Endpoints primary

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. 

Level I Highest level of evidence. Primary endpoint of RCT with adequate sample size or meta-analysis of quahtatively outstanding RCTs. 

The primary endpoint for monitoring treatment of fluid and electrolyte disorders is the correction of the abnormal serum electrolyte. The frequency depends on the presence of symptoms and degree of abnormality. In general, monitoring is initially performed at frequent intervals and, as homeostasis is restored, subsequently performed at less frequent intervals. 

A phase II study of EVT-201, a partial positive modulator of GABAa receptor, has recently been initiated in the US in elderly patients with chronic insomnia with the maintenance as primary endpoint (no structure disclosed). 

NG2-73 is a GABAa receptor partial agonist that, according to the information given by the company, modulates preferentially the a3 subunit - a subunit that is hypothesized to be associated with sleep induction - and is undergoing phase II trials for chronic insomnia with primary endpoints measuring sleep onset as well as maintenance (no structure disclosed) [25]. 

Primary endpoints Secondary endpoints In vivo model selection Species-specific effects Effects independent of species Animal model of disease... 

Endpoint. An indicator measured in a patient or biological sample to assess safety, efficacy, or another trial objective. Some endpoints are derived from primary endpoints (e.g., cardiac output is derived from stroke volume and heart rate). Synonyms include outcome, variable, parameter, marker, and measure. See surrogate endpoint in the text. Also defined as the final trial objective by some authors. 

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 primary endpoint of the toxicokinetic studies is the concentration-time prohle of the substance in plasma/blood and other biological fluids as well as in tissues. The excretion rate over time and the amount of metabolites in urine and bile are further possible primary endpoints of kinetic studies, sometimes providing information on the mass balance of the compound. From the primary data, clearance and half-life can be derived by several methods. From the excretion rate over time and from cumulative urinary excretion data and plasma/blood concentration measured during the sampling period, renal clearance can be calculated. The same is the case for the bUiary excretion. 

Clinical trials generate vast quantities of data, most of which are processed by the sponsor. Assessments should be kept to the minimum that is compatible with the safety and comfort of the subject. Highest priority needs to be given to assessment and recording of primary endpoints, as these will determine the main outcome of the study. The power calculation for sample size should be based on the primary critical endpoint. Quite frequently, trials have two or more evaluable endpoints. It must be stated clearly in the protocol whether the secondary endpoints are to be statistically evaluated, in which case power statements will need to be given, or are simply... 

The chances of detecting differences between intermediate doses based on the primary endpoint responses. 

The variability of the measurement of the primary endpoints, that is, the mean and the standard deviation of this primary outcome measure. 

The general rule is that the smaller the difference in effect to be detected between the two treatment groups, and the greater the variability in the measurement of the primary endpoint, the larger the sample size must be. Figure 6.5 gives an example of power curves, or statistical normogram, that relate sample size to size of effect to be detected. 

The aim of any clinical trial is to have low risk of Type I and II errors and sufficient power to detect a difference between treatments, if it exists. Of the three factors in determining sample size, the power (probability of detecting a true difference) is arbitrarily chosen. The magnitude of the drug s effect can be estimated with more or less accuracy from previous experience with drugs of the same or similar action, and the variability of the measurements is often known from published experiments on the primary endpoint, with or without the drug. These data will, however, not be available for novel substances in a new class and frequently the sample size in the early phase of development has to be chosen on an arbitrary basis. 

It is also necessary to decide how the primary endpoint variables will be analysed, what factors will be taken into account and how the result will be expressed. This most frequently involves analysis of variance or covariance. Predetermined comparisons of two or more treatments or doses can be made at specific time points, (e.g. each visit or selected visits) or may be assessed over time, giving an area imder the time curve analysis which will avoid multiple time-point analyses. 

In clinical trials intended to provide sufficient evidence for marketing approval of drugs, what is most important is to collect rmequivocal evidence of a positive risk-benefit profQe relative to an active comparator or placebo. For diseases that are life-threatening or those associated with severe morbidity, it is preferable that the primary endpoint is of clinical relevance, examples being mortality, a measurement of the patient s quality of life, such as rehef of disease-related s)unp-toms, improvement in ability to carry out normal activities or reduced hospitalization time. Unfortunately such trials may need to be very large consequently they tend to have a long duration, and can be extremely costly. 

There are two potential solutions to this problem. First, we can pre-specify a single test (group) on the primary endpoint at a single point in time, much in line with Hill s views. Or, we can attempt a statistical solution based on adjusting the type-1 error for the individual tests. 

It was noted in Section 8.3.3 that in choosing the primary endpoint to be used in a study there are a number of questions that need to be considered ... 

The data in Table 8.4 have been extracted from an investigation reported by Miranda-FiUio et al who compared the treatment of tetanus by the intrathecal route with the standard intramuscular route. The primary endpoints of the study were disease progression and death and we concentrate here on the former. 

In Table 8.5, we compare the response rates for the two primary endpoints - disease deterioration and mortality for the Flindle et al. study. What is interesting is that for the mortality endpoint ARR shows less deviation from the null than in the case of disease deterioration, while the converse holds for the RR. This is often regarded as a major defect of the RR as a measure of treatment effect, in that it does... 

In recent years, there has been a growth in the field of mega-studies, usually clinical outcome studies involving 5000-25 000 patients, with a simple primary endpoint such as mortality and a number of secondary morbidity endpoints. The potential for studies of this magnitude to throw up less frequent side effects than those seen in the preregistration programme is clear. 

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