Within-patient designs

An alternative design is the within-patient design. Such designs are not universally applicable but can be very powerful under certain circumstances. One form... 

Another example of the within-patient design is the cross-over design. Again each subject receives each of the treatments but now sequentially in time with some subjects receiving the treatments in the order A followed by B and some in the order B followed by A. 

The cross-over trial was mentioned in the previous section as one example of a within-patient design. In order to discuss some issues associated with these designs we will consider the simplest form of cross-over trial two treatments A and B and two treatment periods I and II. 

The paired t-test also known as the one-sample t-test was also developed by Cosset. This test is primarily used for the analysis of data arising from within-patient designs, although we also see it applied when comparing a baseline value with a final value within the same treatment group. 

Comments as above for the between-patient designs apply also for the within-patient designs and in many cases the best approach will be to focus on a sequence of pairwise comparisons using the paired t-test. 

In the context of within-patient designs, for example the multi-period crossover, there could however, be some additional considerations. Such designs are frequently used in phase I where sample sizes are small and the gains afforded by the common estimation of standard deviation could well be worthwhile, so we should not by any means dismiss these methods completely. 

The greatest difficulty with ascending-dose, within-patient designs is usually in treatment masking. Double-blind requirements have to take into account a wide variety of dose sizes, and that contemporaneous placebo formulations will be needed. Some studies of this type are hybridized with a crossover strategy (see below). Dose tailing at the end of the study may be viewed as the same... 

Thus, there is a point at issue here between those who believe that the problem of carry-over is potentially so devastating as to preclude within-patient studies and those who think that the predictive power of random-effect models in conjunction with appropriate within-patient designs is so great that the opportunity to conduct them must not be passed up. 

Embedded Figures Test. For the Embedded Figures Test, patients are shown a complex design and must identify as quickly as possible a simple figure that is embedded within the design. Twenty-four embedded figures are included, and a maximum of three minutes is allowed for each one. 

Calculate the value of the test statistic (usually = signal/noise). The formula for the test statistic will be based on a standard approach determined by the data type, the design of the trial (between- or within-patient) and the hypotheses of interest. Mathematics has provided us with optimum procedures for all the common (and not so common) situations and we will see numerous examples in subsequent sections. 

Fig.2. Glanzmaim thrombasthenia mutations within the GPma sequence including the MIDAS-like motif. The amino terminal sequence of GPIIIa from residues 110-289 showing the residues (in bold) that form the MIDAS-like motif . The Glanzmann thomba enia mutations are shown under the sequence and are listed by the patient designations as represented in Table 2.

Fig. 4. Glazmann thrombasdienia mutations within the P-propeller sequence for GPIIb The amino-terminal sequence of GPIIb from residues 1-452 that form the seven blades of the p-propeller. The Glanzmann thrombosthenia mutations are shown under the GPIIb sequence and are listed by the patient designations as represented in Table 1. W1-W7 refer to the seven blades and the bold letters designate the amino acids that form the P-strands. The dashed line above the sequence in the second and third P-strand sequence of W2 designates the disulfide bond formed by the two cysteine residues affected by the Arab and patient CW deletion mutations and the italic letter that are underlined by dashes in W4-W7 represent the calcium-binding domains. ...

The study design is an important element in assessment of quality protocols. The overall purpose of the study design is to reduce the variability or bias inherent in all research. Good study design will always address control methods that reduce experimental bias. These control methods will often include treatment blinding, randomization and between- or within-patient study designs. The Schedule of Assessments describes a schedule of time and events and provides a complete... 

This test has very low power, however, for three reasons. (1) It is a between-patient test for a trial which has been designed to use within-patient differences to detect treatment effects. (2) The carry-over effect where it occurs is likely to be somewhat smaller than the pure effect of treatment. (3) The carry-over is in any case only manifested in the second period. Therefore, although it is necessary to use the totals to compare sequences to account for other effects that might bias the test of carry-over, the direct information for carry-over comes only from the second period and the effect of this is diluted. In short, although a test of carry-over is available it is too weak to be of much use. 

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. 

---