis sets and the choice of A. In a particular therapeutic setting it is self-evident that the requisite guidelines should be studied carefully in order to extract relevant information for statistical aspects of design and analysis. 

The clinical endpoint is a clinically meaningful measure of how patients feel, function or survive. Investigator-rated or self-assessed rating instruments are the most frequently used clinical endpoints. A primary endpoint is the main outcome that a study protocol is designed to evaluate. The statistical power and the sample size calculation of a particular trial are determined by the primary endpoint. Depending on the purpose of a study the primary endpoint can be... 

The study design included three comparisons ACTIVE W ACTIVE A, and ACTIVE I in 14,000 patients, (Maximum follow-up was for 48 months), The primary endpoint was the time to first vascular event (stroke, Ml, vascular death, systemic emboli). ACTIVE W arm was halted when 6600 patients were enrolled because there a clear benefit from warfarin treatment compared to clopidogrel + aspirin 3.63% of vascular events versus 5,64% (P = 0,0002). Subgroup analysis showed that these disappointing results were observed in patients on warfarin prior to study (HR = 1.5, P = 0.0006), but there was no difference between the two strategies—when the patients were not on warfarin prior to study (HR = 1.32, P = 0,17), Nevertheless, further results are awaited from the ACTIVE-A arm (ASA or ASA + clopidogrel) in patients who cannot or would not take OAC. 

The PACT study was designed to examine the efficacy of pravastatin given within 24 hours of the onset of unstable angina or Ml. The aim was to recruit 10,000 patients, but the study was stopped early by the sponsor after 3408 patients had been enrolled, thus it was underpowered. In the early phase of the study, pravastatin 20 mg daily was compared with placebo, although the dose of pravastatin was later increased to 40 mg daily. There was no statistical difference in the primary endpoint of death, recurrent Ml, or rehospitalization for unstable angina at one month (I 1.6% pravastatin arm vs. 12.4% placebo arm P = 0.48). 

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... 

Reference Design Delivery Dose (pg/kg) Size (n) Primary Endpoints Results... 

Elemental considerations may be broad comparisons, such as parallel group versus randomized crossover designs. Simulation also may assist in assigning the trial s primary endpoint, where the simulated probabilities of a successful trial for several clinically meaningful outcomes could be used to determine the most appropriate primary endpoint. 

Trial (Ref.) Date N Entry Criteria Design Primary Endpoint(s)/Outcome... 

The phase III trial is designated as STOP for its expected endpoints survival, tumour-free survival, overall survival, and progression-free survival, where overall survival is the primary endpoint. It is expected to enroll up to 700 patients with advanced-stage disease who have been treated with at least one prior platinum-based chemotherapy regimen. Patients will be randomised to receive Lucanix or placebo, administered i.d., once monthly for 18 months and then once at 21 months and at 24 months. 

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. 

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. 

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