Primary endpoints sample size

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

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 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. 

In a placebo-controlled hypertension trial, the primary endpoint is the fall in diastolic blood pressure. It is required to detect a clinically relevant difference of 8 mmHg in a 5 per cent level test. Fiistorical data suggests that CT= 10 mmHg. Table 8.4 provides sample sizes for various levels of power and differences around 8 mmHg the sample sizes are per group. 

Which statistical test was to be used for the comparison of the treatment groups in terms of the primary endpoint do you think This is a comparison between two independent groups in a parallel group trial and the primary endpoint is continuous so the sample size calculation will undoubtedly have been based on the two-sample t-test (although this is not specified). 

There were two reasons for increasing the sample size a larger than expected standard deviation (variance) for the primary endpoint and a higher drop-out rate (15 per cent compared to 10 per cent). 

Most of the elements are contained within the sample size section according to the requirements set down in the CONSORT statement the only omissions seem to be specification of the statistical test on which the sample size calculation was based, the assumed standard deviation of the primary endpoint and the basis of that assumption. 

The power of a study where the primary endpoint is time-to-event depends not so much on the total patient numbers, but on the number of events. So a trial with 1000 patients with 100 deaths has the same power as a trial with only 200 patients, but with also 100 deaths. The sample size calculation for survival data is therefore done in two stages. Firstly, the required number of patients suffering events is... 

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... 

In a randomized, double-blind, 6-week study, the test treatment (one tablet taken once a day) was compared with placebo. The primary endpoint of the study was the mean change from baseline SBP. Given the small sample size of the study, the primary analysis is based on the Wilcoxon rank sum test with a = 0.05 (two-sided). 

Having a single primary objective has an additional advantage in a study. It means that sample-size estimation can be based on that objective and the associated estimated treatment effect of interest (recall our discussion of sample-size estimation in Section 12.2). Having multiple primary endpoints requires adjustments for multiplicity and can be difficult to interpret if only one of multiple primary endpoints is found to have a statistically significant effect. 

Some of the first trials involving P-carotene used an intermediate endpoint as the outcome for the trial. Trials of intermediate endpoints generally require smaller sample sizes and interventions of shorter duration than trials with incident cancer as the outcome of interest. However, an important limitation to the use of intermediate markers in chemoprevention trials is that it has not been demonstrated for any of the intermediate endpoints that modulation of the endpoint by an agent is predictive of modulation of invasive malignancy. Therefore, trials that use cancer incidence or mortality as the primary endpoint have also been conducted, the results of which are detailed below. 

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